Disrupted parahippocampal and midbrain function underlie slower verbal learning in adolescent-onset regular cannabis use Abstract Rationale Prolonged use of cannabis, the most widely used illicit drug worldwide, has been consistently associated with impairment in memory and verbal learning. Although the neurophysiological underpinnings of these impairments have been investigated previously using functional magnetic resonance imaging (fMRI), while performing memory tasks, the results of these studies have been inconsistent and no clear picture has emerged yet. Furthermore, no previous studies have investigated trial-by-trial learning. Objectives We aimed to investigate the neural underpinnings of impaired verbal learning in cannabis users as estimated over repeated learning trials. Methods We studied 21 adolescent-onset regular cannabis users and 21 non-users using fMRI performed at least 12 h after last cannabis use, while they performed a paired associate verbal learning task that allowed us to examine trial-by-trial learning. Brain activation during repeated verbal encoding and recall conditions of the task was indexed using the blood oxygen level-dependent haemodynamic response fMRI signal. Results There was a significant improvement in recall score over repeated trials indicating learning occurring across the two groups of participants. However, learning was significantly slower in cannabis users compared to non-users (p = 0.032, partial eta-squared = 0.108). While learning verbal stimuli over repeated encoding blocks, non-users displayed progressive increase in recruitment of the midbrain, parahippocampal gyrus and thalamus (p = 0.00939, partial eta-squared = 0.180). In contrast, cannabis users displayed a greater but disrupted activation pattern in these regions, which showed a stronger correlation with new word-pairs learnt over the same blocks in cannabis users than in non-users. Conclusions These results suggest that disrupted medial temporal and midbrain function underlie slower learning in adolescent-onset cannabis users.

The effects of nicotinamide on reinstatement to cocaine seeking in male and female Sprague Dawley rats Abstract Rationale Interventions for psychostimulant use disorders are of significant need. Nicotinamide (NAM) is a small molecule that can oppose cellular adaptations observed following cocaine exposure in the rodent self-administration and reinstatement model of addiction. In addition, utility of NAM against symptoms of withdrawal and vulnerability to relapse to cocaine use has been suggested by case studies and anecdotal reports. However, the empirical effects of NAM on drug-seeking behaviors have not been examined. Objective The objective of the current study was to investigate the effects of systemic NAM administration on reinstatement to cocaine seeking, using the rat self-administration/extinction/reinstatement model of cocaine addiction. Methods Male and female Sprague Dawley rats were trained to self-administer i.v. cocaine or food pellets for 2 hrs per day for 12 days, followed by 14–17 days of extinction, during which i.p. NAM injections (0–120 mg/kg) were given 30 minutes prior to each extinction or reinstatement session. Rats were tested on cue-, cocaine-, or food-primed reinstatement, as well as locomotor activity. Results Chronic NAM administered throughout extinction dose dependently attenuated cue-primed reinstatement in male rats, but not female rats. In contrast, acute NAM given once prior to reinstatement had no effect on reinstatement. Chronic NAM had no effect on locomotor activity or reinstatement to food seeking. Conclusions The specificity of NAM against cue-primed reinstatement indicates that NAM may influence responsiveness to drug-associated cues, specifically in males. Future studies will examine the mechanism(s) by which NAM may exert this effect.

A role for leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction Abstract Rational Caloric restriction increases the risk of relapse in abstinent drug users. Hormones involved in the regulation of energy balance and food intake, such as leptin and ghrelin, are implicated in drug-related behaviors. Objectives We investigated the role of leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. Methods Rats self-administered heroin (0.1 mg/kg/infusion) for 10 days followed by 14 days of drug withdrawal. During withdrawal, rats were food restricted to 90% of their original body weight or were given free access to food. In experiment 1, we measured the plasma concentrations of leptin and ghrelin following heroin self-administration and withdrawal. In experiment 2, leptin was administered centrally (2.0 or 4.0 μg; i.c.v.) prior to a heroin-seeking test under extinction conditions. High density of both leptin and ghrelin receptors was previously identified in the ventral tegmental area (VTA), suggesting a direct effect on reward and motivation. Hence, we administered leptin (experiment 3; 0.125 or 0.250 μg/side), or ghrelin receptor antagonist JMV 2959 (experiment 4; 2.0 or 10.0 μg/side) directly into the VTA prior to the heroin-seeking test. Results Chronic food restriction significantly decreased plasma levels of leptin and elevated plasma levels of ghrelin. Central administration of leptin had no statistically significant effect on heroin seeking. Intra-VTA administration of either leptin or JMV 2959 dose-dependently and selectively decreased heroin seeking in the food-restricted rats. Conclusions Leptin and ghrelin transmission in the VTA can modulate the augmentation of heroin seeking induced by chronic food restriction.

