Figure - available from: Molecular Neurobiology
This content is subject to copyright. Terms and conditions apply.
Effect of artificial low-frequency ultrasound on anxiety-like behavior and ultrasonic vocalizations. a Ultrasound waves recorded from the artificial low-frequency ultrasound (ALFUS) generator (left). The generator was installed 140 cm over center of elevated plus maze (right). b–d Effect of ALFUS in elevated plus maze test. Representative activity traces from naïve (Con) and ALFUS-treated rats (ALFUS; b). Effect of ALFUS on the percentage of time spent in open arms of the maze (c). ALFUS significantly decreased time spent in the open arms, compared to control group (ALFUS vs. Con; *p = 0.003, n = 5/group). Effect of ALFUS on total distance traveled (d). e, f Effect of ALFUS on 22-kHz ultrasonic vocalizations (USVs). e Schematic for USVs recordings (left) and representative examples of 22 kHz USVs (right). f The numbers of USVs before (Pre) and after 30-s stimulation of ALFUS (Post-ALFUS, n = 6). Pre vs. Post-ALFUS, *p = 0.001
Source publication
Although previous studies have suggested an association between unpleasant sounds and the use of drugs, scientific evidence supporting this is lacking. This study investigated in rats (male Sprague-Dawley rats) if aversive sounds modulate dopamine (DA) transmission in the mesolimbic reward system and cocaine reinforcement. For sound stimulation, we...
Citations
... Cocaine self-administration, extinction, and reinstatement procedures. Food training and cocaine self-administration were performed in operant chambers equipped with active and inactive levers (Med Associates), as described previously with slight modifications (Chang et al., 2019). Initially, rats were food restricted with 16 g of lab chow per day and trained to press the active lever to gain 45 mg food pellets (Bio-Serve). ...
... Activation of non-nociceptive cervical spine mechanoreceptors with a vibrational stimulus for 1-2 min inhibits the firing of VTA GABA neurons for min and DA release for hours (Bills et al., 2020). Furthermore, we and others have shown that somatosensory stimuli reduce drug-induced craving behaviors through modulating the mesolimbic DA systems in rats (Yang et al., 2010;Chang et al., 2019). Application of acupuncture, widely accepted as a form of peripheral sensory stimulation (Andersson and Lundeberg, 1995), decreases DA release in the NAc by activating GABA interneurons in the VTA and thus suppresses addictionrelated behaviors caused by drugs such as cocaine, morphine, and ethanol (Yang et al., 2010;Chang et al., 2019). ...
... Furthermore, we and others have shown that somatosensory stimuli reduce drug-induced craving behaviors through modulating the mesolimbic DA systems in rats (Yang et al., 2010;Chang et al., 2019). Application of acupuncture, widely accepted as a form of peripheral sensory stimulation (Andersson and Lundeberg, 1995), decreases DA release in the NAc by activating GABA interneurons in the VTA and thus suppresses addictionrelated behaviors caused by drugs such as cocaine, morphine, and ethanol (Yang et al., 2010;Chang et al., 2019). How the somatosensory stimulation affects mesolimbic DA systems is largely unknown. ...
Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here we show that the LH-LHb pathway is necessary for nociceptive modulation of this system using male Sprague-Dawley rats. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail-pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail-pinch increased activity of GABA neurons in ventral tegmental area (VTA), decreased extracellular DA level in the nucleus accumbens ventrolateral shell in intact rats and reduced cocaine-increased DA concentration, which was blocked by disruption of the LH. Furthermore, tail-pinch attenuated cocaine-induced locomotor activity, 22- and 50-kHz ultrasonic vocalizations, and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement.SIGNIFICANCE STATEMENT:The lateral habenula (LHb) and the lateral hypothalamus (LH) have been implicated in processing nociceptive signals and modulating dopamine (DA) release in the mesolimbic DA system. Here we show that the LH-LHb pathway is critical for nociception-induced modulation of mesolimbic DA release and cocaine reinstatement. Nociceptive stimulation alleviates extracellular DA release in the mesolimbic DA system, cocaine-induced psychomotor activities, and reinstatement of cocaine-seeking behaviors through the LH-LHb pathway. These findings provide novel evidence for sensory modulation of mesolimbic DA system and drug addiction.
