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Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain
Abstract
A major goal of research on addiction is to identify the molecular mechanisms of long-lasting behavioural alterations induced by drugs of abuse. Cocaine and delta-9-tetrahydrocannabinol (THC) activate extracellular signal-regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho-ERK immunoreactive neurons in CD-1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor-dependent mechanism. Although some non-addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long-term effects of drugs of abuse, and suggest mapping ERK activation in brain as a way to identify potential sites of action of psychoactive drugs.
... Within MSNs, simultaneous activation of D1Rs and NMDARs initiates a second messenger signaling cascade that converges on the Ras/Raf/MEK/ERK pathway (Baker et al. 2002;Berke and Hyman 2000;Lu et al. 2006), leading to activation of transcription factors which induce expression of immediate early genes (IEGs) (Girault et al. 2007;Lu et al. 2006;Sun et al. 2016). Indeed, MEK inhibitors block cocaine-induced locomotion (CIL) (Valjent et al. 2000), phosphorylation of ERK (pERK) (Valjent et al. 2006;Valjent et al. 2004), and expression of the IEG c-fos in the NAcc and amygdala (Valjent et al. 2000;Valjent et al. 2006;Valjent et al. 2004). ...
... Within MSNs, simultaneous activation of D1Rs and NMDARs initiates a second messenger signaling cascade that converges on the Ras/Raf/MEK/ERK pathway (Baker et al. 2002;Berke and Hyman 2000;Lu et al. 2006), leading to activation of transcription factors which induce expression of immediate early genes (IEGs) (Girault et al. 2007;Lu et al. 2006;Sun et al. 2016). Indeed, MEK inhibitors block cocaine-induced locomotion (CIL) (Valjent et al. 2000), phosphorylation of ERK (pERK) (Valjent et al. 2006;Valjent et al. 2004), and expression of the IEG c-fos in the NAcc and amygdala (Valjent et al. 2000;Valjent et al. 2006;Valjent et al. 2004). ...
... The remarkable correlation between c-fos and pERK induction following cocaine exposure is consistent with previous findings (Valjent et al. 2000;Valjent et al. 2006;Valjent et al. 2004). Pharmacological studies indicate that cocaineinduced hyperlocomotion and c-fos expression require DAergic signaling through D1Rs (Fricks-Gleason and Marshall 2011; Karlsson et al. 2008), glutamatergic signaling through NMDARs (Sun et al. 2008;Torres and Rivier 1993), and activation of the Ras/Raf/MEK/ERK pathway (Lu et al. 2006;Papale et al. 2016;Sun et al. 2016). ...
Rationale
In rodents, exposure to novel environments or psychostimulants promotes locomotion. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity-restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been examined mostly in the context of hippocampal physiology and memory.
Objective
We investigated whether RGS14 modulates novelty- and cocaine-induced locomotion (NIL and CIL, respectively) and neuronal activity.
Methods
We assessed Rgs14 knockout (RGS14 KO) mice and wild-type (WT) littermate controls using NIL and CIL behavioral tests, followed by quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that normally express RGS14.
Results
RGS14 KO mice were less active than WT controls in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. RGS14 KO mice exhibited increased thigmotaxis, as well as greater c-fos and pERK induction in the central amygdala and dorsal hippocampus, when cocaine and novelty were paired.
Conclusions
RGS14 KO mice exhibited anti-correlated locomotor responses to novelty and cocaine, but displayed increased thigmotaxis in response to either stimuli which was augmented by their combination. Our findings also suggest RGS14 may reduce neuronal activity in limbic subregions by inhibiting ERK-dependent signaling.
... Within MSNs, simultaneous activation of D1Rs and NMDARs initiates a second messenger signaling cascade that converges on the Ras/Raf/MEK/ERK pathway (Baker et al. 2002;Berke and Hyman 2000;Lu et al. 2006), leading to activation of transcription factors which induce expression of immediate early genes (IEGs) (Lu et al. 2006;Sun et al. 2016). Indeed, MEK inhibitors block cocaine-induced locomotion (CIL) (Valjent et al. 2000), phosphorylation of ERK (pERK) (Valjent et al. 2006;Valjent et al. 2004), and expression of the IEG c-fos in the NAcc and amygdala (Valjent et al. 2000;Valjent et al. 2006;Valjent et al. 2004). ...
... Within MSNs, simultaneous activation of D1Rs and NMDARs initiates a second messenger signaling cascade that converges on the Ras/Raf/MEK/ERK pathway (Baker et al. 2002;Berke and Hyman 2000;Lu et al. 2006), leading to activation of transcription factors which induce expression of immediate early genes (IEGs) (Lu et al. 2006;Sun et al. 2016). Indeed, MEK inhibitors block cocaine-induced locomotion (CIL) (Valjent et al. 2000), phosphorylation of ERK (pERK) (Valjent et al. 2006;Valjent et al. 2004), and expression of the IEG c-fos in the NAcc and amygdala (Valjent et al. 2000;Valjent et al. 2006;Valjent et al. 2004). ...
... The remarkable correlation between c-fos and pERK induction following cocaine exposure is consistent with previous findings (Valjent et al. 2000;Valjent et al. 2006;Valjent et al. 2004). ...
Rationale: In rodents, exposure to novel environments or psychostimulants promotes locomotor activity. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been studied almost entirely in the context of hippocampal physiology and hippocampus-dependent behaviors.
Objective: We sought to determine whether RGS14 modulates novelty- and psychostimulant-induced locomotion and neuronal activity.
Methods: We assessed Rgs14 knockout (RGS14 KO) mice and wild-type (WT) littermate controls using novelty-induced locomotion (NIL) and cocaine-induced locomotion (CIL) behavioral tests with subsequent quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that express RGS14.
Results: Compared to WT controls, RGS14 KO mice exhibited attenuated locomotor responses in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. The absence of RGS14 enhanced induction of c-fos and pERK in the central amygdala and hippocampus (areas CA1 and CA2) when cocaine was administered in a novel environment.
Conclusions: RGS14 regulates novelty- and psychostimulant-induced hyperlocomotion, particularly with respect to thigmotaxis. Further, our findings suggest RGS14 may reduce neuronal activity in discrete limbic subregions by inhibiting ERK-dependent signaling and transcription.
... ERK 1/2 is a member of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade which is highly expressed throughout the brain in mature, post-mitotic neurons (Davis and Laroche 2006). In particular, in learning-and reward-related brain regions, dually phosphorylated ERK 1/2 triggers a signaling cascade that mediates multiple cellular processes critically involved in learning and memory, including neuronal growth and proliferation, differentiation, apoptosis and synaptic plasticity (Acquas et al. 2007;Brami-Cherrier et al. 2005;Ciccarelli and Giustetto 2014;Giorgi et al. 2015;Ibba et al. 2009;Marotta et al. 2014;Peana et al. 2013;Salzmann et al. 2003;Selcher et al. 2001;Valjent et al. 2000Valjent et al. , 2001Valjent et al. , 2004Zhang et al. 2004). ...
... Notably, it has been suggested that the ability of a number of addictive drugs to increase phosphorylated ERK 1/2 (pERK 1/2 ) expression in the Acb Salzmann et al. 2003;Valjent et al. 2000Valjent et al. , 2001 may represent a molecular correlate of their ability to elicit conditioned place preference (CPP) Zhai et al. 2008), although this does not apply to the case of morphine. Accordingly, morphine elicits CPP in rats (Acquas et al. 1989;Leone and Di Chiara 1987) and mice (Solecki et al. 2009;Funada et al. 1993;Suzuki et al. 1995), but reduces pERK 1/2 expression in the Acb of the Sprague-Dawley and Wistar rats (Rosas et al. 2016) and, conversely, increases it in the Acb of CD-1 and C57BL/6J mice (Rosas et al. 2016;Valjent et al. 2004). These findings argue against the suggestion that increased ERK 1/2 phosphorylation in the Acb represents a critical biochemical event for morphine to exert its reinforcing properties that may underlie its ability to allow the acquisition of CPP Rosas et al. 2016). ...
... The decrease in the number of pERK 1/2 -positive neurons in the AcbSh and AcbC of RLA rats elicited by morphine (40 min) is in agreement with our previous study in the Sprague-Dawley and Wistar rats (Rosas et al. 2016) but, as discussed in that paper, is in contrast with the finding that, in mice, morphine stimulates pERK 1/2 expression in the AcbSh (Rosas et al. 2016;Valjent et al. 2004). As a control for the timing observed during the CPP experiments in which morphine-treated rats were confined in the assigned compartment for 60 min, we also assessed the effects of morphine on pERK 1/2 expression upon the same time interval. ...
Rationale Extracellular signal Regulated Kinase (ERK1/2) phosphorylation is critical for neuronal and behavioural functions; in particular, pERK1/2 expression in the nucleus accumbens (Acb) of the rat is stimulated by addictive drugs with the exception of morphine, which decreases accumbal ERK1/2 phosphorylation in Sprague-Dawley and Wistar rats. The psychogenetically selected Roman low- (RLA) and high-avoidance (RHA) rats differ behaviourally and neurochemically in many responses to addictive drugs. In particular, morphine elicits a greater increment in locomotor activity and in dopamine transmission in the Acb of RHA vs RLA rats. However, the effects of morphine on place conditioning (CPP) and ERK1/2 phosphorylation in the Roman lines remain unknown.
Objectives and Methods To characterize in the Roman lines the reinforcing properties of morphine (i.e. morphine-elicited CPP acquisition) and the relationship between these properties and its effects on ERK1/2 phosphorylation in the Acb, the behavioural effects of morphine were evaluated in a place conditioning apparatus and ERK1/2 phosphorylation was assessed by immunohistochemistry in the shell and core subregions of the Acb of rats both acutely-administered morphine or undergoing conditioning.
Results Morphine elicited CPP in both Roman lines and decreased pERK1/2 expression in the Acb of RLA but not RHA rats. Such decrease was prevented by conditioning.
Conclusions These findings indicate that the selective breeding of the Roman lines has generated a divergence, in terms of morphine-elicited pERK1/2 expression but not of morphine-elicited CPP, between RLA and RHA rats and sustain the observation that changes in pERK1/2 expression in the Acb are not a requisite for the reinforcing effects of morphine.
... Similarly, non-selective mAChR antagonists (scopolamine and atropine) potentiated the efficacy of dopamine in stimulating gene expression [16][17][18][19][20][21]. However, while the dopaminemediated regulation of ERK phosphorylation has been thoroughly investigated [7,[22][23][24][25], the ACh regulation of ERK phosphorylation via mAChRs is poorly understood in both the striatum and mPFC. ...
