Development Of Psychomotor Sensitization Research Articles

Methamphetamine abstinence induces changes in μ-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype

The major challenge in treating methamphetamine addicts is the maintenance of a drug free-state since they experience negative emotional symptoms during abstinence, which may trigger relapse. The neuronal mechanisms underlying long-term withdrawal and relapse are currently not well-understood. There is evidence suggesting a role of the oxytocin (OTR), μ-opioid receptor (MOPr), dopamine D2 receptor (D2R), corticotropin-releasing factor (CRF) systems and the hypothalamic-pituitary-adrenal (HPA)-axis in the different stages of methamphetamine addiction. In this study, we aimed to characterize the behavioral effects of methamphetamine withdrawal in mice and to assess the modulation of the OTR, MOPr, D2R, CRF and HPA-axis following chronic methamphetamine administration and withdrawal. Ten-day methamphetamine administration (2 mg/kg) increased OTR binding in the amygdala, whilst 7 days of withdrawal induced an upregulation of this receptor in the lateral septum. Chronic methamphetamine treatment increased plasma OT levels that returned to control levels following withdrawal. In addition, methamphetamine administration and withdrawal increased striatal MOPr binding, as well as c-Fos+/CRF+ neuronal expression in the amygdala, whereas an increase in plasma corticosterone levels was observed following METH administration, but not withdrawal. No differences were observed in the D2R binding following METH administration and withdrawal. The alterations in the OTR, MOPr and CRF systems occurred concomitantly with the emergence of anxiety-related symptoms and the development of psychomotor sensitization during withdrawal. Collectively, our findings indicate that chronic methamphetamine use and abstinence can induce brain-region specific neuroadaptations of the OTR, MOPr and CRF systems, which may, at least, partly explain the withdrawal-related anxiogenic effects.

Pairing mild stress with increased serotonin‐1B receptor expression in the nucleus accumbens increases susceptibility to amphetamine

Both serotonin-1B (5-HT(1B)) receptors and stress modulate the behavioral and neurobiological effects of psychostimulant drugs. In order to examine how these factors interact to influence the development of behaviors associated with addiction, we used viral-mediated gene transfer to transiently increase expression of 5-HT(1B) receptors in the nucleus accumbens (NAc) shell along with exposure to repeated mild stress (novelty + saline injection) in rats. Once the viral-mediated increases in gene expression had dissipated, the resulting effects of this 5-HT(1B)/stress pairing on the acute locomotor response to amphetamine and on the development of psychomotor sensitization were examined. We report that the increasing expression of 5-HT(1B) receptors on the terminals of NAc shell neurons that project to the ventral tegmental area and repeatedly exposing rats to mild stress subsequently enhance the acute locomotor-activating effects of amphetamine. In addition, the development of psychomotor sensitization (both locomotor activity and stereotypy components) is facilitated. These results suggest that serotonin signaling through NAc 5-HT(1B) heteroreceptors can interact with stress to increase susceptibility to the enduring forms of drug-induced plasticity that are associated with addiction.

Effects of chronic nicotine administration and its withdrawal on striatal FosB/ΔFosB and c-Fos expression in rats and mice

ΔFosB, a member of Fos family of transcription factors, is implicated in behavioural responses and synaptic plasticity induced by abused drugs. We studied the expressions of FosB/ΔFosB and c-Fos immunohistochemically in two dopaminergic brain areas, nucleus accumbens (NAcc) and caudate-putamen (CPu). In mice neither 2- nor 7-week oral nicotine treatment induced expression of long-lived ΔFosB isoforms although during the treatment in the NAcc FosB/ΔFosB expression was increased as was c-Fos in the CPu. In rats given nicotine subcutaneously once daily for 5 days FosB/ΔFosB expression was elevated in the NAcc still after 24-h withdrawal suggesting accumulation of ΔFosB but in the CPu neither FosB/ΔFosB nor c-Fos expression was altered. Thus, in rats repeated nicotine administration seems mainly affect the NAcc paralleling with the evidence that nicotine stimulates preferentially mesolimbic dopamine system. Also, repeated nicotine induced behavioural sensitization in rats agreeing with suggested role of ΔFosB in the development of psychomotor sensitization. However, in mice given nicotine via drinking fluid although striatal fosB and c-fos were activated by nicotine even after 7-week treatment no evidence of accumulation of long-lived ΔFosB was found suggesting perhaps a species difference or more likely a role for the manner of administration.

Effects of the H 3-receptor inverse agonist thioperamide on the psychomotor effects induced by acutely and repeatedly given cocaine in C57BL/6J mice

Previous studies have shown that histamine H 3 blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H 3 receptor agonist, on the development of psychomotor sensitization and stereotyped activity induced by acute or intermittent cocaine in C57BL/6J mice. In the first experiment, mice were injected i.p. with saline, 10 or 20 mg/kg thioperamide and saline or 8 mg/kg cocaine, 10 min apart, before being tested for their locomotor activity (providing data on the acute effects of thioperamide on cocaine-induced activity). Subsequently, mice were treated in the same manner every other day over six additional sessions. Sensitization was assessed by the responsiveness to a cocaine challenge (8 mg/kg, i.p.) given 2 and 14 days following the intermittent treatment. In experiments 2 and 3, we tested the effects of thioperamide (10 or 20 mg/kg, i.p.) on gnawing and sniffing induced or affected by relatively high doses of cocaine (24 or 32 mg/kg, s.c.), the drugs being given 10 min apart. In the first experiment, both doses of thioperamide amplified cocaine-induced psychomotor hyperactivity almost on all experimental sessions. However, the histamine inverse agonist did not affect the induction of a psychomotor sensitization. All cocaine-treated mice showed similar levels of sensitized activity 2 and 14 days after the intermittent treatments, whether they received thioperamide or not. The second and the third experiments showed that thioperamide did not affect gnawing and sniffing induced by cocaine. Taken together, these results indicate that H 3 receptors clearly contribute to the neurobiological mechanisms of the locomotor component of cocaine-induced psychomotor activation, but less likely to those underlying the development of cocaine behavioral sensitization or the expression of cocaine-induced oro-facial stereotypies.