Neural correlates of reward magnitude and delay during a probabilistic delay discounting task in alcohol use disorder Abstract Rationale Alcohol-use disorder (AUD) is associated with the propensity to choose smaller sooner options on the delay discounting task. It is unclear, however, how inherent risk underlies delay discounting behavior. As impulsive choice is a hallmark feature in AUD, it is important to understand the neural response to reward and delay while accounting for risk in impulsive decision-making. Objective This study examined activation associated with delay and reward magnitude, while controlling for risk in a probabilistic delay discounting task in AUD and examined if differences in activation were associated with treatment outcomes. Methods Thirty-nine recently abstinent alcohol-dependent volunteers and 46 controls completed a probabilistic delay discounting task paired with functional magnetic resonance imaging. Alcohol use was collected using a self-report journal for 3 months following baseline scan. Results During delay stimulus presentations, Controls exhibited greater activation compared to the Alcohol group notably in the anterior insula, middle/dorsal anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (PFC), and inferior parietal lobule. For magnitude, the Alcohol group exhibited greater activation than Controls primarily in medial PFC, rostral ACC, left posterior parietal cortex, and right precuneus. Within the Alcohol group, alcohol craving severity negatively correlated with right lateral PFC activation during reward magnitude in individuals who completed the 3-month study without relapse, while non-completers showed the opposite relationship. Conclusions The results of this study extend previous findings that alcohol use disorder is associated with differences in activation during an immediate or delayed choice by delineating activation associated with the parameters of impulsive choice.

The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice Abstract Rationale Cocaine is a psychostimulant drug that facilitates monoaminergic neurotransmission. The endocannabinoid system, comprising the cannabinoid receptors (CB1R and CB2R), the endocannabinoids, and their metabolizing-enzymes, modulates the mesolimbic dopaminergic pathway and represents a potential target for the treatment of addiction. Objectives Here, we tested the hypothesis that the cannabinoid receptors are implicated in cocaine-induced motor sensitization, conditioned place preference (CPP), and hippocampal activation. Methods Male Swiss mice received injections of AM251 (CB1R antagonist; 0.3–10 mg/kg) or JWH133 (CB2R agonist; 1–10 mg/kg) before acquisition or expression of cocaine (20 mg/kg)-induced sensitization and CPP. After the CPP test, cFos-staining was employed as a marker of neuronal activation in the hippocampus. Results AM251 inhibited the acquisition (0.3, 1, and 3 mg/kg) and expression (1 and 3 mg/kg) of sensitization, as well as the acquisition (10 mg/kg) of CPP. JWH133 inhibited the acquisition (0.3 and 1 mg/kg) and expression (1 and 3 mg/kg) of both sensitization and CPP. JWH133 effects were reversed by AM630 (CB2R antagonist; 5 mg/kg). AM251 and JWH133 also prevented neuronal activation (c-Fos expression) in the hippocampus of CPP-exposed animals. Conclusions CB1R and CB2R have opposite roles in modulating cocaine-induced sensitization and CPP, possibly by preventing neuronal activation in the hippocampus.

The effects of alcohol on sequential decision-making biases during gambling Abstract Rationale Gambling and alcohol use are recreational behaviours that share substantial commonalities at a phenomenological, clinical and neurobiological level. Past studies have shown that alcohol can have a disinhibiting effect on gambling behaviour, in terms of bet size and persistence. Objectives This study was conducted in order to characterise how alcohol affects biases in judgment and decision-making that occur during gambling, with a focus on sequential decision-making including the gambler’s fallacy. Methods Sequential biases were elicited via a roulette-based gambling task. Using a standard between-groups alcohol challenge procedure, male participants played the roulette task 20 min after receiving an alcoholic (0.8 g/kg; n = 22) or placebo (n = 16) beverage. The task measured colour choice decisions (red/black) and bet size, in response to varying lengths of colour runs and winning/losing feedback streaks. Results Across both groups, a number of established sequential biases were observed. On colour choice, there was an effect of run length in line with the gambler’s fallacy, which further varied by previous feedback (wins vs losses). Bet size increased with feedback streaks, especially for losing streaks. Compared to placebo, the alcohol group placed higher bets following losses compared to wins. Conclusions Increased bet size after losses following alcohol consumption may reflect increased loss chasing that may amplify gambling harms. Our results do not fit a simple pattern of enhanced gambling distortions or reward sensitivity, but help contextualise the effects of alcohol on gambling to research on decision-making biases.

