Psychopharmacology

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.

Modeling the effects of methylphenidate on interference and evidence accumulation processes using the conflict linear ballistic accumulator Abstract Rationale Although methylphenidate and other stimulants have been demonstrated to improve task performance across a variety of domains, a computationally rigorous account of how these drugs alter cognitive processing remains elusive. Recent applications of mathematical models of cognitive processing and electrophysiological methods to this question have suggested that stimulants improve the integrity of evidence accumulation processes for relevant choices, potentially through catecholaminergic modulation of neural signal-to-noise ratios. However, this nascent line of work has thus far been limited to simple perceptual tasks and has largely omitted more complex conflict paradigms that contain experimental manipulations of specific top-down interference resolution processes. Objectives and methods To address this gap, this study applied the conflict linear ballistic accumulator (LBA), a newly proposed model designed for conflict tasks, to data from healthy adults who performed the Multi-Source Interference Task (MSIT) after acute methylphenidate or placebo challenge. Results Model-based analyses revealed that methylphenidate improved performance by reducing individuals’ response thresholds and by enhancing evidence accumulation processes across all task conditions, either by improving the quality of evidence or by reducing variability in accumulation processes. In contrast, the drug did not reduce bottom-up interference or selectively facilitate top-down interference resolution processes probed by the experimental conflict manipulation. Conclusions Enhancement of evidence accumulation is a biologically plausible and task-general mechanism of stimulant effects on cognition. Moreover, the assumption that methylphenidate’s effects on behavior are only visible with complex executive tasks may be misguided.

Ethanol-induced changes in synaptic amino acid neurotransmitter levels in the nucleus accumbens of differentially sensitized mice Abstract Rationale Ethanol-induced behavioural sensitization (EBS) does not occur uniformly in mice exposed to the sensitization paradigm. This suggests innate differential responses to ethanol (EtOH) in the reward circuitry of individual animals. Objectives To better characterize the adaptive differences between low-sensitized (LS) and high-sensitized (HS) mice, we examined excitatory amino acid (EAA) and inhibitory amino acid (IAA) neurotransmitter levels in the nucleus accumbens (NAc) during EBS expression. Methods Male DBA/2J mice received five ethanol (EtOH) (2.2 g/kg) or saline injections, and locomotor activity (LMA) was assessed during EBS induction. EtOH mice were classified as LS or HS on the basis of final LMA scores. Following an EtOH challenge (1.8 g/kg) 2 weeks later, LMA was re-evaluated and in vivo microdialysis samples were collected from the NAc. Results Most differences in amino acid levels were observed within the first 20 min after EtOH challenge. LS mice exhibited similar glutamate levels compared with acutely treated (previously EtOH naïve) mice, and generally increased levels of the IAAs GABA, glycine, and taurine. By contrast, HS mice exhibited increased glutamate and attenuated levels of GABA, glycine, and taurine. Conclusion These data suggest that the profile of amino acid neurotransmitters in the NAc of LS and HS mice significantly differs. Elucidating these adaptive differences contributes to our understanding of factors that confer susceptibility/resilience to alcohol use disorder.

Impact of modulation of the α7 nicotinic acetylcholine receptor on nicotine reward in the mouse conditioned place preference test Abstract Rationale The α7 nicotinic acetylcholine receptor (nAChR) has been implicated as a target in modulating nicotine reward. However, the effect of pharmacological agents that have been shown to alter the channel properties of the α7 nAChR is not well understood in nicotine reward. Objectives This study aimed to investigate the impact of α7 nAChR pharmacological modulation on nicotine conditioned place preference (CPP) in mice by using positive allosteric modulators (PAMs) and a silent agonist. Methods The effect of the orthosteric α7 nAChR full agonist PNU282987 (1.3 and 9 mg/kg, s.c.), Type I α7 PAM NS1738 (1 and 10 mg/kg; i.p.), the Type II α7 PAM PNU120596 (0.3, 1, and 3 mg/kg, i.p.), and the α7 silent agonist NS6740 (1 and 3 mg/kg, i.p) on nicotine CPP was measured in mice. Mice were conditioned with either saline or nicotine (0.5 mg/kg) for 3 days in the CPP paradigm. Results The α7 full orthosteric agonist PNU282987 and the Type II α7 nAChR PAM PNU120596 reduced nicotine CPP, while the silent agonist NS6740 and Type I PAM NS1738 had no effect. The effects of PNU282987 and PNU120596 did not have an effect on morphine CPP. Conclusions Taken together, our results suggest that modulation of the α7 nAChR can play important roles in nicotine CPP in mice. In addition, the Type II α7 nAChR PAM PNU120596 attenuated nicotine reward suggesting that endogenous acetylcholine/choline tone is sufficient to reduce nicotine CPP. These findings highlight a beneficial effect of using α7 nAChR PAMs in nicotine reward.