... D1Rs, as G s -coupled receptors [31], are expressed in striatonigral output neurons of the striatum and are positively linked to ERK phosphorylation [22,23]. To determine the role of D1Rs in maintaining basal ERK phosphorylation and in contributing to the scopolamine-stimulated ERK phosphorylation in the striatum, we investigated the effect of a common D1R antagonist SCH23390 on basal and scopolamine-stimulated ERK phosphorylation in the CPu and NAc. ...
... The carbachol-stimulated ERK phosphorylation in the hippocampus is believed to be mediated by M 1 receptors because ERK responses to carbachol were blocked by knocking out M 1 but not M 2 /M 3 /M 4 receptors [36]. In the mouse striatum, the number of pERK immunopositive nuclei was insignificantly altered by an acute injection of scopolamine (1 or 2 mg/kg, i.p., 15 min), although scopolamine increased the number of pERK positive nuclei in the lateral part of the bed nucleus of the stria terminalis and the central nucleus of the amygdala as detected by immunohistochemistry [23]. In this study, we found that scopolamine at a dose of 5 mg/kg induced a significant increase in phosphorylation of synaptic ERKs in the striatum. ...
Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.
... In particular, besides its involvement in neuronal plasticity (Cerovic et al., 2013;Ciccarelli and Giustetto, 2014) and longterm potentiation (Sweatt, 2001), critical components of this cascade, such as the extracellular signal-regulated kinase (ERK), are abundantly expressed in the brain regions that are strategic for associative learning (e.g. nucleus accumbens, and central and basolateral amygdala) Lyons et al., 2013;Valjent et al., 2004) and for memory acquisition and consolidation (e.g. hippocampus and prefrontal cortex) (Marotta et al., 2014;Reul, 2014). ...
... Accordingly, phosphorylated ERK (pERK) was involved in a number of distinct experimental models of learning, such as the Morris water maze (Selcher et al., 1999), conditioned fear (Atkins et al., 1998), conditioned taste aversion (Marotta et al., 2014), as well as drug-elicited place conditioning Longoni et al., 2011;Valjent et al., 2000). Markers of this kinase cascade (pERK-positive neurons) are also abundantly expressed in the nuclei of the reward circuit such as the nucleus accumbens, the ventral tegmental area (VTA) and the nuclei of the extended amygdala (bed nucleus of stria terminalis, and central and basolateral nuclei of the amygdala) (Ibba et al., 2009;Valjent et al., 2004;Vinci et al., 2010). Their activation by either non-contingent (Acquas et al., 2007;Ibba et al., 2009;Lin et al., 2010;Valjent et al., 2004) or contingent (Faccidomo et al., 2015;Peana et al., 2013;Radwanska et al., 2008) drug exposure represents a critical biochemical event that bridges drug exposure to long-term behavioral consequences (Shiflett and Balleine, 2011;Sweatt, 2001). ...
... Markers of this kinase cascade (pERK-positive neurons) are also abundantly expressed in the nuclei of the reward circuit such as the nucleus accumbens, the ventral tegmental area (VTA) and the nuclei of the extended amygdala (bed nucleus of stria terminalis, and central and basolateral nuclei of the amygdala) (Ibba et al., 2009;Valjent et al., 2004;Vinci et al., 2010). Their activation by either non-contingent (Acquas et al., 2007;Ibba et al., 2009;Lin et al., 2010;Valjent et al., 2004) or contingent (Faccidomo et al., 2015;Peana et al., 2013;Radwanska et al., 2008) drug exposure represents a critical biochemical event that bridges drug exposure to long-term behavioral consequences (Shiflett and Balleine, 2011;Sweatt, 2001). Accordingly, the role of MEK was shown to be critical for the acquisition of place preference conditioned by d-amphetamine , ecstasy (Salzmann et al., 2003), morphine (Lin et al., 2010;Mazzucchelli et al., 2002;Rosas et al., 2016;Spina et al., 2010) and cocaine (Valjent et al., 2000); with the exception, to the best of our knowledge, of ethanol (Groblewski et al., 2011). ...
The involvement of mitogen-activating extracellular kinase (MEK) in place conditioning may vary depending on the motivational sign (positive or
negative) and nature (pharmacological or nociceptive) of the unconditioned stimulus (US) and on the phase (acquisition or expression) of the of the
learning process. This study investigated the role of MEK on the acquisition and expression of ethanol-elicited (given 2 g/kg) backward preference
(CPP) and forward aversion (CPA) place conditioning. The MEK inhibitor SL327 (50 mg/kg for CPP; and 50 and 100 mg/kg for CPA) was administered
to CD-1 mice 60 minutes before an ethanol dose (acquisition) or 60 minutes before the post-conditioning tests (expression). Ethanol significantly
elicited CPP and CPA; SL327 (50 mg/kg) significantly blocked the acquisition of ethanol-elicited CPP, but not that of CPA. Moreover, SL327 (50 and
100 mg/kg) significantly reduced the expression of ethanol-elicited CPP, but not that of CPA. Finally, SL327 also prevented ethanol-elicited (given
2 g/kg) increases of phosphorylated extracellular signal regulated kinase (pERK)-positive neurons in the nucleus accumbens and other nuclei of the
extended amygdala. Overall, these results confirmed the differential involvement of MEK in the acquisition and expression of drug-elicited place
conditioning and suggested its differential involvement in distinct behavioral outcomes, depending on the motivational sign of the (same) US and on
the significance of the experimental phase of the learning process.
... ERK 1/2 is an intracellular kinase involved in many functions of eukaryotic cells (Sweatt 2004) and, in mature neurons, plays a critical role in synaptic plasticity Girault et al. 2007;Lu et al. 2006;Shiflett and Balleine 2011;Zhai et al. 2008). Moreover, ERK 1/2 is highly expressed in reward-related brain areas (Acb and extended amygdala) and the activation of ERK 1/2 signaling takes place upon either acute (Acquas et al. 2007;Brami-Cherrier et al. 2005;Ibba et al. 2009;Salzmann et al. 2003;Valjent et al. 2000Valjent et al. , 2001Valjent et al. , 2004Zhang et al. 2004) or chronic (Berhow et al. 1996;Muller and Unterwald 2004) administration of addictive drugs. Notably, ERK 1/2 is optimally activated in the striatum by the combined stimulation of n-methyl-D-aspartate (NMDA) and DA D 1 receptors (Girault et al. 2007), and likewise, activated ERK 1/2 enables corticostriatal plasticity at least in part through regulation of transcription factors such as cAMP response element binding protein (CREB). ...
... In this scenario, however, a closer examination of the present literature (Zhai et al. 2008) on the effects of morphine in the Acb reveals that upon its acute administration, it either increases (Valjent et al. 2004) or decreases (Eitan et al. 2003;Muller and Unterwald 2004) ERK 1/2 phosphorylation in this brain region. These discrepancies appear of great relevance in light of the behavioral significance attributed to drug-elicited ERK 1/2 phosphorylation in the Acb Girault et al. 2007;Lu et al. 2006;Shiflett and Balleine 2011;Zhai et al. 2008). ...
... These discrepancies appear of great relevance in light of the behavioral significance attributed to drug-elicited ERK 1/2 phosphorylation in the Acb Girault et al. 2007;Lu et al. 2006;Shiflett and Balleine 2011;Zhai et al. 2008). In particular, such discrepancies might depend on a number of variables including the doses of morphine (ranging from 5 to 100 mg/kg), the time of sacrifice after morphine administration (ranging from 20 to 240 min), the experimental approach used to assess pERK 1/2 expression (immunohistochemistry versus western blotting), and the species used (rats and mice) (Eitan et al. 2003;Liu et al. 2007;Muller and Unterwald 2004;Valjent et al. 2004). Hence, considering (i) the ability of acute morphine to preferentially stimulate DA transmission in the rat and mouse AcbSh compared with the AcbC (Cadoni and Di Chiara 1999;Pontieri et al. 1995;Zocchi et al. 2003) and (ii) the critical role attributed to the activation of ERK 1/2mediated signaling in the neuroadaptive changes resulting from exposure to addictive drugs (Girault et al. 2007) as well as (iii) the role of the Acb in the motivational properties of drugs Di Chiara et al. 2004;Girault et al. 2007;Lu et al. 2006), the aim of the present study was twofold: (1) to characterize the differential effects of the acute administration of morphine on pERK 1/2 expression in the AcbSh and AcbC, taking into account a number of variables such as animal species/ strain (Sprague-Dawley versus Wistar rats and CD-1 versus C57BL/6J mice), dose of morphine (1 and 5 mg/kg), and time of sacrifice after morphine administration (20 and 40 min) and (2) to determine the role of DA D 1 and μopioid receptors in these effects. ...
Psychopharmacology, (), 1-12
DOI
10.1007/s00213-016-4340-8
... ERK 1/2 is an intracellular kinase involved in many functions of eukaryotic cells (Sweatt 2004) and, in mature neurons, plays a critical role in synaptic plasticity Girault et al. 2007;Lu et al. 2006;Shiflett and Balleine 2011;Zhai et al. 2008). Moreover, ERK 1/2 is highly expressed in reward-related brain areas (Acb and extended amygdala) and the activation of ERK 1/2 signaling takes place upon either acute (Acquas et al. 2007;Brami-Cherrier et al. 2005;Ibba et al. 2009;Salzmann et al. 2003;Valjent et al. 2000Valjent et al. , 2001Valjent et al. , 2004Zhang et al. 2004) or chronic (Berhow et al. 1996;Muller and Unterwald 2004) administration of addictive drugs. Notably, ERK 1/2 is optimally activated in the striatum by the combined stimulation of n-methyl-D-aspartate (NMDA) and DA D 1 receptors (Girault et al. 2007), and likewise, activated ERK 1/2 enables corticostriatal plasticity at least in part through regulation of transcription factors such as cAMP response element binding protein (CREB). ...
... In this scenario, however, a closer examination of the present literature (Zhai et al. 2008) on the effects of morphine in the Acb reveals that upon its acute administration, it either increases (Valjent et al. 2004) or decreases (Eitan et al. 2003;Muller and Unterwald 2004) ERK 1/2 phosphorylation in this brain region. These discrepancies appear of great relevance in light of the behavioral significance attributed to drug-elicited ERK 1/2 phosphorylation in the Acb Girault et al. 2007;Lu et al. 2006;Shiflett and Balleine 2011;Zhai et al. 2008). ...