PSPH-D-18-00526: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence Abstract Rationale Sleep difficulties are one of the problems associated with adolescent binge drinking. However, the mechanisms underlying adolescent alcohol-associated sleep disturbances and potential targets for therapy remain under investigated. Orexin receptor antagonists may have therapeutic value in the treatment of insomnia, yet the use of this class of drugs in the treatment of sleep disturbances following adolescent alcohol exposure has not been studied. Objectives This study employed a model whereby ethanol vapor exposure occurred for 5 weeks during adolescence (AIE), and waking event-related oscillations (EROs) and EEG sleep were subsequently evaluated in young adult rats. The ability of two doses (10, 30 mg/kg PO) of a dual orexin receptor antagonist (DORA-12) to modify sleep, EEG, and EROs was investigated in AIE rats and controls. Results Adolescent vapor exposure was found to produce a fragmentation of sleep, in young adults, that was partially ameliorated by DORA-12. DORA-12 also produced increases in delta and theta power in waking EROs recorded before sleep, and deeper sleep as indexed by increases in delta and theta power in the sleep EEG in both ethanol and control rats. Rats given DORA-12 also fell asleep faster than vehicle-treated rats as measured by a dose-dependent reduction in the latency to both the first slow wave and REM sleep episodes. Conclusions This study showed that DORA-12 can affect the sleep disturbance that is associated with a history of adolescent ethanol exposure and also has several other sleep-promoting effects that are equivalent in both ethanol and control rats.

Correction to: Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson’s disease After publication of this paper, the authors determined that the “Acknowledgments” section was omitted. Below is the “Acknowledgments” statement.

Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning Abstract Rationale Several findings indicate that early-life dysfunction of N-methyl-d-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. Objectives In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). Methods Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. Results The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. Conclusions The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.

mGlu5 in GABAergic neurons modulates spontaneous and psychostimulant-induced locomotor activity Abstract Rationale A role of group I metabotropic glutamate receptor 5 (mGlu5) in regulating spontaneous locomotion and psychostimulant-induced hyperactivity has been proposed. Objectives This study aims to determine if mGlu5 in GABAergic neurons regulates spontaneous or psychostimulant-induced locomotion. Methods We generated mice specifically lacking mGlu5 in forebrain GABAergic neuron by crossing DLX-Cre mice with mGlu5flox/flox mice to generate DLX-mGlu5 KO mice. The locomotion of adult mice was examined in the open-field assay (OFA) and home cage setting. The effects of the mGlu5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP), cocaine, and methylphenidate on acute motor behaviors in DLX-mGlu5 KO and littermate control mice were assessed in OFA. Striatal synaptic plasticity of these mice was examined with field potential electrophysiological recordings. Results Deleting mGlu5 from forebrain GABAergic neurons results in failure to induce long-term depression (LTD) in the dorsal striatum and absence of habituated locomotion in both novel and familiar settings. In a familiar environment (home cage), DLX-mGlu5 KO mice were hyperactive. In the OFA, DLX-mGlu5 KO mice exhibited initial hypo-activity, and then gradually increased their locomotion with time, resulting in no habituation response. DLX-mGlu5 KO mice exhibited almost no locomotor response to MPEP (40 mg/kg), while the same dose elicited hyperlocomotion in control mice. The DLX-mGlu5 KO mice also showed reduced hyperactivity response to cocaine, while they retained normal hyperactivity response to methylphenidate, albeit with delayed onset. Conclusion mGlu5 in forebrain GABAergic neurons is critical to trigger habituation upon the initiation of locomotion as well as to mediate MPEP-induced hyperlocomotion and modulate psychostimulant-induced hyperactivity.