... However, stressor effects on neuronal firing in VTA are not uniform and firing patterns and downstream dopamine release can vary according to output pathway. Whereas stressors reliably produce robust activation of VTA neurons that project to the PFC [124][125][126][127], effects on NAc dopamine are more complex (see [128] for review) with reports of increases, reductions, or no effect, depending on the NAc subregion, stressor, context, and timeframe [116,[129][130][131][132][133][134][135][136][137][138]. ...
The neuropeptide, corticotropin releasing factor (CRF), has been an enigmatic target for the development of medications aimed at treating stress-related disorders. Despite a large body of evidence from preclinical studies in rodents demonstrating that CRF receptor antagonists prevent stressor-induced drug seeking, medications targeting the CRF-R1 have failed in clinical trials. Here, we provide an overview of the abundant findings from preclinical rodent studies suggesting that CRF signaling is involved in stressor-induced relapse. The scientific literature that has defined the receptors, mechanisms and neurocircuits through which CRF contributes to stressor-induced reinstatement of drug seeking following self-administration and conditioned place preference in rodents is reviewed. Evidence that CRF signaling is recruited with repeated drug use in a manner that heightens susceptibility to stressor-induced drug seeking in rodents is presented. Factors that may determine the influence of CRF signaling in substance use disorders, including developmental windows, biological sex, and genetics are examined. Finally, we discuss the translational failure of medications targeting CRF signaling as interventions for substance use disorders and other stress-related conditions. We conclude that new perspectives and research directions are needed to unravel the mysterious role of CRF in substance use disorders.
... Adult rats emit USVs in two main ranges that are thought to correspond roughly to negative and positive emotional or anticipatory states [2,4,12,13]: Lower-frequency USVs (LF; 18-30 kHz; also called "22 kHz" vocalizations) are linked to stress and fear states [14][15][16][17][18][19]; higher-frequency USVs are linked instead to reward anticipation or experience [6][7][8][20][21][22][23]. LF vocalizations are generally not frequency-modulated, and can occur with short or long durations, potentially reflecting the intensity of negative effects [24][25][26]. In contrast, high-frequency USVs (also called "50 kHz" vocalizations), are more complex, with at least 14 distinct patterns [27]. ...
Adult rats emit ultrasonic vocalizations (USVs) related to their affective states, potentially providing information about their subjective experiences during behavioral neuroscience experiments. If so, USVs might provide an important link between invasive animal preclinical studies and human studies in which subjective states can be readily queried. Here, we induced USVs in male and female Long Evans rats using acute amphetamine (2 mg/kg), and asked how reversibly inhibiting nucleus accumbens neurons using designer receptors exclusively activated by designer drugs (DREADDs) impacts USV production. We analyzed USV characteristics using “Deepsqueak” software, and manually categorized detected calls into four previously defined subtypes. We found that systemic administration of the DREADD agonist clozapine-n-oxide, relative to vehicle in the same rats, suppressed the number of frequency-modulated and trill-containing USVs without impacting high frequency, unmodulated (flat) USVs, nor the small number of low-frequency USVs observed. Using chemogenetics, these results thus confirm that nucleus accumbens neurons are essential for production of amphetamine-induced frequency-modulated USVs. They also support the premise of further investigating the characteristics and subcategories of these calls as a window into the subjective effects of neural manipulations, with potential future clinical applications.
... Dopamine plays a crucial role in regulating behavior and emotions, and dopamine alteration lead to abnormal behaviors such as impulsivity and hyperactivity (Nieoullon and Coquerel, 2003;Strafella, 2019). Dysregulation of dopamine neurotransmission in dorsal striatal dopamine system is associated with the processing of negative human emotions (Badgaiyan, 2010;Chang et al., 2019). Persistent and developmental Pb exposure induces depressive behavior both in rats and children (Sciarillo et al., 1992;de Souza et al., 2005;Liu et al., 2014a,b). ...
