Selective 5HT3 antagonists and sensory processing: a systematic review.

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson's disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers: An FMRI study.

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and "value signals" where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain.

Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion.

Background: Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable effects users seek. Here, we investigate the effects of cannabis on listening to music, a rewarding activity that frequently occurs in the context of recreational cannabis use. We additionally tested how these effects are influenced by cannabidiol, which may offset cannabis-related harms. Methods: Across 3 sessions, 16 cannabis users inhaled cannabis with cannabidiol, cannabis without cannabidiol, and placebo. We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance Imaging within regions identified in a meta-analysis of music-evoked reward and emotion. All results were False Discovery Rate corrected (P<.05). Results: Compared with placebo, cannabis without cannabidiol dampened response to music in bilateral auditory cortex (right: P=.005, left: P=.008), right hippocampus/parahippocampal gyrus (P=.025), right amygdala (P=.025), and right ventral striatum (P=.033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings (P=.002) and increased functional connectivity with auditory cortex (right: P< .001, left: P< .001), supporting its involvement in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by cannabidiol (right: P=.003, left: P=.030), and cannabis with cannabidiol did not differ from placebo on any functional Magnetic Resonance Imaging measures. Both types of cannabis increased ratings of wanting to listen to music (P<.002) and enhanced sound perception (P<.001). Conclusions: Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were offset by a key cannabis constituent, cannabidol.