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Measurements of haloperidol levels in control and PRS rats. In (A), rats were treated with 2 mg/kg of haloperidol, and drug levels were measured in the serum and neostriatum after 30, 60, and 120 minutes. In (B), treated daily for 6 days with 0.5 mg/kg of haloperidol, drug levels were measured in serum 60 minutes after the last injection. Drug levels were measured in the same animals used for the assessment of catalepsy. Values are means 6 S.E.M. of five determinations. *P , 0.05 versus the respective controls (Student's t test). CONT, control.
Source publication
The use of classical antipsychotic drugs is limited by the occurrence of extrapyramidal motor symptoms, which are caused by dopamine (DA) receptor blockade in the neostriatum. We examined the impact of early life stress on haloperidol-induced catalepsy using the rat model of prenatal restraint stress (PRS). Adult "PRS rats", i.e. the offspring of m...
Contexts in source publication
Context 1
... and PRS rats injected with 2 mg/kg of haloperidol. We found no difference in haloperidol levels between control and PRS rats at 30 or 60 minutes after injection. In contrast, both serum and striatal levels were markedly reduced in PRS rats at 120 minutes (ANOVA group effect, serum: F (1,4) 5 13.54, P , 0.05; striatum: F (1,4) 5 9.82, P , 0.05) (Fig. 2A). Thus, changes in the pharmacokinetics of haloperidol could only explain the resistance to catalepsy at 120 minutes, but not at 30 or 60 minutes. Serum haloperidol levels did not differ between control and PRS rats treated daily for 6 days with 0.5 mg/kg of haloperidol (Fig. ...
Context 2
... F (1,4) 5 13.54, P , 0.05; striatum: F (1,4) 5 9.82, P , 0.05) (Fig. 2A). Thus, changes in the pharmacokinetics of haloperidol could only explain the resistance to catalepsy at 120 minutes, but not at 30 or 60 minutes. Serum haloperidol levels did not differ between control and PRS rats treated daily for 6 days with 0.5 mg/kg of haloperidol (Fig. ...
Citations
... There are only a few studies on how early-life stress programs the activity of the basal ganglia motor circuit in adult life. For example, PRS has been shown to affect the symmetry of D 2 receptor expression in the medial caudate-putamen (Adrover et al., 2007), attenuate haloperidol-induced catalepsy, and enhance apomorphine-induced stereotypies (Marrocco et al., 2013). However, no studies have been performed in old rats, despite a well-known decline in mobility with age and the identification of age as a risk factor for motor disorders, as observed in PD. ...
Early-life stress involved in the programming of stress-related illnesses can have a toxic influence on the functioning of the nigrostriatal motor system during aging. We examined the effects of perinatal stress (PRS) on the neurochemical, electrophysiological, histological, neuroimaging, and behavioral correlates of striatal motor function in adult (4 months of age) and old (21 months of age) male rats. Adult PRS offspring rats showed reduced dopamine (DA) release in the striatum associated with reductions in tyrosine hydroxylase-positive (TH⁺) cells and DA transporter (DAT) levels, with no loss of striatal dopaminergic terminals as assessed by positron emission tomography analysis with fluorine-18-l-dihydroxyphenylalanine. Striatal levels of DA and its metabolites were increased in PRS rats. In contrast, D2 DA receptor signaling was reduced and A2A adenosine receptor signaling was increased in the striatum of adult PRS rats. This indicated enhanced activity of the indirect pathway of the basal ganglia motor circuit. Adult PRS rats also showed poorer performance in the grip strength test and motor learning tasks. The aged PRS rats also showed a persistent reduction in striatal DA release and defective motor skills in the pasta matrix and ladder rung walking tests. In addition, the old rats showed large increases in the levels of SNAP-25 and synaptophysin, which are synaptic vesicle-related proteins in the striatum, and in the PRS group only, reductions in Syntaxin-1 and Rab3a protein levels were observed. Our findings indicated that the age-dependent threshold for motor dysfunction was lowered in PRS rats. This area of research is underdeveloped, and our study suggests that early-life stress can contribute to an increased understanding of how aging diseases are programmed in early-life.
... Moreover, hypolocomotor effects of haloperidol in the OF for Wistar rats have been described using high doses of 2.5 and 10 mg/kg, immediately after injection (Bernardi et al. 1981). Finally, IP Haloperidol 0.5 mg/kg causes cataleptic effects in rats (Marrocco et al. 2013;Jain et al. 2015). Thus, the reduction of activity observed with this dose can be attributed to these effects. ...