Estimating the optimal dose of flupentixol decanoate in the maintenance treatment of schizophrenia—a systematic review of the literature Abstract Rationale The licensed dose range for the long-acting injectable antipsychotic flupentixol decanoate (Depixol®) in the treatment of schizophrenia is very broad. This provides little useful direction to prescribers and may ultimately result in patients receiving unnecessarily high doses. Objectives We aimed to estimate the effect of dose of flupentixol decanoate on relapse rates in schizophrenia and on tolerability by expanding on an earlier review and including non-RCT and German-language studies, as well as using pharmacokinetic and pharmacodynamic data to offer guidance on dosing. Methods A literature review using EMBASE, Medline, PsycINFO and PubMed was conducted. Treatment success rates at 6 months were extracted or extrapolated from the studies and plotted against dose to estimate a dose-response curve. Results Data from 16 studies (n = 514) allowed estimation of a dose-response curve which rises steeply between the chosen placebo anchor (25% success rate) and 10 mg every 2 weeks before reaching a maximum between 20 and 40 mg every 2 weeks (80–95% success rates). Extrapyramidal side effects (EPSEs) were frequently seen (12–71% of participants) in that dose range. Two -weekly injections seem to provide the highest trough plasma concentration per dose administered and the lowest peak-to-trough concentration ratio. Plasma concentration varied up to 5-fold among individuals receiving the same dose. Conclusions The optimal dose of flupentixol decanoate is likely to be between 20 mg and 40 mg every 2 weeks although higher doses may be required in some individuals owing to variation in drug handling. Doses of flupentixol should be individually established in the range of 10 to 40 mg every 2 weeks according to response and tolerability.

The effects of acute stress on consummatory and motivational responses for sucrose in rats after long-term withdrawal from morphine Abstract Background Negative affective states, e.g., anhedonia, may be linked to the long-lasting motivational processes associated with relapse. Here, this study investigated whether, and how, anhedonic states are influenced by stressful events that contribute to craving and relapse. Methods All male rats were pretreated with a binge-like morphine paradigm for five days. After 12 to 16 days of withdrawal, rats were subjected to a one-hour free consumption test or three operant tasks with increasing cost/benefit ratio, i.e., fixed ratio 1 (FR1), progressive ratio (PR), and PR-punishment procedure of reinforcement, with sucrose solutions of three concentrations (4%, 15%, and 60%) as rewards. The consumption and operant responses under FR1 and PR procedures were measured following exposure to acute foot-shock stress (intermittent foot shock, 0.5 mA × 0.5 s × 10 min; mean intershock interval, 40 s), and the operant responses for 60% sucrose solution under PR-punishment procedure was measured following a forced-swim stress (5 minutes). Result Foot-shock stress increased water consumption in a subpopulation of rats and decreased consumption of sucrose solutions, while it did not influence the operant responses for sucrose solutions under either FR1 or PR procedure. The forced-swim stress reduced operant responses for 60% sucrose solution under PR-punishment procedure, but did not influence responding for 60% sucrose solution under PR procedure. In addition, the forced-swim stress also elevated anxiety level of rats in an open area test. Conclusions Acute stress induced hedonic but not motivational deficit for sucrose reward in protracted drug-abstinent animals. Additional negative emotional states besides anhedonia were evoked by acute stress.

Alcohol, empathy, and morality: acute effects of alcohol consumption on affective empathy and moral decision-making Abstract Rationale Hypothetical moral dilemmas, pitting characteristically utilitarian and non-utilitarian outcomes against each other, have played a central role in investigations of moral decision-making. Preferences for utilitarian over non-utilitarian responses have been explained by two contrasting hypotheses; one implicating increased deliberative reasoning, and the other implicating diminished harm aversion. In recent field experiments, these hypotheses have been investigated using alcohol intoxication to impair both social and cognitive functioning. These studies have found increased utilitarian responding, arguably as a result of alcohol impairing affective empathy. Objectives The present research expands existing investigations by examining the acute effects of alcohol on affective empathy and subsequent moral judgments in traditional vignettes and moral actions in virtual reality, as well as physiological responses in moral dilemmas. Methods Participants (N = 48) were administered either a placebo or alcohol in one of two dosages; low or moderate. Both pre- and post intervention, participants completed a moral action and moral judgment task alongside behavioural measures of affective empathy. Results Higher dosages of alcohol consumption resulted in inappropriate empathic responses to facial displays of emotion, mirroring responses of individuals high in trait psychopathy, but empathy for pain was unaffected. Whilst affective empathy was influenced by alcohol consumption in a facial responding task, both moral judgments and moral actions were unaffected. Conclusions These results suggest that facets, beyond or in addition to deficits in affective empathy, might influence the relationship between alcohol consumption and utilitarian endorsements.