... These discrepancies appear of great relevance in light of the behavioral significance attributed to drug-elicited ERK 1/2 phosphorylation in the Acb Girault et al. 2007;Lu et al. 2006;Shiflett and Balleine 2011;Zhai et al. 2008). In particular, such discrepancies might depend on a number of variables including the doses of morphine (ranging from 5 to 100 mg/kg), the time of sacrifice after morphine administration (ranging from 20 to 240 min), the experimental approach used to assess pERK 1/2 expression (immunohistochemistry versus western blotting), and the species used (rats and mice) (Eitan et al. 2003;Liu et al. 2007;Muller and Unterwald 2004;Valjent et al. 2004). Hence, considering (i) the ability of acute morphine to preferentially stimulate DA transmission in the rat and mouse AcbSh compared with the AcbC (Cadoni and Di Chiara 1999;Pontieri et al. 1995;Zocchi et al. 2003) and (ii) the critical role attributed to the activation of ERK 1/2mediated signaling in the neuroadaptive changes resulting from exposure to addictive drugs (Girault et al. 2007) as well as (iii) the role of the Acb in the motivational properties of drugs Di Chiara et al. 2004;Girault et al. 2007;Lu et al. 2006), the aim of the present study was twofold: (1) to characterize the differential effects of the acute administration of morphine on pERK 1/2 expression in the AcbSh and AcbC, taking into account a number of variables such as animal species/ strain (Sprague-Dawley versus Wistar rats and CD-1 versus C57BL/6J mice), dose of morphine (1 and 5 mg/kg), and time of sacrifice after morphine administration (20 and 40 min) and (2) to determine the role of DA D 1 and μopioid receptors in these effects. ...
Rationale
Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial.
Objectives
In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and μ-opioid receptors in Sprague-Dawley rats and CD-1 mice.
Methods
The pERK1/2 expression was assessed by immunohistochemistry.
Results
In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice.
Conclusions
These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine’s ability to decrease pERK1/2 expression is mediated by Acb μ-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb.
... In particular, phosphorylated ERK (pERK) in the core (AcbC) and shell (AcbSh) subregions of the Acb increases after acute EtOH administration (Ibba et al., 2009;Spanos et al., 2012). In addition, pERK seems also to increase, at least in prefrontal and cingulate cortices, after caffeine administration (Acquas et al., 2010;Valjent et al., 2004), and this effect is mediated by D 1 receptors (Acquas et al., 2010). ...
... We have previously observed in rats that EtOH (at an intragastric dose of 1.0 g/kg) significantly increased postsynaptic intracellular markers related to DA D 1 signaling, pERK in AcbC and AcbSh (Ibba et al., 2009). However, caffeine (10 mg/kg) alone did not have an effect on this parameter in the 2 Acb subregions (Acquas et al., 2010;Valjent et al., 2004). Interestingly, in the present study using mice, EtOH (1.5 g/kg) significantly induced pERK, and this effect was counteracted by caffeine at both doses in both AcbC and AcbSh. ...
Background
Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)‐related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD‐1 mice.
Methods
Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol‐induced (1.5 to 3.5 g/kg) changes in open‐field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor‐dependent phosphorylation markers were assessed: extracellular signal‐regulated kinase (pERK), and dopamine‐and cAMP‐regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP‐32‐Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol‐sensitized (1.5 g/kg) mice.
Results
Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol ‐induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol‐induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol‐sensitized mice in an ethanol‐free state resulted in blunted stimulant effects compared with those seen in ethanol‐naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP‐32(Thr75) immunoreactivity.
Conclusions
The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol‐sensitized animals.
... Extracellular regulated kinase (ERK) is significantly involved in the signaling cascade of dopamine. Previously, it was reported that an acute dose of THC (1 mg/kg) activated pERK1/2 in mouse NAc and dorsal striatum, primarily via dopamine D1 receptors and partly via the D2 receptor (Valjent et al., 2001(Valjent et al., , 2004. NAc of monkeys treated repeatedly with THC showed dramatic decreases in phosphorylation of both subunits of pERK1/2 compared with vehicle (46.10% ...
... These chronic THC-induced effects contrast with the acute effects of THC on these same pathways. For example, acute THC (1 mg/kg) in mice led to the activation of pERK1/2 in the NAc and in the dorsal striatum (Valjent et al., 2001(Valjent et al., , 2004) through a mechanism involving dopamine D1 receptor and partially involving D2 receptor. This effect was not observed with a higher dose of THC (5 mg/kg; Valjent et al., 2001), and was even inhibited in the dorsal striatum at a dose of 10 mg/kg. ...
Long-term cannabis users manifest deficits in dopaminergic functions, reflecting Δ9-tetrahydrocannabinol (THC)-induced neuroadaptive dysfunctional dopamine signaling, similar to those observed upon dopamine D1-D2 heteromer activation. The molecular mechanisms remain largely unknown. We show evolutionary and regional differences in D1-D2 heteromer abundance in mammalian striatum. Importantly, chronic THC increased the number of D1-D2 heteromer-expressing neurons, and the number of heteromers within individual neurons in adult monkey striatum. The majority of these neurons displayed a phenotype co-expressing the characteristic markers of both striatonigral and striatopallidal neurons. Furthermore, THC increased D1-D2-linked calcium signaling markers (pCaMKIIα, pThr75-DARPP-32, BDNF/pTrkB) and inhibited cyclic AMP signaling (pThr34-DARPP-32, pERK1/2, pS845-GluA1, pGSK3). Cannabidiol attenuated most but not all of these THC-induced neuroadaptations. Targeted pathway analyses linked these changes to neurological and psychological disorders. These data underline the importance of the D1-D2 receptor heteromer in cannabis use-related disorders, with THC-induced changes likely responsible for the reported adverse effects observed in heavy long-term users. : Drugs; Neuroscience; Cellular Neuroscience Subject Areas: Drugs, Neuroscience, Cellular Neuroscience
... This hypothesis was grounded in the observations that alcohol-elicited place conditioning is prevented by DA receptor antagonists (15,16), that caffeine exerts, through an antagonistic action on A 2A adenosine receptors (A 2A R) (17), a direct negative control on neuronal ring of DA cells in the posterior ventral tegmental area (pVTA) (18), and that caffeine administration prior to alcohol also prevents its DAdependent (19) ability to increase the expression of phosphorylated Extracellular signal Regulated Kinase (pERK) in the shell of the nucleus accumbens (AcbSh) (13,20). Notably, increased pERK expression is a DA receptor-dependent marker of activation of mesolimbic DA transmission by alcohol (19,21) and other addictive substances (22,23), but not by caffeine (22,24), as well as a DA-dependent mechanism at the basis of associative learning (14,(25)(26)(27). ...
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
... These neuroadaptations primarily occur in the mesocorticolimbic DA system, resulting in increased sensitivity to drug-related cues, impulsive decisionmaking, and habit-like behaviors [27,28]. The underlying molecular changes involve synaptic plasticity, modifications in glutamatergic signaling [29][30][31], and dysregulation of protein kinase activity, such as ERK [32][33][34][35][36]. Understanding these molecular adaptations within the reward system is crucial for the development of effective interventions for drug reward and addiction. ...
The rostromedial tegmental nucleus (RMTg) plays a crucial role in regulating reward-related behavior by exerting inhibitory control over the ventral tegmental area (VTA). This modulation of dopamine neuron activity within the VTA is essential for maintaining homeostasis in the reward system. Recently we have shown that activation of RMTg projections to the VTA during the acquisition of cocaine-conditioned place preference (CPP) reduces the rewarding properties of cocaine and decreases VTA dopamine neuron activity. By inhibiting dopamine neurons in the VTA, we hypothesized that RMTg projections hold the potential to restore reward system homeostasis disrupted by repeated cocaine use, and attenuate molecular adaptations in the reward system, including alterations in signaling pathways. Our study demonstrates that enhancing the GABAergic inputs from the RMTg to the VTA can mitigate cocaine-induced molecular changes in key regions, namely the VTA, nucleus accumbens (NAc), and prefrontal cortex (PFC). Specifically, we found that cocaine-induced alteration in the phosphorylation state of ERK (pERK) and GluA1 on serine 845 (S845) and serine 831 (S831), that play a major role in plasticity by controlling the activity and trafficking of AMPA receptors, were significantly reversed following optic stimulation of RMTg afferents to the VTA. These findings highlight the therapeutic potential of targeting the RMTg-VTA circuitry for mitigating cocaine reward. Ultimately, this research may pave the way for novel therapeutic interventions that restore balance in the reward system and alleviate the detrimental effects of cocaine.
... These neuroadaptations primarily occur in the mesocorticolimbic DA system, resulting in increased sensitivity to drug-related cues, impulsive decision-making, and habitlike behaviors 27,28 . The underlying molecular changes involve synaptic plasticity, modifications in glutamatergic signaling [29][30][31] , and dysregulation of protein kinase activity, such as ERK [32][33][34][35][36] . Understanding these molecular adaptations within the reward system is crucial for the development of effective interventions for drug reward and addiction. ...
The rostromedial tegmental nucleus (RMTg) plays a crucial role in regulating reward-related behavior by exerting inhibitory control over the ventral tegmental area (VTA). This modulation of dopamine neurons activity within the VTA is essential for maintaining homeostasis in the reward system. Recently we have shown that activation of RMTg projections to the VTA during the acquisition of cocaine-conditioned place preference (CPP) reduces the rewarding properties of cocaine and decreases VTA dopamine neuron activity. By inhibiting dopamine neurons in the VTA, we hypothesized that RMTg projections hold the potential to restore reward system homeostasis disrupted by repeated cocaine use, and attenuate molecular adaptations in the reward system, including alterations in signaling pathways. Our study demonstrates that enhancing the GABAergic inputs from the RMTg to the VTA can mitigate cocaine-induced molecular changes in key regions, namely the VTA, nucleus accumbens (NAc), and prefrontal cortex (PFC). Specifically, we found that cocaine-induced alteration in the phosphorylation state of ERK (pERK) and GluA1 on serine 845 (S845) and serine 831 (S831), that play a major role in plasticity by controlling the activity and trafficking of AMPA receptors, were significantly reversed following optic stimulation of RMTg afferents to the VTA. These findings highlight the therapeutic potential of targeting the RMTg-VTA circuitry for mitigating cocaine reward and addiction. Ultimately, this research may pave the way for novel therapeutic interventions that restore balance in the reward system and alleviate the detrimental effects of cocaine.