The protective effect of Geniposide on diabetic cognitive impairment through BTK/TLR4/NF-κB pathway Abstract The purpose of the present study was to elucidate the pharmacological effects of Geniposide (GEN) on high diet fed and streptozotocin (STZ)-caused diabetic cognitive impairment. The mice were fed with high fat diet (HFD) for 4 weeks and intraperitoneally injected with 60 mg/kg STZ for three times within 72 h. The mice with glucose level over 15 mmol/l were regarded as diabetic and selected for further studies. The animals were intragastrically treated with metformin or GEN once daily for 4 weeks. Afterwards, the animals were applied for Y maze, novel object recognition (NOR) test, step-through passive avoidance test, and Morris water maze (MWM) test. The blood glucose and body weight were examined. The SH-SY5Y cells were treated with GEN in the presence or absence of ibrutinib and stimulated with high-glucose culture medium. The tumor necrosis factor-a (TNF-α) and interleukin (IL)-6 in serum, hippocampus, and supernatant were measured using ELISA method. The protein expressions of Bruton’s tyrosine kinase (BTK), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), nuclear factor kappa-B (NF-κB), p-NF-κB, brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), p-CREB, and glucagon-like peptide-1 receptor (GLP-1R) were detected by western blot analyses. As a result, the GEN treatment notably attenuated the body weight, blood glucose, and cognitive decline. GEN also inhibited the generations of inflammatory cytokines. Furthermore, the administrations of GEN ameliorated the alterations of BTK, TLR4, MyD88, NF-κB, and BDNF in HFD + STZ–induced mice. With the application of ibrutinib, the selective inhibitor of BTK, it was also found that BTK/TLR4/NF-κB pathway was associated with the GEN treatment in high glucose–induced SH-SY5Y cells. In summary, the results suggested that GEN exerted the protective effect on STZ-induced cognitive impairment possibly through the modulation of BTK/TLR4/NF-κB signaling.

Varenicline for cognitive impairment in people with schizophrenia: systematic review and meta-analysis Abstract Background People with schizophrenia frequently have cognitive dysfunction, which does not respond to pharmacological interventions. Varenicline has been identified as a potential treatment option for nicotinic receptor dysfunction with a potential to treat cognitive impairment in schizophrenia. Methods We conducted a systematic review of Pubmed, Embase, Psycinfo, CINAHL and the Cochrane Schizophrenia Trial Registry for randomised controlled trials of varenicline in people with schizophrenia for cognitive dysfunction. We excluded trials among people with dementia. We then undertook a meta-analysis with the primary outcome of difference in change of cognitive measures between varenicline and placebo as well as secondary outcomes of difference in rates of adverse events. We conducted a sensitivity analysis on smoking status and study duration. Results We included four papers in the meta-analysis (n = 339). Varenicline was not superior to placebo for overall cognition (SMD = −0.022, 95% CI −0.154–0.110; Z = −0.333; p = 0.739), attention (SMD = −0.047, 95% CI −0.199–0.104; Z = −0.613; p = 0.540), executive function (SMD = −0.060, 95% CI −0.469–0.348; Z =− 0.290; p = 0.772) or processing speed (SMD = 0.038, 95% CI −0.232–0.308; Z = 0.279; p = 0.780). There was no difference in psychotic symptoms, but varenicline was associated with higher rates of nausea. Sensitivity analyses for smoking status and study duration did not alter the results. Conclusion Within the present literature, varenicline does not appear to be a useful target compound for improving cognitive impairment in schizophrenia. Based on these results, a trial would need over 2500 participants to be powered to show statistically significant findings.

The influence of gender and oxytocin on stress reactivity, cigarette craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm Abstract Rationale Female cigarette smokers tend to show greater cessation failure compared with males. Variables that contribute to the maintenance of smoking, including stress and craving, may differentially impact male and female smokers. Novel pharmacotherapies, such as oxytocin, may attenuate stress reactivity and craving in smokers, but work in this area is limited. Objectives This study assessed the influence of gender and oxytocin on stress reactivity, craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm. Methods Male and female adult cigarette smokers (ages 18–45) were enrolled (women oversampled 2:1) and completed a laboratory session, in which intranasal oxytocin or placebo was administered followed by a laboratory social stress task. The role of gender and oxytocin were assessed on measures of stress reactivity, cigarette craving, latency to smoke in a resistance task, subjective responses to smoking, and ad-libitum smoking. Results Participants (N = 144) had a mean age of 31 were 63% female and 56% White. Following stress induction, female smokers evidenced greater subjective stress than males, though males demonstrated greater neuroendocrine reactivity and smoking intensity than females. No gender differences were demonstrated for craving. Oxytocin did not attenuate any aspect of stress reactivity, craving, smoking, or subjective responses to smoking compared with placebo. Conclusions Gender differences in stress reactivity were shown in the hypothesized direction, but oxytocin appeared to exert little impact on subjective or behavioral metrics. Results highlight the complex relationship between gender, stress, and smoking, as well as the implications for oxytocin as a potential pharmacotherapy for smoking cessation.