As a neurotoxicant, lead (Pb) primarily affects central nervous system, and particularly impacts developing brain. This study explores the associations of blood Pb level and children’s behavioral health. A total of 213 preschool children aged 3 to 7 years old were recruited from Guiyu (the e-waste-exposed area) and Haojiang (the reference area). The behavioral health of children was assessed using the ‘behavioral symptoms’ subscale of the Strengths and Difficulties Questionnaire (SDQ). Results showed that there was a significant difference in percent of children categorized as "at risk" between Guiyu (48.2%) and Haojiang (13.9%) (p < 0.001). The blood Pb level of children in Guiyu was significantly higher than those in Haojiang (median: 5.19 μg/dL vs. 3.42 μg/dL, p < 0.001). The serum Neuropeptide Y (NPY) was significantly lower in Guiyu children than those in Haojiang. Spearman correlation analyses demonstrated that blood Pb levels was negatively correlated with NPY (rs = -0.25, p < 0.001), but positively correlated with behavioral symptom scores; while serum NPY levels were negatively associated with behavioral symptom scores. Behavioral symptom scores were higher in children with blood Pb level ≥ 5.00 μg/dL (high) than those with blood Pb level < 5.00 μg/dL (low). After adjusting for confounding factors, children with lower NPY levels were at higher risk of having behavioral difficulties. In conclusion, Pb exposure in e-waste-exposed areas may lead to decrease in serum NPY and increase in the risk of children’s behavioral problems. In addition, NPY may mediate the association between Pb exposure and behavioral difficulties.
... Human models of addiction suggest that there is a hedonic shift from positive to negative affect as the disease progresses, in which negative affect comes to outweigh the initial positive affect sustained during the subjective drug "high" (Koob 1996;Volkow et al. 1997). Recent preclinical work demonstrated that negative emotionality in the form of 22-kHz calls (1) was associated with reinstated drug-seeking and decreased dopamine transmission in the nucleus accumbens (Chang et al. 2019) and (2) transiently increased cocaine SA upon playback of calls (Montanari et al. 2020). The present results provide further preclinical evidence that cocaine use disorder is characterized by a shift from positive to negative affect, with negative affect emerging as the more salient motivator of drug-taking behaviors. ...
RationaleThe role of negative affect as a motivational factor in animal models of drug addiction has been underexplored in the context of cocaine self-administration.Objectives
The present investigation studied the relationship between magnitude of affective response and quantity of cocaine consumed in order to clarify the affective components that drive drug use in a preclinical model.Methods
Rats self-administered (SA) cocaine 6 h/day for 14 consecutive days while their ultrasonic vocalizations (USVs) were recorded.ResultsAnimals displayed an increase in 50-kHz call rates (indicating positive affect) when their drug levels were rapidly rising and an increase in 22-kHz call rates (indicating negative affect) when forced to abstain. The rate of 50-kHz calls predicted drug consumption during the 1st week of SA, but not week two. Contrarily, there was a strongly predictive positive association between rate of 22-kHz calls and amount of drug consumed during the 2nd week of SA.Conclusions
Experimental results indicate that after chronic cocaine self-administration, negative affect emerges when animals are deprived of expected drug during withdrawal. Moreover, the increase in USVs indicating negative affect when deprived of drug was directly related to drug intake, concurrent with a decay in the direct relationship between USVs indicating positive affect and drug intake. The present preclinical support for the widely hypothesized shift from positive to negative affect as a salient motivational factor in human drug abuse adds to growing evidence of the unique value of rat USVs for understanding the role of emotion in drug addiction.
Invasive bioelectrodes are widely used as an effective treatment for several acute and chronic diseases. In earlier work using high surface area invasive porous bioelectrodes evaluated in an animal model of alcoholism withdrawal, we demonstrated significantly improved electrophysiological and behavioral responses. In this study, we further modify the surface of these invasive porous bioelectrodes with noble metal (Ag, Au, Pt) nanoparticles. Compared to both conventional and porous bioelectrodes, noble metal sensitized invasive porous bioelectrodes show markedly increased low threshold (LT) and wide dynamic range (WDR) neuronal activity. In particular, Pt-sensitized invasive porous bioelectrodes show the highest WDR neuronal activity only upon insertion. In addition, Ag-sensitized invasive porous bioelectrodes, whose surface area is about 37 times greater than that of conventional bioelectrodes, show improved electrochemical properties with higher LT and WDR neuronal activity when stimulated. In an animal model of chronic alcoholism, using normal and alcohol-treated Sprague-Dawley (SD) rats evaluated with the elevated plus maze (EPM) test, the Ag-sensitized invasive porous bioelectrodes show about 20% higher open arms time. These results suggest that these noble metal-sensitized invasive bioelectrodes may offer improved therapeutic outcomes for the treatment of chronic alcoholism, and given these enhanced electrophysiological properties, for other conditions as well.