... Among them, ERK-related signals are well studied in cocaine addiction. For example, acute cocaine administration is sufficient to increase phosphorylation of ERK in PFC, which contributes to the long-term plastic changes by cocaine in the brain (Valjent et al, 2004;Radwanska et al, 2006;Sun et al, 2016), while blockade of ERK activation during re-exposure to cocaine erased previously cocaine-preferred behaviors . The ERK signaling pathway has been implicated in synaptic plasticity and neuronal growth (Sweatt, 2001). ...
Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity, and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neuron activity and blocks sdC-induced CPP in ACE mice during adulthood. On the contrary, depleting DUSP1 in CaMKII-positive neurons activates more neurons and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use.
... Extracellular signal-regulated kinases activation is involved in long-lasting behavioral consequences of drugs abuse [7]. Especially, the activation of ERKs signaling in the striatum, extended amygdala, and deep layers of the prefrontal cortex has been a hallmark of drug addiction [8]. Importantly, ERKs activation in the striatum by addictive drugs depends on the stimulation of dopamine (DA) receptor and is related to drug-rewarding properties [9]. ...
Dopamine D2 receptor (D2R) has been shown to activate extracellular signal‐regulated kinases (ERKs) via distinct pathways dependent on either G‐protein or β‐arrestin. However, there has not been a systematic study of the regulatory process of D2R‐mediated ERKs activation by G protein‐ versus β‐arrestin‐dependent signaling since D2R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D2R‐mediated ERKs activation via these two pathways. Our results showed that G protein‐dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β‐arrestin‐dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein‐ and β‐arrestin‐dependent pathway‐mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2‐CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3‐kinase inhibitor all blocked G protein‐dependent ERKs activation. In contrast, GRK2 and β‐Arr2 played a main role in β‐arrestin‐dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho‐ERKs, β‐Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes.
... Among them, ERK-related signals are well studied in cocaine addiction. For example, acute cocaine administration is sufficient to increase phosphorylation of ERK in PFC, which contributes to the long-term plastic changes by cocaine in the brain (Valjent et al, 2004;Radwanska et al, 2006;Sun et al, 2016), while blockade of ERK activation during re-exposure to cocaine erased previously cocaine-preferred behaviors . The ERK signaling pathway has been implicated in synaptic plasticity and neuronal growth (Sweatt, 2001). ...
Cocaine abuse during adolescence increases the risk for developing drug addiction in later life, but the underlying molecular mechanism remains unclear. Here, adolescent cocaine-exposed (ACE) male mice models were established by giving once-daily intraperitoneal injections of 15 mg/kg cocaine to mice during adolescence (P28-P42). We found that ACE mice exhibited a higher sensitivity to subthreshold dose of cocaine (1 mg/kg) in adulthood, accompanied with triggered activities and dendritic spine density of pyramidal neuron, increased Dusp1 gene, as well as reduced protein levels and activity of dual specificity phosphatase 1 (DUSP1) in mPFC. Specific overexpression of DUSP1 on mPFC glutamatergic neurons efficiently blocked cocaine-preferred behaviors and reduced mPFC activity, while knockdown of DUSP1 maintained cocaine-preferred behaviors and increased mPFC activity in ACE mice. MAPK-related signals, especially ERK1/2, might underlie the mediating effects of DUSP1. Collectively, these findings suggested that targeting mPFC DUSP1 may represent a promising therapeutic strategy for the treatment and attenuation of addiction susceptibility, particularly in addicts with a history of adolescent drugs exposure.
Significance statement
Cocaine-exposed experience during adolescence enhances the sensitivity of mice to drugs and triggers more activity of medial prefrontal cortex (mPFC) in adulthood, which is rescued by specific overexpression of dual specificity phosphatase 1 (DUSP1) on glutamatergic neurons of mPFC. MAPK-related signals, especially ERK1/2, might underlie the regulatory effects of DUSP1.
... Elevation of ERK phosphorylation by addictive drugs has been reported previously. 109,110 which triggers the rewarding behavior. 111 Therefore, activation of ERK seems to be critical for drug cravings 112 , and high persistent activity of ERK observed after a long period of withdrawal. ...
Introduction: In chronic drug abuse, opioidergic, dopaminergic signaling, and endocytosis are implicated in neural circuit disruption. We evaluate the impact of Methadone Maintenance Therapy (MMT) on opioid addiction.
Method: The expression of dopamine (DRD1- DRD5) and opioid (mu-, delta-, and kappa) receptors, Catechol-O-methyltransferase (COMT), Dynamin 1 like (DNM1L), and RAS-associated (RAB22A) genes in Peripheral Blood Mononuclear Cells from MMT (n= 40) and control (n= 40) were detected by qPCR. Protein-protein interaction (PPI) investigation into addiction-associated genes was performed to elucidate the possible pathways which may have an interference impact on the treatment of addiction.
Results: We found that DRD1, DRD2, MOR, DOR, and KOR expressions increased, and the COMT and DNM1L expressions were decreased in MMT. A complex brain network orchestrated by three stages of interactions I) opioid receptors II) Dopamine receptors III) Intracellular vesicular transport (RAB22A), and synaptic vesicle recycling (DNM1L), involved which led to resistance. We elucidate possible pathways that may have an interfering effect on the opioid use disorder (OUD) treatment, and protein-protein interaction (PPI) studies were performed on addiction-associated genes.
Conclusion: We introduce Mitogen-Activated Protein Kinase (MAPK) signaling as a significant mediator in addiction and represent DRD2 as a potential therapeutic target for OUD. PPI downstream off-target stimulation may involve ERK activation. Thus, the use of novel agonists and antagonists, in combination with ERK inhibitors, may be of particular interest for future research in addiction treatment.
... We attribute this discrepancy to the differential development of opioid tolerance as a result of MOPr expression and immune microenvironments at the spinal and supraspinal levels (Jokinen et al., 2018;Roerig et al., 1984;Yoburn et al., 1990). Taken Previous studies have focused on only males to evaluate intracellular kinases after morphine treatment (Eitan et al., 2003;Macey et al., 2009;Sanna et al., 2014;Valjent et al., 2004). To our knowledge, this is the first study to directly compare males to females using quantification of kinase activity specifically within the vlPAG, which is challenging to accomplish with conventional protein quantification methods given the size of the vlPAG in mice. ...
Morphine is a potent opioid analgesic with high propensity for the development of antinociceptive tolerance. Morphine antinociception and tolerance are partially regulated by the midbrain ventrolateral periaqueductal gray (vlPAG). However, the majority of research evaluating mu‐opioid receptor signaling has focused on males. Here, we investigate kinase activation and localization patterns in the vlPAG following acute and chronic morphine treatment in both sexes. Male and female mice developed rapid antinociceptive tolerance to morphine (10 mg/kg i.p.) on the hot plate assay, but tolerance did not develop in males on the tail flick assay. Quantitative fluorescence immunohistochemistry was used to map and evaluate the activation of extracellular signal‐regulated kinase 1/2 (ERK 1/2), protein kinase‐C (PKC), and protein kinase‐A (PKA). We observed significantly greater phosphorylated ERK 1/2 in the vlPAG of chronic morphine‐treated animals which co‐localized with the endosomal marker, Eea1. We note that pPKC is significantly elevated in the vlPAG of both sexes following chronic morphine treatment. We also observed that although PKA activity is elevated following chronic morphine treatment in both sexes, there is a significant reduction in the nuclear translocation of its phosphorylated substrate. Taken together, this study demonstrates increased activation of ERK 1/2, PKC, and PKA in response to repeated morphine treatment. The study opens avenues to explore the impact of chronic morphine treatment on G‐protein signaling and kinase nuclear transport.
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... The ERK1/2 signalling pathway plays a crucial role in regulating diverse neuronal processes in response to external stimuli. In particular, its expression in the striatum has been associated J o u r n a l P r e -p r o o f with the effects of most drugs of abuse including psychostimulants, opiates and nicotine (Valjent et al., 2004;Pascoli et al., 2014). Blocking ERK1/2 phosphorylation or inhibiting its binding to its downstream molecular targets can prevent many behavioural consequences of drugs of abuse including their rewarding and locomotor sensitizing properties as well as incubation of craving (Valjent et al., 2000;Lu et al., 2005;Besnard et al., 2011). ...
Stress has been acknowledged as one of the main risk factors for the onset of psychiatric disorders. Social stress is the most common type of stressor encountered in our daily lives. Uncovering the molecular determinants of the effect of stress on the brain would help understanding the complex maladaptations that contribute to pathological stress-related mental states. We examined molecular changes in the reward system following social defeat stress in mice, as increasing evidence implicates this system in sensing stressful stimuli. Following acute or chronic social defeat stress, the activation (i.e. phosphorylation) of extracellular signal-regulated kinases ERK1 and ERK2 (pERK1/2), markers of synaptic plasticity, was monitored in sub-regions of the reward system. We employed pharmacological antagonists and inhibitory DREADD to dissect the sequence of events controlling pERK1/2 dynamics. The nucleus accumbens (NAc) showed marked increases in pERK1/2 following both acute and chronic social stress compared to the dorsal striatum. Increases in pERK1/2 required dopamine D1 receptors and GluN2B-containing NMDA receptors. Paraventricular thalamic glutamatergic inputs to the NAc are required for social stress-induced pERK1/2. The molecular adaptations identified here could contribute to the long-lasting impact of stress on the brain and may be targeted to counteract stress-related psychopathologies.
... c No direct comparator data. However, Valjent et al. (2004) reported increased phosphorylation of ERK only in the lateral BNST and central amygdala in mouse. Antidepressants (desipramine and fluoxetine) increased phosphorylation in the hippocampus and cerebral cortex. ...