Opposite environmental gating of the experienced utility (‘liking’) and decision utility (‘wanting’) of heroin versus cocaine in animals and humans: implications for computational neuroscience Abstract Background In this paper, we reviewed translational studies concerned with environmental influences on the rewarding effects of heroin versus cocaine in rats and humans with substance use disorder. These studies show that both experienced utility (‘liking’) and decision utility (‘wanting’) of heroin and cocaine shift in opposite directions as a function of the setting in which these drugs were used. Briefly, rats and humans prefer using heroin at home but cocaine outside the home. These findings appear to challenge prevailing theories of drug reward, which focus on the notion of shared substrate of action for drug of abuse, and in particular on their shared ability to facilitate dopaminergic transmission. Aims Thus, in the second part of the paper, we verified whether our findings could be accounted for by available computational models of reward. To account for our findings, a model must include a component that could mediate the substance-specific influence of setting on drug reward Results It appears of the extant models that none is fully compatible with the results of our studies. Conclusions We hope that this paper will serve as stimulus to design computational models more attuned to the complex mechanisms responsible for the rewarding effects of drugs in real-world contexts.

Establishing operant conflict tests for the translational study of anxiety in mice Abstract Rationale In conflict-based anxiety tests, rodents decide between actions with simultaneous rewarding and aversive outcomes. In humans, computerised operant conflict tests have identified response choice, latency, and vigour as distinct behavioural components. Animal operant conflict tests for measurement of these components would facilitate translational study. Objectives In C57BL/6 mice, two operant conflict tests for measurement of response choice, latency, and vigour were established, and effects of chlordiazepoxide (CDZ) thereon investigated. Methods Mice were moderately diet-restricted to increase sucrose reward salience. A 1-lever test required responding under medium-effort reward/threat conditions of variable ratio 2–10 resulting in sucrose at p = 0.7 and footshock at p = 0.3. A 2-lever test mandated a choice between low-effort reward/threat with a fixed-ratio (FR) 2 lever yielding sucrose at p = 0.7 and footshock at p = 0.3 versus high-effort reward/no threat with a FR 20 lever yielding sucrose at p = 1. Results In the 1-lever test, CDZ (7.5 or 15 mg/kg i.p.) reduced post-trial pause (response latency) following either sucrose or footshock and reduced inter-response interval (increased response vigour) after footshock. In the 2-lever test, mice favoured the FR2 lever and particularly at post-reward trials. CDZ increased choice of FR2 and FR20 responding after footshock, reduced response latency overall, and increased response vigour at the FR2 lever and after footshock specifically. Conclusions Mouse operant conflict tests, especially 2-lever choice, allow for the translational study of distinct anxiety components. CDZ influences each component by ameliorating the impact of both previous punishment and potential future punishment.

Beer? Over here! Examining attentional bias towards alcoholic and appetitive stimuli in a visual search eye-tracking task Abstract Rationale Experimental tasks that demonstrate alcohol-related attentional bias typically expose participants to single-stimulus targets (e.g. addiction Stroop, visual probe, anti-saccade task), which may not correspond fully with real-world contexts where alcoholic and non-alcoholic cues simultaneously compete for attention. Moreover, alcoholic stimuli are rarely matched to other appetitive non-alcoholic stimuli. Objectives To address these limitations by utilising a conjunction search eye-tracking task and matched stimuli to examine alcohol-related attentional bias. Methods Thirty social drinkers (Mage = 19.87, SD = 1.74) were asked to detect whether alcoholic (beer), non-alcoholic (water) or non-appetitive (detergent) targets were present or absent amongst a visual array of matching and non-matching distractors. Both behavioural response times and eye-movement dwell time were measured. Results Social drinkers were significantly quicker to detect alcoholic and non-alcoholic appetitive targets relative to non-appetitive targets in an array of matching and mismatching distractors. Similarly, proportional dwell time was lower for both alcoholic and non-alcoholic appetitive distractors relative to non-appetitive distractors, suggesting that appetitive targets were relatively easier to detect. Conclusions Social drinkers may exhibit generalised attentional bias towards alcoholic and non-alcoholic appetitive cues. This adds to emergent research suggesting that the mechanisms driving these individual’s attention towards alcoholic cues might ‘spill over’ to other appetitive cues, possibly due to associative learning.