The SHR and SLA16 inbred strains present behavioral differences in anxiety/emotionality that could be under the influence of dopaminergic neurotransmission. In order to investigate the role of D2 receptors in modulating such differences, an agonist (quinpirole) and an antagonist (haloperidol) of this receptor were administered, either via systemic injection (IP), or microinjected into the ventral area of the hippocampus (vHIP). Quinpirole and haloperidol IP decreased locomotor activity, only in SLA16 rats in the open-field (OF), and in both strains in the elevated plus-maze (EPM). Quinpirole also increased the preference for the aversive areas of the EPM. Quinpirole vHIP decreased locomotor activity in both strains. Haloperidol vHIP did not elicit behavioural changes and no differences in the levels of D2 receptors and of dopamine transporter in the hippocampus were found. Results indicate that systemic activation/blocking of D2 receptors caused a strain-dependent hypolocomotion, whereas activation of D2 receptors in the vHIP, but not D2 receptor antagonism, regardless of dose, decreased general locomotor activity in the two strains. Therefore, we suggest that genomic differences in the chromosome 4 can influence the locomotor activity regulated by the D2 dopaminergic receptor, especially in the vHIP.
... The injection and recording times of both the experimental and control groups are presented in Figs 2 and 3. Subsequent injections of haloperidol (half-life 2 hours [27]) and buprenorphine (half-life 2-4 hours [28]) were given in order to maintain an appropriate depth of anaesthesia, which was regularly monitored via toe pinch reflexes. After the end of the day, the rats were still anesthetized, they were given an overdose of ketamine (100mg/ml)/xylazine (20 mg/ml), systemically administered, without any sign of adverse reaction. ...
Research question:
Recent discoveries have challenged the traditional view that the thalamus is the primary source driving spike-and-wave discharges (SWDs). At odds, SWDs in genetic absence models have a cortical focal origin in the deep layers of the perioral region of the somatosensory cortex. The present study examines the effect of unilateral and bilateral surgical resection of the assumed focal cortical region on the occurrence of SWDs in anesthetized WAG/Rij rats, a well described and validated genetic absence model.
Methods:
Male WAG/Rij rats were used: 9 in the resected and 6 in the control group. EEG recordings were made before and after craniectomy, after unilateral and after bilateral removal of the focal region.
Results:
SWDs decreased after unilateral cortical resection, while SWDs were no longer noticed after bilateral resection. This was also the case when the resected areas were restricted to layers I-IV with layers V and VI intact.
Conclusions:
These results suggest that SWDs are completely abolished after bilateral removal of the focal region, most likely by interference with an intracortical columnar circuit. The evidence suggests that absence epilepsy is a network type of epilepsy since interference with only the local cortical network abolishes all seizures.
... This observation suggests that, in wild-type mice, the early induction of the Grm4 gene in the striatum may shorten the duration of catalepsy in spite of the slow decline of haloperidol concentrations in the mouse brain (12e24 h following a single injection of haloperidol - Zetler and Baumann, 1985 -). It will be interesting to compare the efficacy of mGlu4 receptor PAMs with that of anticholinergic drugs or other putative antiparknsonian drugs (e.g., mGlu5 receptor NAMs and A 2A receptor antagonists) in rats or mice chronically treated with haloperidol (see Marrocco et al., 2013), which more closely model drug-induced parkinsonism in humans. ...
... Further studies are required to investigate the effect of acute early DMI on disease progression. Recent evidence has highlighted the role of glutamate in anxiety and mood disorders and several compounds with antidepressant activity are known to restore glutamatergic transmission to physiological levels (Bonanno et al., 2005;Marrocco et al., 2013;Nasca et al., 2013). The DMI-induced restoration of glutamate exocytosis might therefore well account for the decreased anxiety-like behaviour observed in EAE mice at 13 d.p.i. ...
... Besides the well-known role of cortical noradrenergic and glutamatergic transmission in mood disorders (Pittaluga et al., 2007;Marrocco et al., 2013;Nasca et al., 2013), recent evidence strongly supports the notion that depression and anxiety is an inflammatory condition and that elevated levels of endogenous cytokines (including TNF-α, Hashmi et al., 2013) might have a role in eliciting these behaviours. Whether pathologically-relevant amounts of CCL5 could participate in determining anxiety and depression in MS patients remains to be established, although the positive effects acute DMI exerts on thigmotaxis (being inactive on motor behaviour and clinical scores) could support this hypothesis. ...