Conventional antidepressants typically require weeks of daily dosing to achieve full antidepressant response in antidepressant responders. A newly evolving group of compounds can engender more rapid response times in depressed patients. These drugs include the newly approved antidepressant (S)-ketamine (esketamine, Spravato). A seminal study by Furey and Drevets in 2006 showed antidepressant response in patients after only a few doses with the antimuscarinic drug scopolamine. Several clinical reports have generally confirmed scopolamine as a rapid-acting antidepressant. The data with scopolamine are consistent with the adrenergic/cholinergic hypothesis of mania/depression derived from clinical reports originating in the 1970s from Janowsky and colleagues. Additional support for a role for muscarinic receptors in mood disorders comes from the greater efficacy of conventional antidepressants that have relatively high levels of muscarinic receptor blocking actions (e.g., the tricyclic antidepressant amitriptyline vs the selective serotonin reuptake inhibitor fluoxetine). There appears to be appreciable overlap in the mechanisms of action of scopolamine and other rapid-acting antidepressants (ketamine) or putative rapid-acting agents (mGlu2/3 receptor antagonists) although gaps exist in the experimental literature. Current hypotheses regarding the mechanisms underlying the rapid antidepressant response to scopolamine posit an M1 receptor subtype-initiated cascade of biological events that involve the amplification of AMPA receptors. Consequent impact on brain-derived neurotrophic factor and mTor signaling pathways result in the induction of dendritic spines that enable augmented functional connectivity in brain areas regulating mood. Two major goals for research in this area focus on finding ways in which scopolamine might best be utilized for depressed patients and the discovery of alternative compounds that improve upon the efficacy and safety of scopolamine.
... Preclinical studies, based on the theory of activation of extracellular signal-regulated kinase, assume that each drug has a distinct type of activation, both in terms of anatomical location and intensity. 30,31 A patient required progressive adjustments to the stimulation parameters with no therapeutic success, and died from overdose. 19 In this case, it is important to discuss how long the patients benefit from DBS. ...
Substance-related disorders are psychiatric conditions that have a worldwide impact. Their multifactorial cycle has been treated pharmacologically and with therapeutic support. However, high refractoriness rates and difficulty to control relapses are among the pitfalls associated with these disorders. Thus, recent studies have shown that deep brain stimulation (DBS) is a promising treatment, with a direct intervention in the neurocircuitry of addiction. The results of the present systematic review of the use of DBS for the treatment of drug addiction show that this surgical procedure can reduce the desire for the drug, and, in some cases, establish abstinence, improve psychiatric symptoms related to mood and quality of life, and reintroduce the patient into the social and family environments. Nevertheless, this approach is still limited to the academic realm, based mainly on case reports, with ethics and therapeutic protocols still to be defined. Further in-depth scientific investigations are required to recommend its clinical application.
... Downstream from these receptors, the ERK (extracellular signal-regulated kinase) pathway is activated by virtually all drugs of abuse (78). Global ERK inhibition blocks long-term potentiation of glutamate synapses impinging onto D1R-SPNs (61), cocaine-induced locomotor sensitization, and CPP (79,80) and the reconsolidation of drug-associated memories (81,82). ...
Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal that are thought to result from persistent adaptations within brain reward circuits. Drugs of abuse increase dopamine (DA) concentration in these brain areas, including the striatum, which shapes an abnormal memory trace of drug consumption that virtually highjacks reward processing. Long-term neuronal adaptations of gamma-aminobutyric acidergic striatal projection neurons (SPNs) evoked by drugs of abuse are critical for the development of addiction. These neurons form two mostly segregated populations, depending on the DA receptor they express and their output projections, constituting the so-called direct (D1 receptor) and indirect (D2 receptor) SPN pathways. Both SPN subtypes receive converging glutamate inputs from limbic and cortical regions, encoding contextual and emotional information, together with DA, which mediates reward prediction and incentive values. DA differentially modulates the efficacy of glutamate synapses onto direct and indirect SPN pathways by recruiting distinct striatal signaling pathways, epigenetic and genetic responses likely involved in the transition from casual drug use to addiction. Herein we focus on recent studies that have assessed psychostimulant-induced alterations in a cell-type-specific manner, from remodeling of input projections to the characterization of specific molecular events in each SPN subtype and their impact on long-lasting behavioral adaptations. We discuss recent evidence revealing the complex and concerted action of both SPN populations on drug-induced behavioral responses, as these studies can contribute to the design of future strategies to alleviate specific behavioral components of addiction.
... Important differences were observed in the phosphorylation of both MAPKs according to the type of cocaine exposure. Relative ERK1/2 phosphorylation was transiently increased in both acute and repeated cocaine-treated mice, and these cocaine-induced increases are in agreement with previous studies in mice exposed to cocaine showing higher ERK1/2 phosphorylation in the dorsal hippocampus (Tropea et al., 2008;Valjent et al., 2004). The increases in the expression of ERK1/2 were extremely rapid and they could be associated with the synthesis/release of these inflammatory mediators, mainly IL1β. ...
... Cocaine also increases ERK activation throughout the extended amygdala and interconnected reward circuitry (Valjent et al., 2004) and GRM5 AA/AA mice exhibit blunted cocaine-induced locomotor sensitization (Park et al., 2013). Thus, we determined whether disrupting mGlu5 phosphorylation might also alter the perception of cocaine's interoceptive effects. ...
The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.
... Intra NAc injection of ERK kinase inhibitor, U0126 (4 µg/side), attenuated the propofol self-administration. These results were consistent with several previous studies showing an increased p-ERK expression in the NAc following cocaine and ethanol self-administration [28]. Thus, the study hypothesized that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc is critical for downstream regulation of DA signal transmission in the NAc, mediating the increased self-administration and rewarding effects observed with propofol. ...
Propofol is a short-acting intravenous anesthetic agent suitable for induction and maintenance of general anesthesia as well as for procedural and intensive care unit sedation. As such it has become an unparalleled anesthetic agent of choice in many institutional and office practices. However, in addition to its idealistic properties as an anesthetic agent, there is accumulating evidence suggesting its potential for abuse. Clinical and experimental evidence has revealed that not only does propofol have the potential to be abused, but also that addiction to propofol shows a high mortality rate. Based on this evidence, different researchers have shown interest in determining the probability of propofol to be an addictive agent by comparing it with other drugs of abuse and depicting a functional similitude that involves the mesocorticolimbic pathway of addiction. In light of this, the Drug Enforcement Agency and the American Society of Anesthesiologists have put forth certain safety recommendations for the use of propofol. Despite this, the abuse potential of propofol has been challenged at different levels and therefore the preeminent focus will be to further validate the linkage from medicinal and occasional use of propofol to its addiction, as well as to explore the cellular and molecular targets involved in establishing this linkage, so as to curb the harm arising out of it. This review incorporates the clinical and biomolecular evidence supporting the abuse potential of propofol and brings forth the promising targets and the foreseeable mechanism causing the propofol addiction phenotypes, which can be called upon for future developments in this field.
... Furthermore, the inverse agonist GR113808 normalized the number of pERK positive cells to WT levels (Figures 3i-k), confirming that the increase in pERK was due to elevated 5-HT 4 receptor expression and/or signaling. Interestingly and consistent with our qPCR data and with findings by others, 43,44 we did not detect a signal for phosphorylated ERK in hippocampus (Figure 3i) or striatum (not shown) where 5-HT4 mRNA levels remain unchanged. ...
The serotonergic neurotransmitter system has been widely implicated in the pathophysiology of mood-related disorders such as anxiety and major depressive disorder (MDD). The onset of therapeutic efficacy of traditional antidepressants is delayed by several weeks. The 5-HT4 receptor has emerged as a new therapeutic target since agonists of this receptor induce rapid antidepressant-like responses in rodents. Here we show that the 5-HT4 receptor is regulated by CK2, at transcriptional and post-transcriptional levels. We present evidence, in two different CK2α knockout mouse lines, that this regulation is region-specific, with the 5-HT4 receptor upregulated in prefrontal cortex (PFC) but not striatum or hippocampus where CK2α is also ablated. 5-HT4 receptor signaling is enhanced in vitro, as evidenced by enhanced cAMP production or receptor plasma membrane localization in the presence of CK2 inhibitor or shRNA targeting CK2α. In vivo, 5-HT4 receptor signaling is also upregulated since ERK activation is elevated and sensitive to the inverse agonist, GR113808 in the PFC of CK2α KO mice. Behaviorally, KO mice as well as mice with AAV-mediated deletion of CK2α in the PFC show a robust ‘anti-depressed-like’ phenotype and display an enhanced response to antidepressant treatment when tested in paradigms for mood and anxiety. Importantly, it is sufficient to overexpress the 5-HT4 receptor in the mPFC to generate mice with a similar ‘anti-depressed-like’ phenotype. Our findings identify the mPFC as the region that mediates the effect of enhanced 5-HT4 receptor activity and CK2 as modulator of 5-HT4 receptor levels in this brain region that regulates mood-related phenotypes.
... Addictive drugs modulate the expression of neuroplasticity-related genes and ultimately disturb intracellular signaling cascades associated with addiction [65]. Within the reward system, including dopaminoceptive neurons of the striatum and NAc, both cocaine and morphine activate common signaling cascades including the extracellular signal-regulated kinase (ERK) pathway [66]. Activated by D1 and D2 receptors, ERK takes parts in different physiological responses, such as cell death and development, as well as synaptic plasticity [67,68]. ...
... SCH23390 attenuated DAMGO-induced ERK1/2 phosphorylation and morphine-induced c-Fos expression in HEK cells expressing μ receptors and D 1 receptors ERK1/2 is an important downstream signalling molecule regulated by opioid receptors. The activation of μ receptors by DAMGO or morphine results in an increase in the phosphorylation of ERK1/2 (Gomes et al., 2000;Valjent et al., 2004). Next, we examined the effect of SCH23390 on DAMGOinduced activation of ERK1/2 in HEK293 cells expressing μ receptors and D 1 receptors or expressing μ receptors only. ...
Background and purpose:
Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behavior. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner, however, the underlying mechanisms are unclear.
Experimental approach:
The coimmunoprecipitation, BRET and cross-antagonism assays were used to demonstrating the existence of receptor heterodimers. The function of heterodimers was evaluated by behavioral studies of locomotor sensitization.
Key results:
We demonstrated that dopamine D1 receptor (D1R) antagonist SCH23390 antagonized the signaling originated by stimulation of μ opioid receptor (μOR) with agonists in transfected cells expressing two receptors and in wild type but not D1R knockout (KO) mouse striatal tissues, suggesting that D1R antagonist SCH23390 was able to modify μOR function via receptor heteromers, since the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a biochemical characteristic of receptor heteromers. The existence of D1R/μOR heterodimers was further supported by biochemical and biophysical assays. Moreover, in vivo we demonstrated that, on condition that dopamine release was absent (e.g. destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited μ agonist-induced behavioral responses in rats. Additionally, we demonstrated that D1R or μOR KO mice, which were unable to form D1R/μOR heterodimers, failed to express locomotor sensitization to morphine.