Psychopharmacology in its 60th year

Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice Abstract Rationale Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD. Objective To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol. Methods The effects of DOI were examined using ethanol-induced place conditioning (1.8 g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3 mg/kg) that produced the maximal response in the serotonin 2A (5-HT2A) receptor-dependent head-twitch assay. Interactions between DOI and ethanol (3 g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation. Results DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT2A receptors, was selective for alcohol over water, and was selective for high alcohol-preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release. Conclusions Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.

Effects of cocaine base paste on anxiety-like behavior and immediate-early gene expression in nucleus accumbens and medial prefrontal cortex of female mice Abstract Rationale Cocaine base paste (CBP) is an illegal drug of abuse usually consumed by adolescents in a socio-economically vulnerable situation. Repeated drug use targets key brain circuits disrupting the processes that underlie emotions and cognition. At the basis of such neuroadaptations lie changes in the expression of immediate-early genes (IEGs). Nevertheless, changes in transcriptional regulation associated with CBP consumption remain unknown. Objectives We aimed to describe behavioral phenotype related to locomotion, anxiety-like behavior, and memory of CBP-injected mice and to study IEGs expression after an abstinence period. Methods Five-week-old female CF-1 mice were i.p. injected daily with vehicle or CBP (40 mg/kg) for 10 days and subjected to a 10-day period of abstinence. Open field and novel object recognition tests were used to evaluate locomotion and anxiety-like behaviors and recognition memory, respectively, during chronic administration and after abstinence. After abstinence, prefrontal cortex (mPFC) and nucleus accumbens (NAc) were isolated and gene expression analysis performed through real-time PCR. Results We found an increase in locomotion and anxiety-like behavior during CBP administration and after the abstinence period. Furthermore, the CBP group showed impaired recognition memory after abstinence. Egr1, FosB, ΔFosB, Arc, Bdnf, and TrkB expression was upregulated in CBP-injected mice in NAc and FosB, ΔFosB, Arc, and Npas4 expression was downregulated in mPFC. We generated an anxiety score and found positive and negative correlations with IEGs expression in NAc and mPFC, respectively. Conclusion Our results suggest that chronic CBP exposure induced alterations in anxiety-like behavior and recognition memory. These changes were accompanied by altered IEGs expression.

Acute alcohol exposure dose-dependently alleviates social avoidance in adolescent mice and inhibits social investigation in adult mice Abstract Background Motivations for alcohol consumption often focus on ethanol’s purported prosocial effects: social enhancement and reduction of socially focused anxiety. Despite substantial research supporting prosocial effects, contrary research exists demonstrating alcohol-elicited antisocial and asocial behaviours. Additionally, evidence typically fails to delineate whether alcohol-induced prosocial effects are due to alcohol expectancies or pharmacological actions of ethanol. Studies exploring ethanol’s pharmacological effects on social behaviour and factors that modulate apparent contradictory prosocial versus asocial effects are lacking. Objectives This study investigated whether factors of age, ethanol dose and social fear modulate ethanol-induced pharmacological effects on sociability and social anxiety–like avoidance. Methods Experiments examined the acute effects of ethanol doses (0, 0.25, 0.8, 1.6 g/kg; i.p.) in adult (10-week-old) and adolescent (PND 31–33) C57BL/6J male mice on social interaction using a social fear conditioning paradigm. Control experiments assessed whether ethanol-induced effects were social-specific. Results In adult mice, no specific effects of ethanol on social avoidance were observed at any dose. However, high-dose ethanol (1.6 g/kg) suppressed social approach in all adult mice. In contrast, low-dose ethanol (0.25 g/kg) alleviated social avoidance in adolescent mice and no social suppression was observed at higher ethanol doses. Thus, higher doses of ethanol impair social behaviour in adult mice, whereas lower doses specifically alleviate social anxiety–like avoidance in adolescent mice. Conclusions Age, dose and social fear are critical modulators of acute ethanol-induced pharmacological effects on social behaviour. Inconsistencies in ethanol-induced social consequences appear at least partly mediated by pharmacological interactions—not solely alcohol expectancies.