Sex differences in the acute effects of smoked cannabis: evidence from a human laboratory study of young adults Abstract Rationale Animal studies have found robust sex differences in the pharmacokinetics and pharmacodynamics of Δ9-tetrahydrocannabinol (THC). However, the human evidence remains equivocal, despite findings that women may experience more severe consequences of cannabis use than men. Objectives The objective of this secondary analysis was to examine sex differences in THC pharmacokinetics and in acute subjective, physiological, and cognitive effects of smoked cannabis in a sample of regular cannabis users (use 1–4 days per week) aged 19–25 years. Methods Ninety-one healthy young adults were randomized to receive active (12.5% THC; 17 females, 43 males) or placebo (< 0.1% THC; 9 females, 21 males) cannabis using a 2:1 allocation ratio. Blood samples to quantify concentrations of THC, 11-OH-THC, and 11-Nor-carboxy-THC (THC-COOH), as well as measures of subjective drug effects, vital signs, and cognition were collected over a period of 6 h following ad libitum smoking of a 750-mg cannabis cigarette. Results Females smoked less of the cannabis cigarette than males (p = 0.008) and had a lower peak concentration of THC and THC-COOH than males (p ≤ 0.01). Blood THC concentrations remained lower in females even when adjusting for differences in estimated dose of THC inhaled. There was very little evidence of sex differences in visual analog scale (VAS) ratings of subjective drug effects, mood, heart rate, blood pressure, or cognitive effects of cannabis. Conclusions Females experienced the same acute effects of smoked cannabis as males at a lower observed dose, highlighting the need for more research on sex differences in the pharmacology of THC, especially when administered by routes in which titrating to the desired effect is more difficult (e.g., cannabis edibles).

Effects of the monoamine stabilizer (-)OSU6162 on cognitive function in alcohol dependence Abstract Introduction Alcohol dependence (AD) is associated with a dysregulated mesolimbocortical dopamine system—a pathway which is also implicated in both reward and cognition. The monoamine stabilizer (-)-OSU6162 (OSU) is a novel pharmacological compound with the ability to reduce ethanol intake and ethanol seeking in long-term drinking rats as well as reducing alcohol craving in AD patients. Dopaminergic drugs can both impair and improve cognitive functions, and the aim of the current study was to investigate the effect of OSU treatment on cognitive functioning in AD patients. Method In a randomized double-blind placebo-controlled study, 56 individuals with AD received 14 days of OSU or placebo treatment. Neuropsychological tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB®) and other tasks were used to evaluate treatment effect on executive function/impulsivity, working memory, attention, emotional recognition, and divergent thinking. Results Treatment with OSU did not impair neuropsychological function in any of the cognitive domains investigated (all p > 0.1). In fact, OSU treatment did, compared to placebo, improve future planning ability (F(1,46) = 6.9; p = 0.012; Cohen’s d = 0.54), verbal divergent thinking (F(1,44) = 10.1; p = 0.003; d = 0.96), and response time for emotional recognition (F(1,47) = 6.7; p = 0.013; d = 0.44). Conclusion OSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings.

Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole Abstract Rationale Changing antipsychotics of patients with chronic schizophrenia involves several risks. Switching to aripiprazole is especially difficult. We investigated switching methods and related factors for successful switching patients with chronic schizophrenia to aripiprazole. Objectives This study was a multi-center historical cohort study and approved by the research ethics committee of Okayama University Hospital and Okayama Psychiatric Medical Center. We compared survival proportions of 178 chronic schizophrenia patients who continued aripiprazole monotherapy for 6 months after non-direct switching (add-on switching (n = 45), cross switching (n = 62)) or direct switching (n = 71). We adjusted possible confounders using a Cox proportional hazards model. Results Of patients with chronic schizophrenia, 56.7% (101/178) were switched to aripiprazole monotherapy, and 55.0% (98/178) showed improvement in symptoms as demonstrated by the Clinical Global Impression Severity score. Kaplan-Meier survival curves showed that non-direct switching had a higher survival proportion than direct switching (log-rank test, p = 0.012). Even after adjusting for several variables using a Cox proportional hazards model, add-on switching had a significantly lower hazard at 6 months than direct switching (hazard ratio 0.42, 95% confidence interval 0.21–0.82, P = 0.01). In cases of switching to aripiprazole for psychiatric symptoms, non-direct switching had a lower hazard than direct switching (hazard ratio 0.41, 95% confidence interval 0.21–0.81, P = 0.01) but was not significant for adverse reaction. When aripiprazole was switched from olanzapine, add-on switch showed the lowest hazard ratio for continuation (hazard ratio 0.29, 95% confidence interval 0.07–1.11, P = 0.07). Conclusions Flexibility in strategies when switching to aripiprazole may induce a better outcome for patients with chronic schizophrenia.