Conclusion and implications:
These results suggest that D1R/μOR heterodimers may be involved in dopamine independent expression of locomotor sensitization to opiates.
... Only a few studies have to date associated these pathways with the serotonergic components of cocaine action. SSRIs induce ERK phosphorylation in the prefrontal cortex (Valjent et al., 2004), and cocaine occludes hippocampal long-term potentiation via 5-HT 1A receptors and ERK signalling (Grzegorzewska et al., 2010). Importantly, these network hub molecules were not themselves differentially expressed between genotypes, indicating that our network analyses were able to bring their potential roles to light in a way that would not be established by simply examining individual DEGs. ...
Background and purpose:
The psychostimulant cocaine induces complex molecular, cellular and behavioral responses as a consequence of inhibiting presynaptic dopamine, noradrenaline and serotonin (5-HT) transporters. To elucidate 5-HT transporter (SERT)-specific contributions to cocaine action, we evaluated cocaine effects in the SERT Met172 knock-in mouse, which expresses a SERT coding substitution that eliminates high-affinity cocaine recognition.
Experimental approach:
We validated the impact of SERT Met172 on cocaine antagonism of 5-HT re-uptake using ex vivo synaptosome preparations and in vivo microdialysis. We assessed SERT-dependence of cocaine actions behaviorally through acute and chronic locomotor activation, sensitization, conditioned place preference (CPP), and oral cocaine consumption. We implemented c-Fos, quantitative RT-PCR, and RNA sequencing approaches for insights into cellular and molecular networks supporting SERT-dependent cocaine actions.
Key results:
SERT Met172 mice demonstrated functional insensitivity for cocaine at SERT. Though they displayed wildtype levels of acute cocaine-induced hyperactivity or chronic sensitization, the pattern of acute motor activation was distinct, with a bias toward thigmotaxis. CPP was increased, and a time-dependent elevation in oral cocaine consumption was observed. SERT Met172 mice displayed relatively higher levels of neuronal activation in the hippocampus, piriform cortex and prelimbic cortex (PrL), accompanied by region-dependent changes in immediate early gene (IEG) expression. Distinct SERT-dependent gene expression networks triggered by acute and chronic cocaine administration were identified, including PrL Akt and nucleus accumbens ERK1/2 signaling.
Conclusion and implications:
Our studies reveal distinct SERT contributions to cocaine action, reinforcing the possibility of targeting specific aspects of cocaine addiction by modulation of 5-HT signaling.
... While the ventral striatum is an established target for neuroadaptations in response to nicotine (Koob and Volkow, 2010), nicotine also induces neuroplasticity in the dorsal striatum (Pascual et al., 2009;Ortega et al., 2013;Clemens et al., 2014;Valjent et al., 2004). The dorsal striatum is anatomically and functionally segregated into medial and lateral zones. ...
Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well-documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (21 day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior.
... dopaminergic terminal fields. Thus, the increment in the extracellular concentration of dopamine in the PFCx and the Acb upon the inhibition of the presynaptic dopamine transporter by the systemic administration of cocaine [14,21] or MDMA (Ecstasy) is associated with an increase in the expression of pERK in the same brain areas, and this effect is prevented by the administration of a selective D1 dopamine receptor antagonist [22,30,31]. Therefore, based on the above findings, we predicted that (1) FS would increase the expression of pERK and pH3 in the PrLCx and ILCx as well as in the AcbCo and AcbSh of the Roman lines, and (2) the increment in the expression of pERK and, probably, of pH3 would be more robust in the PFCx of RHA vs. RLA rats because the increase in dopamine release induced by stressors in this brain area is more pronounced in the former than in the latter line [20]. ...
Stressful events evoke molecular adaptations of neural circuits through chromatin remodeling and regulation of gene expression. However, the identity of the molecular pathways activated by stress in experimental models of depression is not fully understood. We investigated the effect of acute forced swimming (FS) on the phosphorylation of the extracellular signal-regulated kinase (ERK)1/2 (pERK) and histone H3 (pH3) in limbic brain areas of genetic models of vulnerability (RLA, Roman low-avoidance rats) and resistance (RHA, Roman high-avoidance rats) to stress-induced depression-like behavior. We demonstrate that FS markedly increased the density of pERK-positive neurons in the infralimbic (ILCx) and the prelimbic area (PrLCx) of the prefrontal cortex (PFCx), the nucleus accumbens, and the dorsal blade of the hippocampal dentate gyrus to the same extent in RLA and RHA rats. In addition, FS induced a significant increase in the intensity of pERK immunoreactivity (IR) in neurons of the PFCx in both rat lines. However, RHA rats showed stronger pERK-IR than RLA rats in the ILCx both under basal and stressed conditions. Moreover, the density of pH3-positive neurons was equally increased by FS in the PFCx of both rat lines. Interestingly, pH3-IR was higher in RHA than RLA rats in PrLCx and ILCx, either under basal conditions or upon FS. Finally, colocalization analysis showed that in the PFCx of both rat lines, almost all pERK-positive cells express pH3, whereas only 50% of the pH3-positive neurons is also pERK-positive. Moreover, FS increased the percentage of neurons that express exclusively pH3, but reduced the percentage of cells expressing exclusively pERK. These results suggest that (i) the distinctive patterns of FS-induced ERK and H3 phosphorylation in the PFCx of RHA and RLA rats may represent molecular signatures of the behavioural traits that distinguish the two lines and (ii) FS-induced H3 phosphorylation is, at least in part, ERK-independent.
... In addition to its contribution to signaling that directly involves the cAMP pathway, DARPP-32 contributes to other types of signaling in MSNs. For example, the ERK pathway plays an important role in behavioral and synaptic plasticity induced by drugs of abuse, most studied in the case of cocaine (Valjent et al., 2000;Valjent, Corvol, Trzaskos, Girault, & Herve, 2006;Valjent, Pages, Herve, Girault, & Caboche, 2004;Pascoli, Turiault, & Luscher, 2012). Stimulation of ERK by drugs of abuse takes place in D1-MSNs (Bertran-Gonzalez et al., 2008) and requires the activation of both D1R and NMDAR resulting in activation of DARPP-32 (Valjent et al., 2000;Valjent et al., 2005). ...
Striatal medium spiny projection neurons (MSNs) play key roles in basal ganglia circuits by integrating excitatory corticostriatal and thalamostriatal input with modulatory nigrostriatal dopamine input. MSNs express specific sets of genes involved in intercellular communication and intracellular signaling, some being highly enriched in all MSNs and others specific to either D1 dopamine receptor–containing striatonigral or D2 dopamine receptor–containing striatopallidal neurons. Whereas the role of many of these genes remains to be investigated, much research has focused on the regulation of protein phosphatases. Three small regulatory phosphoproteins, termed DARPP-32 (dopamine- and cAMP-regulated phosphoprotein), RCS (regulator of calmodulin signaling), and ARPP-16, play key roles in dopamine signaling by regulating the activity of three of the four major classes of serine/threonine protein phosphatases. This chapter provides an overview of the main characteristics of signaling in MSNs with a focus on the role of protein phosphatase regulation in mediating the modulatory role of dopamine.
... Evidence, in this regard, originated from the observation that, similarly to ethanol, 54 orally administered acetaldehyde can also stimulate spontaneous ring of dopaminergic neurons in the ventral tegmental area (VTA), 55 a nding also in agreement with the observation that acetaldehyde stimulates dopamine transmission in the nucleus accumbens as determined by in vivo brain microdialysis. 56,57 Furthermore, indirect evidence of the involvement of the mesolimbic dopaminergic system in the e ects of either acetaldehyde or ethanol-derived acetaldehyde (as demonstrated by the combined administration of ethanol and 4-MP or -penicillamine, a compound able to sequester acetaldehyde) arose from the studies reporting their ability to elicit the activation of the extracellular signal-regulated kinase pathway 58,59 in the nucleus accumbens. 60 Until now, at least the following four distinct pieces of evidence support the role of ethanol-derived acetaldehyde in these e ects of ethanol: 50,53 (i) the demonstration that the e ects of peripherally administered ethanol may be prevented by drugs able to contrast peripheral ethanol metabolism (ADH inhibitors); 32,55,56,60 (ii) the demonstration of the ability to prevent the e ects of systemic administration of ethanol by drugs that inhibit and/or interfere with catalase-H 2 O 2 system; 41-43,61 (iii) the demonstration that a reduction in acetaldehyde availability by sequestering drugs could produce a reduction in the e ects of ethanol either after its peripheral administration or after its central administration; 32,61-67 (iv) the demonstration that acetaldehyde exerts e ects similar to those of ethanol after its peripheral 32,60,65,68-71 or local, intracerebral, 72-75 administration. ...
In spite of the global reputation of ethanol as the psychopharmacologically active ingredient of alcoholic drinks, the neurobiological basis
of the central e!ects of ethanol still presents some dark sides due to a number of unanswered questions related to both its precise mechanism of action and
its metabolism. Accordingly, ethanol represents the interesting example of a compound whose actions cannot be explained as simply due to the involvement
of a single receptor/neurotransmitter, a scenario further complicated by the robust evidence that two main metabolites, acetaldehyde and salsolinol, exert
many e!ects similar to those of their parent compound. "e present review recapitulates, in a perspective manner, the major and most recent advances that
in the last decades boosted a signi#cant growth in the understanding on the role of ethanol metabolism, in particular, in the neurobiological basis of its
central e!ects.
... ERK is expressed in the brain [11], and is especially abundant in the mesocorticolimbic DA system. Recently, accumulating evidence has indicated that ERK signal transduction pathways in mesocorticolimbic areas are involved in drug dependence and addiction [12,13]. Acute or repeated administration of cocaine, nicotine, and morphine enhances ERK phosphorylation in the nucleus accumbens (NAc), which is a major terminal area of the mesolimbic DA projection systems and a crucial component of the neuronal circuitry mediating reward-related behaviors. ...
Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobiological mechanism underlying propofol reward is not fully understood. The purpose of this study was to investigate the role of extracellular signal-regulated kinase (ERK) signal transduction pathways in the nucleus accumbens (NAc) in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self-administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 (4 µg/side) attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.
