Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity.

As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11 C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11 C]Ro15-4513 total distribution volume (VT ) in the right hippocampus in the GD group compared with HV. We found higher levels of the 'Negative Urgency' construct of impulsivity in GD, and these were positively associated with higher [11 C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11 C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.

Nalmefene Reduces Reward Anticipation in Alcohol Dependence: An Experimental Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nalmefene is a µ and δ opioid receptor antagonist, κ opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol-dependent individuals with "high-risk drinking levels" to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level-dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge. METHODS: Twenty-two currently heavy-drinking, non-treatment-seeking alcohol-dependent males were recruited. The effect of single dose nalmefene (18 mg) on changes in a priori defined striatal region of interest BOLD signal change during reward anticipation compared with placebo was investigated using functional magnetic resonance imaging. Both conditions were performed under intravenous alcohol administration (6% vol/vol infusion to achieve a target level of 80 mg/dL). RESULTS: Datasets from 18 participants were available and showed that in the presence of the alcohol infusion, nalmefene significantly reduced the BOLD response in the striatal region of interest compared with placebo. Nalmefene did not alter brain perfusion. CONCLUSIONS: Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene's actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers.

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [(11)C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [(11)C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [(11)C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [(11)C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.

Biperiden (an M1 antagonist) reduces memory consolidation of cocaine-conditioned place preference.

It is well-known that cocaine dependence is a public health issue, and several studies stress the need to look for new and more effective treatments. Although the mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA) and projects to several forebrain structures, is known to be critically involved in the neurobiology of cocaine dependence, acetylcholine (ACh) has also been shown to play an important role in cocaine dependence via its action on this reward system. ACh is also important in the formation of hippocampal memory associated with appetitive behavior. Thus, the aim of this study was to evaluate the effect of biperiden, an ACh antagonist with high affinity for muscarinic M1 type receptors, on the acquisition of cocaine-conditioned place preference (CPP) in mice. The cocaine and biperiden were dissolved in sterile saline and were administered intraperitoneally at a dose of 10mg/kg. The conditioning regime was 8 days long, and the cholinergic antagonist was given immediately at the end of each conditioning session. The test for CPP occurred 24h after the last session. The results showed that animals treated with biperiden spent significantly less time in the cocaine-paired compartment than did the ones treated with saline. This finding represents a reduction in the consolidation of cocaine-induced CPP. One hypothesis that could explain this outcome focuses on the action of cholinergic antagonists on the consolidation of contextual memories. The amnesic effect of M1 antagonists on aversive tasks and on morphine CPP has been demonstrated when administered before the training or the conditioning session. The present study highlights the possibility of impairment in the acquisition of an appetitive memory, even when the cholinergic drug is administered after the conditioning session. This protocol also rejects the possibility of performance disturbance and suggests a possible pharmacological tool in the treatment of cocaine dependence.

Biperiden (M1 antagonist) impairs the expression of cocaine conditioned place preference but potentiates the expression of cocaine-induced behavioral sensitization.

Cocaine addiction is a public health issue in many countries, stressing the need for more effective treatments. As all drugs of abuse, cocaine acts on the brain reward system, increasing dopamine (DA) levels. Other neurotransmitters such as acetylcholine (ACh) are involved in the mechanisms underlying the development and the maintenance of cocaine addiction. ACh plays an important role in learning and memory processes and also regulates DA in some specific regions of the central nervous system. The present study investigated the effects of biperiden, a muscarinic cholinergic (mACh) antagonist in two animal models: conditioned place preference (CPP) and behavioral sensitization. Male C57BL/6J mice were used in both studies. The CPP protocol was unbiased and carried out in three phases: habituation, conditioning and testing. For conditioning, cocaine was injected at a dose of 10mg/kg in eight 15 min-sessions. The treatment with biperiden (doses of 0.1, 1 and 10 mg/kg) was made 30 min prior to the testing session. For behavioral sensitization development, cocaine was administered at the dose of 10 mg/kg for 10 days. After sensitization, two challenges were performed: saline and cocaine (5 mg/kg). Biperiden (10 mg/kg) was administered 30 min before the cocaine challenge. At the dose of 10 mg/kg, biperiden blocked the cocaine-CPP expression, suggesting an effect on conditioned memory retrieval. However, the same dose potentiated the expression of behavioral sensitization, suggesting an increase in DA release, probably in the NAc. Biperiden, as other mACh antagonists, may be a promising drug for the pharmacologic treatment of cocaine addiction.