Altered glutamate exocytosis and cyclic adenosine monophosphate (cAMP) production in cortical terminals of Experimental Autoimmune Encephalomyelitis (EAE) mice occur at the early stage of disease (13 days post immunization, d.p.i.). Neuronal defects were paralleled by central chemokine Regulated upon Activation Normal T cell Expressed and Secreted (RANTES or CCL5) overexpression, suggesting its role in presynaptic impairments. We propose that drugs able to restore CCL5 content to physiological levels also could rescue presynaptic defects. Because of its efficacy in controlling CCL5 overexpression, desipramine (DMI) appeared to be a suitable candidate to test our hypothesis.
Control and EAE mice at 13 d.p.i. were acutely or chronically DMI administered and monitored for behaviour and clinical score. Noradrenaline and glutamate release, cAMP, CCL5 and TNF-α productions were quantified in cortical synaptosomes and homogenates. Peripheral cytokine production was also detected.
Noradrenaline exocytosis and α2-autoreceptor-mediated activity were unmodified in EAE mice at 13 d.p.i. when compared to control. Acute, but not chronic, DMI reduced CCL5 level in cortical homogenates of EAE mice at 13 d.p.i., leaving unaltered peripheral IL-17 and TNF-α contents as well as CCL5 plasma levels. Acute DMI caused a long-lasting restoration of glutamate exocytosis, rescued endogenous cAMP production, and impeded the shift from inhibition to facilitation of the CCL5-mediated control of glutamate exocytosis. Finally, DMI ameliorated anxiety-related behaviour but not motor activity and clinical scores.
We propose DMI as an add-on therapy to normalize neuropsychiatric symptoms in MS patients at the early stage of disease.
Background
Antipsychotic drugs and mood-stabilizers are used routinely to treat acute mania. However, combinations of such drugs can produce adverse effects or reduced clinical efficacy due to drug-drug interactions, even if administered within the accepted range. Despite widespread clinical use of such drug-combinations, few have been evaluated systematically for relative efficacy and safety.
Objective
We report a case of sudden death in a 40-year-old man with acute mania treated aggressively with such drug-combinations with the serum levels demonstrating the effects of pharmacokinetic interactions.
Method and Results
Although administered doses were within accepted ranges, circulating concentrations of some antipsychotics were excessive, suggesting pharmacokinetic drug interactions. In particular, valproate may have increased serum levels of haloperidol, clozapine, and promazine. The proposed cause of death was cardiac arrest, to which the high concentrations of antipsychotics may have contributed.
Conclusions
This case suggests caution in the aggressive treatment of mania with combinations of psychotropic drugs and highlight the need of further clinical studies in order to identify consequences of drug-drug interactions with medications doses within the accepted range.
Palatable food is a strong activator of the reward circuitry and may cause addictive behavior leading to eating disorders. How early life events and sex interact in shaping hedonic sensitivity to palatable food is largely unknown. We used prenatally restraint stressed (PRS) rats, which show abnormalities in the reward system and anxious/depressive-like behavior. Some of the hallmarks of PRS rats are known to be sex-dependent. We report that PRS enhanced and reduced milk chocolate-induced conditioned place preference in males and females, respectively. Male PRS rats also show increases in plasma dihydrotestosterone (DHT) levels and dopamine (DA) levels in the nucleus accumbens (NAc), and reductions in 5-hydroxytryptamine (5-HT) levels in the NAc and prefrontal cortex (PFC). In male rats, systemic treatment with the DHT-lowering drug finasteride reduced both milk chocolate preference and NAc DA levels. Female PRS rats showed lower plasma estradiol (E2 ) levels and lower DA levels in the NAc, and 5-HT levels in the NAc and PFC. E2 supplementation reversed the reduction in milk chocolate preference and PFC 5-HT levels. In the hypothalamus, PRS increased ERα and ERβ estrogen receptor and CARTP (cocaine-and-amphetamine receptor transcript peptide) mRNA levels in males, and 5-HT2 C receptor mRNA levels in females. Changes were corrected by treatments with finasteride and E2 , respectively. These new findings show that early life stress has a profound impact on hedonic sensitivity to high-palatable food via long-lasting changes in gonadal hormones. This paves the way to the development of hormonal strategies aimed at correcting abnormalities in the response to natural rewards.
© 2015 Society for the Study of Addiction.