... Thus, acute morphine administration reduces intracellular cAMP level (Sharma et al., 1975); decrease the conductance of voltage-gated Ca 2+ channels and open rectifying K + channels. Furthermore, acute morphine treatment causes a rapid and transient increase extracellular signal-regulated kinase (ERK) phosphorylation in the nucleus accumbens (NAcc), central amygdala, prefrontal cortex, lateral bed nucleus of stria terminalis (BNST) in mice (Valjent et al., 2004). Acute single morphine injection does not change the proenkephalin (PENK) and prodynorphin (PDYN) mRNA level in the nucleus accumbens or striatum (Turchan et al., 1997) in mice. ...
http://doktori.bibl.u-szeged.hu/2480/1/Liptak.N.PhD.disszertacio.pdf
... This assertion appears to be true, and indeed it extends to the dorsal striatum as well (Fig. 2a). Past studies indicated that drugs of abuse administered in vivo can alter dopamine, dopaminergic markers, dopamine-related immediate-early gene expression, and neuronal activity in dorsal striatum (Chang et al. 1988;Curran et al. 1996;Fadda et al. 1980Fadda et al. , 2005Ferguson et al. 2004;Kiba & Jayaraman 1994;Marshall & Smith 1974;Mathews et al. 2006;Nye & Nestler 1996;Reggiani et al. 1980;Valjent et al. 2004;Vezina et al. 1992). Measurements of dorsal striatal dopamine with microdialysis have revealed increased dopamine following injection of alcohol, cocaine, nicotine and amphetamine (Benwell & Balfour 1997;Di Chiara & Imperato 1988;Mathews et al. 2006). ...
The mammalian forebrain is characterized by the presence of several parallel cortico-basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal-directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico-basal ganglia circuits become involved in drug-related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use.
... Therefore, it is important to estimate to what extent molecular effects of opioids and psychostimulants are common or different. The approach that searches for similarities between various drugs of abuse has long been recognized (Leshner & Koob 1999;Piechota et al. 2010;Valjent et al. 2004). The genes whose expression changes similarly after the administration of HER and METH could be responsible for their common effects, such as sensitization or anhedonia. ...
Both opioids and psychostimulants increase the release of dopamine and activate the mesocorticolimbic reward circuit. This common mechanism of action suggests shared molecular origins and unifies the neurobiological theory of drug addiction. Studies have revealed biochemical and neural pathways that modulate reward, but common and distinct genes regulated by various addictive drugs in the brain are largely unknown. The characterization of drug-induced changes in gene transcription holds promise for a better understanding of drug addiction and polydrug abuse. This review summarizes the current information about changes in gene expression profiles in the brain reward center following administration of opiates and psychostimulants, including heroin and methamphetamine. Here we focus on the evidence that the gene transcription response to opioids and psychostimulants is distinct after acute and prolonged treatments. Acute administration of the drugs in different time-dependent manners activates sets of neuronal activity-dependent genes and, in glia, the genes are controlled by the hypothalamopituitary-adrenal axis and glucocorticoids. Prolonged drug administration alters circadian genes and transcripts encoding neuropeptides.
Preclinical studies suggest that physiological learning processes are similar to changes observed in addiction at the molecular, neuronal and structural levels. Based on the importance of classical and instrumental conditioning in the development and maintenance of addictive disorders, many have suggested cue-exposure-based extinction training of conditioned, drug-related responses as a potential treatment of addiction. Recently, the development of virtual reality-assisted cue-exposure treatment has put forward new approaches to extinction training. Recent data indicated that it may also be possible to facilitate this extinction training through pharmacological interventions that strengthen memory consolidation during cue exposure. Another potential therapeutic intervention is based on the so-called reconsolidation theory. According to this hypothesis, already-consolidated memories return to a labile state when reactivated, allowing them to undergo another phase of consolidation – reconsolidation – which can be interfered with by pharmacological and behavioural interventions. These approaches suggest that the extinction of drug-related memories may represent a viable treatment strategy in the future treatment of addiction.
Nicotine is an addictive substance historically consumed through smoking and more recently through the use of electronic vapor devices. The increasing prevalence and popularity of vaping prompts the need for preclinical rodent models of nicotine vapor exposure and an improved understanding of the impact of vaping on specific brain regions, bodily functions, and behaviors. We used a rodent model of electronic nicotine vapor exposure to examine the cellular and behavioral consequences of acute and repeated vapor exposure. Adult male C57BL/6J mice were exposed to a single 3-h session (acute exposure) or five daily sessions (repeated exposure) of intermittent vapes of 120 mg/ml nicotine in propylene glycol:vegetable glycerol (PG/VG) or PG/VG control. Acute and repeated nicotine vapor exposure did not alter body weight, and both exposure paradigms produced pharmacologically significant serum nicotine and cotinine levels in the 120 mg/ml nicotine group compared with PG/VG controls. Acute exposure to electronic nicotine vapor increased central amygdala (CeA) activity in individual neuronal firing and in expression of the molecular activity marker, cFos. The changes in neuronal activity following acute exposure were not observed following repeated exposure. Acute and repeated nicotine vapor exposure decreased core body temperature, however acute exposure decreased locomotion while repeated exposure increased locomotion. Collectively, these studies provide validation of a mouse model of nicotine vapor exposure and important evidence for how exposure to electronic nicotine vapor produces differential effects on CeA neuronal activity and on specific body functions and behaviors like thermoregulation and locomotion.
Autosomal dominant sleep‐related hypermotor epilepsy (ADSHE; previously autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE), originally reported in 1994, was the first distinct genetic epilepsy shown to be caused by CHNRA4 mutation. In the past two decades, we have identified several functional abnormalities of mutant ion channels and their associated transmissions using several experiments involving single‐cell and genetic animal (rodent) models. Currently, epileptologists understand that functional abnormalities underlying epileptogenesis/ictogenesis in humans and rodents are more complicated than previously believed and that the function of mutant molecules alone cannot contribute to the development of epileptogenesis/ictogenesis but play important roles in the development of epileptogenesis/ictogenesis through formation of abnormalities in various other transmission systems before epilepsy onset. Based on our recent findings using genetic rat ADSHE models, harbouring Chrna4 mutant, corresponding to human S284L‐mutant CRHNA4, this review proposes a hypothesis associated with tripartite synaptic transmission in ADSHE pathomechanisms induced by mutant ACh receptors.
LINKED ARTICLES
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Neurotensin is an endogenous neuropeptide that acts as a potent modulator of ventral tegmental area (VTA) neurotransmission. The present study was aimed at determining VTA cell population and neurotensin receptor subtype responsible for the initiation of amphetamine‐induced psychomotor activity and extracellular signal‐regulated kinases (ERK1/2) sensitization. During an induction phase, rats were injected intra‐VTA on two occasions, every second day, with [D‐Tyr¹¹]‐neurotensin (D‐Tyr‐NT), SR142948 (a mix Ntsr1/Ntsr2 receptor subtype antagonist), SR48692 (a Ntsr1 antagonist), D‐Tyr‐NT + SR142498, D‐Tyr‐NT + SR48692, or the vehicle. Effects of intra‐VTA drugs were evaluated at locomotor activity and ERK1/2 phosphorylation. Five days after the last VTA microinjection, the effect of a systemic injection of amphetamine was tested (sensitization test). Results show that D‐Tyr‐NT stimulated locomotor activity during the induction phase, an effect that was blocked by SR142948, but not SR48692. Amphetamine also induced significantly higher ambulatory activity in rats preinjected with D‐Tyr‐NT than in rats preinjected with the vehicle. This sensitization effect was again attenuated by SR142948, but not SR48692, hence suggesting that this effect is mediated by Ntsr2 receptors. To confirm this, we tested a highly selective Ntsr2 peptide–peptoid hybrid ligand, NT150. At the concentration tested, NT150 stimulated locomotor activity and lead to sensitized locomotor activity and a selective neurochemical (pERK1/2) response in tyrosine hydroxylase‐positive neurons of the VTA. Both effects were prevented by SR142948. Taken together, these results show that neurotensin, acting on Ntsr2 receptor subtypes, stimulates locomotor activity and initiates neural changes (ERK1/2 phosphorylation) that lead to amphetamine‐induced sensitization.
Prescription stimulants, such as d‐amphetamine or methylphenidate are used to treat suffering from attention‐deficit hyperactivity disorder (ADHD). They potently release dopamine (DA) and norepinephrine (NE) and cause phosphorylation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the striatum. Whether other brain regions are also affected remains elusive. Here, we demonstrate that d‐amphetamine and methylphenidate increase phosphorylation at Ser845 (pS845‐GluA1) in the membrane fraction of mouse cerebellum homogenate. We identify Bergmann glial cells as the source of pS845‐GluA1 and demonstrate a requirement for intact NE release. Consequently, d‐amphetamine‐induced pS845‐GluA1 was prevented by β1‐adenoreceptor antagonist, whereas the blockade of DA D1 receptor had no effect. Together, these results indicate that NE regulates GluA1 phosphorylation in Bergmann glial cells in response to prescription stimulants.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. There is currently no cure for PD. Symptomatic drug therapy essentially relies on dopamine (DA) replacement therapy. The spectacular antiparkinsonian effect of levodopa in PD is however hampered by long-term complications, motor fluctuations and dyskinesia in all patients at some time during the disease course. The mechanisms of the maladaptive striatal plasticity leading to dyskinesia are not well understood. The aim of this project was to identify the dysregulations of signaling pathways in striatal projection neurons (SPN) in the absence of dopamine. We used a mouse model of lesion of DA neurons with 6-OHDA and virally transduced biosensors to monitor signaling pathways in live neurons with two-photon imaging of corticostriatal slices. We focused our attention on extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase (PKA) and Ca2+ which are known to be altered in the absence of DA. We first set up a reliable experimental model in adult mice, successfully combining 6-OHDA and viral vector in the same unilateral stereotactic injection into the dorsal striatum. In some experiments we targeted the biosensor expression to specific neuronal populations using Cre-dependent “flexed” biosensors. We used mice expressing Cre under the control of the D1 DA receptor (D1R) promoter to target specifically striatal projection neurons of the direct pathway (dSPNs) or the adenosine A2A receptor (A2AR) to target SPNs of the indirect pathway (iSPNs). We used fluorescence resonance energy transfer (FRET)-based biosensors EKAR-EV and AKAR-3 to monitor ERK and PKA activities, respectively. We also monitored cytosolic free Ca2+ with the genetically encoded calcium indicator GCaMP6S. We used pharmacological tools to modulate glutamate, DA, and adenosine receptors as well as phosphodiesterases (PDE) and kinases activities. We observed that the DA lesion increased ERK responsiveness to stimulation of D1R. Since ERK activation depends on both cAMP and Ca2+ signals, we then investigated these two pathways. We observed an increased activation of PKA in response to D1R but not A2AR. We explored the mechanism of this increased sensitivity using mice deficient for Gαolf, the G protein that couples striatal receptors to adenylyl cyclase. We provided evidence that increased levels of Gαolf contributed to enhanced D1 responses after 6-OHDA lesions and identified a deficit in PDE activity in D1 neurons that was likely to amplify this effect. By monitoring Ca2+ signals we showed an increased spontaneous activity of D1 neurons in lesioned mice. However, unexpectedly the Ca2+ responses to stimulation of AMPA glutamate receptors were increased in iSPNs and not dSPNs. In conclusion, our work using for the first time 2-photon biosensor imaging in the DA-depleted striatum of adult mice confirms and extends previous observations on signaling dysregulations in the absence of DA. It reveals distinct cell type-specific alterations of cAMP, Ca2+ and ERK responses in the two populations of SPNs and suggests possible mechanisms for these alterations.
Prescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by Beta1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.
Addiction is defined as the repeated exposure and compulsive seek of psychotropic drugs that, despite the harmful effects, generate relapse after the abstinence period. The psychophysiological processes associated with drug addiction (acquisition/expression, withdrawal, and relapse) imply important alterations in neurotransmission and changes in presynaptic and postsynaptic plasticity and cellular structure (neuroadaptations) in neurons of the reward circuits (dopaminergic neuronal activity) and other corticolimbic regions. These neuroadaptation mechanisms imply important changes in neuronal energy balance and protein synthesis machinery. Scientific literature links drug‐induced stimulation of dopaminergic and glutamatergic pathways along with presence of neurotrophic factors with alterations in synaptic plasticity and membrane excitability driven by metabolic sensors. Here, we provide current knowledge of the role of molecular targets that constitute true metabolic/energy sensors such as AMPK, mTOR, ERK, or KATP in the development of the different phases of addiction standing out the main brain regions (ventral tegmental area, nucleus accumbens, hippocampus, and amygdala) constituting the hubs in the development of addiction. Because the available treatments show very limited effectiveness, evaluating the drug efficacy of AMPK and mTOR specific modulators opens up the possibility of testing novel pharmacotherapies for an individualized approach in drug abuse. Drug addiction‐induced neuroadaptation changes neuronal energy balance and protein synthesis. We review the role of energy sensors (AMPK, mTOR, ERK, or KATP) on drug addiction. Drug efficacy of AMPK and mTOR modulators opens up promising pharmacotherapies.
La moelle spinale est un relais majeur permettant aux informations sensorielles perçues à la périphérie d’être transférées et intégrées au niveau des centres supra-spinaux. Les afférences primaires somatosensorielles vont arriver au niveau de la corne dorsale. Celle-ci est constituée d’un réseau hétérogène de neurones formant des circuits excitateurs et inhibiteurs complexes. De précédentes études indiquent que ces circuits neuronaux sont modulés par la dopamine, notamment via les D2R. Un dysfonctionnement des voies dopaminergiques descendantes peut engendrer des physiopathologies comme le syndrome des jambes sans repos. Cependant, les mécanismes d’action de la dopamine spinale sont encore très peu connus. Tous les récepteurs à la dopamine sont exprimés au niveau spinal. Le plus abondant est le D2R mais le rôle et l’identité précise des cellules D2R-positives ne sont pas connus. Dans cette étude, nous nous sommes focalisés sur la caractérisation anatomo-fonctionnelle des cellules exprimant les D2R. Grâce au modèle murin Drd2-Cre :RiboTag crée par l’équipe, nous avons mis en avant que les cellules D2R-positives étaient distribuées tout au long de la moelle spinale avec une expression préférentielle au niveau de la corne dorsale. Les D2R sont exprimés dans des populations très hétérogènes, aussi bien excitatrices qu’inhibitrices. Nous avons montré que le KO conditionnel du gène drd2 au niveau lombaire n’entraîne pas d’ataxie, de paralysie ou d’altération de la locomotion. L’état des lieux concernant la caractérisation neurochimique des cellules D2R-positives ouvrent la possibilité d’avoir une approche fonctionnelle plus spécifique et d’avoir des perspectives d’études sur les sous circuits dopaminergiques spinaux.
Intracellular interactions between protein kinases and metabotropic receptors in the striatum regulate behavioral changes in response to drug exposure. We investigated the difference in the degree of interaction between extracellular signal‐regulated kinase (ERK) and metabotropic glutamate receptor subtype 5 (mGluR5) in the nucleus accumbens (NAc) after repeated exposure to nicotine in adult and adolescent rats. The results showed that repeated exposure to nicotine (0.5 mg/kg/day, s.c.) for seven consecutive days increased ERK phosphorylation more in adults than in adolescents. Furthermore, membrane expression of mGluR5 in gamma‐aminobutyric acid (GABA) medium spiny neurons was higher in adults than adolescents as a result of repeated exposure to nicotine. Blockade of mGluR5 with MPEP (0.5 nmol/side) decreased the repeated nicotine‐induced increase in ERK phosphorylation. Either blockade of mGluR5 or inhibition of ERK with SL327 (150 nmol/side) decreased the repeated nicotine‐induced increase in the level of inositol‐1,4,5‐triphosphate (IP3), a key transducer associated with mGluR5‐coupled signaling cascades. Similarly, interference of binding between activated ERK and mGluR5 by the blocking peptide, Tat‐mGluR5‐i (2 nmol/side), decreased the repeated nicotine‐induced increases in IP3 and locomotor activity in adults. These findings suggest that the intracellular interaction between ERK and mGluR5 in the NAc is stronger in adult than in adolescent rats, which enhances the understanding of age‐associated behavioral changes that occur after repeated exposure to nicotine.
Drug relapse among addicts often occurs due to the learned association between drug‐paired cues and the rewarding effects of these drugs, such as morphine. Contextual memory associated with morphine has a central role in maintenance and relapse. We showed that morphine‐conditioned place preference (CPP) activates extracellular‐regulated protein kinase (ERK) in the nucleus accumbens (NAc). The main enzymes that mediate ERK dephosphorylation are members of the dual‐specificity phosphatase (DUSP) superfamily. It is unclear which members regulate the morphine CPP‐induced activation of ERK. After screening, DUSP15 was found to be decreased during both morphine CPP expression and the reinstatement period. Intra‐NAc infusions of AAV‐DUSP15 (overexpression) not only prevented the expression of morphine‐induced CPP but also facilitated extinction, inhibited reinstatement, and abolished ERK activation. However, after repeated morphine exposure and withdrawal in mice, there was no change in the expression of p‐ERK and DUSP15, and the overexpression of DUSP15 in the NAc did not improve the impaired spatial memory or anxiety‐like behaviour induced by morphine. Together, these findings indicate that DUSP15 not only prevents the expression of drug‐paired contextual memory but also promotes the extinction of existing addiction memories, thus providing a novel therapeutic target for the treatment of drug addiction. Morphine CPP significantly activited ERK. Overexpression of DUSP15 in the NAc not only prevented the expression of morphine CPP but also facilitated extinction and inhibited reinstatement by dephosphorylation of ERK. DUSP15 and ERK were not associated with the impaired spatial memory and anxiety‐like behaviour induced by morphine withdrawal.
The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (A‐kinase activity reporter 3) to record protein kinase A signals and by analyzing the distribution of dopamine D1R‐ and D2R‐SPNs in the TS, we characterized three subterritories: a D2R/A2aR‐lacking, a D1R/D2R‐intermingled and a D1R/D2R‐SPNs‐enriched area (corresponding to the amygdalostriatal transition). In addition, we provide evidence that the distribution of D1R‐ and D2R‐SPNs in the TS is evolutionarily conserved (mouse, rat, gerbil). The in vivo analysis of extracellular signal‐regulated kinase (ERK) phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate aversive responses, fasting, satiety, or palatable signals whereas a reduction in ERK phosphorylation occurred following learned avoidance. In contrast, D1R‐SPNs of the intermingled and D2R/A2aR‐lacking areas were strongly activated by both D1R agonists and psychostimulant drugs (d‐amphetamine, cocaine, 3,4‐methyl enedioxy methamphetamine, or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals and discrete aversive stimuli.
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Cover Image for this issue: doi: 10.1111/jnc.14526.
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Introduction: Repeated administration of abused drugs, including Δ⁹-tetrahydrocannabinol (THC), induces the stable transcription factor ΔFosB in dopaminergic terminal field regions of the mesolimbic system. These studies investigated the effect of prior repeated THC treatment on THC-induced ΔFosB expression and regulation of downstream targets in the forebrain.
Methods: Mice received THC (10 mg/kg) or vehicle twice daily for 13 days, and then half of each group received a single injection of THC or vehicle 45 min before brain collection. ΔFosB messenger RNA (mRNA) and protein were measured by polymerase chain reaction and immunoblotting, respectively. Potential downstream targets of ΔFosB induction were measured by immunoblot.
Results: THC injection in mice with a history of repeated THC treatment enhanced ΔFosB expression as compared with vehicle in the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. This change occurred concomitantly with an increase in ΔFosB mRNA in the PFC and NAc. THC injection in mice with a history of repeated THC treatment increased expression of cyclin-dependent kinase 5 (Cdk5) and its regulatory protein p35 only in the PFC. This increase in Cdk5 and p35 expression in PFC was also found in mice that had only received repeated THC administration, suggesting that this effect might be due to induction of ΔFosB. Extracellular signal-regulated kinase (ERK) phosphorylation was increased in PFC after THC injection in repeated THC-treated mice. Phosphorylation of glycogen synthase kinase-3β (GSK3β), a Cdk5 target, was reduced in PFC after repeated THC treatment regardless of THC history, and phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the Cdk5-regulated threonine 75 site was unchanged.
Conclusion: These results suggest that a history of repeated THC administration primes THC-mediated induction of ΔFosB in the NAc and PFC, and that expression of both downstream targets of ΔFosB (e.g., Cdk5 and p35) and upstream activators (e.g., pERK) in the PFC is dependent on THC history, which might have functional implications in addiction and neuropsychiatric disease.
Thèse portant sur l'étude de trois plantes psychotropes consommées en Nouvelle-Calédonie : kava, cannabis et datura. L'étude porte plus spécifiquement sur les aspects médicaux et médico-légaux.
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