Psychopharmacology

Computational psychopharmacology: a translational and pragmatic approach Abstract Rationale Psychopharmacology needs novel quantitative measures and theoretical approaches based on computational modelling that can be used to help translate behavioural findings from experimental animals to humans, including patients with neuropsychiatric disorders. Objectives This brief review exemplifies this approach when applied to recent published studies of the effects of manipulating central dopaminergic and serotoninergic systems in rodents and marmoset monkeys, and possible comparisons with healthy human volunteers receiving systemic agents or patients with depression and schizophrenia. Methods Behavioural effects of central depletions of dopamine or serotonin in monkeys in probabilistic learning paradigms are characterised further by computational modelling methods and related to rodent and human data. Results Several examples are provided of the power of computational modelling to derive new measures and reappraise conventional explanations of regional neurotransmitter depletion and other drug effects, whilst enhancing construct validation in patient groups. Specifically, effects are shown on such parameters as 'stimulus stickiness' and 'side stickiness', which occur over and above effects on standard parameters of reinforcement learning, reminiscent of some early innovations in data analysis in psychopharmacology. Conclusions Computational modelling provides a useful methodology for further detailed analysis of behavioural mechanisms that are affected by pharmacological manipulations across species and will aid the translation of experimental findings to understand the therapeutic effects of medications in neuropsychiatric disorders, as well as facilitating future drug discovery.

Role of dopamine D 1 -like and D 2 -like receptors in the activation of ingestive behaviour in thirsty rats licking for water Abstract Rationale Analysis of lick pattern for sucrose and NaCl and of the forced swimming response after dopamine antagonist administration led us to suggest that dopamine on D1-like receptors is involved in behavioural activation, and the level of activation is "reboosted" on the basis of an evaluation process involving D2-like receptors. Although some studies investigated licking microstructure for water after dopamine antagonists, the within-session time course of their effect was never investigated. Objectives The aims of this study were to further investigate the role of dopamine receptors in the mechanisms governing water ingestion, focussing on the within-session time course of the microstructure parameters, and to test the proposed hypothesis. Materials and methods The effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01–0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025–0.25 mg/kg) on licking microstructure for water were examined in 20-h water-deprived rats in 30-min sessions. Results As previously observed with sucrose and NaCl, SCH 23390 reduced licking by reducing burst number, suggesting reduced behavioural activation. Moreover, it resulted in an increased burst size. Raclopride reduced the size of licking bursts, while their number was either increased or decreased depending on the dose. Conclusion The results support the suggestion that D1 receptors are involved in behavioural activation and D2 receptors are involved in a related evaluation process. Within the framework of the proposed hypothesis, the increased burst size after D1-like receptor blockade might be interpreted as a pro-hedonic effect consequent to the increased cost of the activation of the licking response.

Correction to: The protein kinase Cβ-selective inhibitor, enzastaurin, attenuates amphetamine-stimulated locomotor activity and self-administration behaviors in rats The middle initial of the author should be "A" instead of "C". The correct presentation of the author name is Colleen A. Carpenter.

NMDA receptor antagonists traxoprodil and lanicemine improve hippocampal-prefrontal coupling and reward-related networks in rats Abstract Rationale The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine is known to have not only a rapid antidepressant effect but also dissociative side effects. Traxoprodil and lanicemine, also NMDA antagonists, are candidate antidepressant drugs with fewer side effects. Objectives In order to understand their mechanism of action, we investigated the acute effects of traxoprodil and lanicemine on brain connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). Methods Functional connectivity (FC) alterations were examined using interregional correlation networks. Graph theoretical methods were used for whole brain network analysis. As interest in NMDAR antagonists as potential antidepressants was triggered by the antidepressant effect of ketamine, results were compared to previous findings from our ketamine studies. Results Similar to ketamine but to a smaller extent, traxoprodil increased hippocampal-prefrontal (Hc-PFC) coupling. Unlike ketamine, traxoprodil decreased connectivity within the PFC. Lanicemine had no effect on these properties. The improvement of Hc-PFC coupling corresponds well to clinical result, showing ketamine to have a greater antidepressant effect than traxoprodil, while lanicemine has a weak and transient effect. Connectivity changes overlapping between the drugs as well as alterations of local network properties occurred mostly in reward-related regions. Conclusion The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs.

Relative insensitivity to time-out punishments induced by win-paired cues in a rat gambling task Abstract Rationale Pairing rewarding outcomes with audiovisual cues in simulated gambling games increases risky choice in both humans and rats. However, the cognitive mechanism through which this sensory enhancement biases decision-making is unknown. Objectives To assess the computational mechanisms that promote risky choice during gambling, we applied a series of reinforcement learning models to a large dataset of choices acquired from rats as they each performed one of two variants of a rat gambling task (rGT), in which rewards on "win" trials were delivered either with or without salient audiovisual cues. Methods We used a sampling technique based on Markov chain Monte Carlo to obtain posterior estimates of model parameters for a series of RL models of increasing complexity, in order to assess the relative contribution of learning about positive and negative outcomes to the latent valuation of each choice option on the cued and uncued rGT. Results Rats which develop a preference for the risky options on the rGT substantially down-weight the equivalent cost of the time-out punishments during these tasks. For each model tested, the reduction in learning from the negative time-outs correlated with the degree of risk preference in individual rats. We found no apparent relationship between risk preference and the parameters that govern learning from the positive rewards. Conclusions The emergence of risk-preferring choice on the rGT derives from a relative insensitivity to the cost of the time-out punishments, as opposed to a relative hypersensitivity to rewards. This hyposensitivity to punishment is more likely to be induced in individual rats by the addition of salient audiovisual cues to rewards delivered on win trials.

Reward and avoidance learning in the context of aversive environments and possible implications for depressive symptoms Abstract Background Aversive stimuli in the environment influence human actions. This includes valence-dependent influences on action selection, e.g., increased avoidance but decreased approach behavior. However, it is yet unclear how aversive stimuli interact with complex learning and decision-making in the reward and avoidance domain. Moreover, the underlying computational mechanisms of these decision-making biases are unknown. Methods To elucidate these mechanisms, 54 healthy young male subjects performed a two-step sequential decision-making task, which allows to computationally model different aspects of learning, e.g., model-free, habitual, and model-based, goal-directed learning. We used a within-subject design, crossing task valence (reward vs. punishment learning) with emotional context (aversive vs. neutral background stimuli). We analyzed choice data, applied a computational model, and performed simulations. Results Whereas model-based learning was not affected, aversive stimuli interacted with model-free learning in a way that depended on task valence. Thus, aversive stimuli increased model-free avoidance learning but decreased model-free reward learning. The computational model confirmed this effect: the parameter lambda that indicates the influence of reward prediction errors on decision values was increased in the punishment condition but decreased in the reward condition when aversive stimuli were present. Further, by using the inferred computational parameters to simulate choice data, our effects were captured. Exploratory analyses revealed that the observed biases were associated with subclinical depressive symptoms. Conclusion Our data show that aversive environmental stimuli affect complex learning and decision-making, which depends on task valence. Further, we provide a model of the underlying computations of this affective modulation. Finally, our finding of increased decision-making biases in subjects reporting subclinical depressive symptoms matches recent reports of amplified Pavlovian influences on action selection in depression and suggests a potential vulnerability factor for mood disorders. We discuss our findings in the light of the involvement of the neuromodulators serotonin and dopamine.

False memory formation in cannabis users: a field study Abstract Rationale Cannabis use is widespread and has previously been associated with memory impairments. However, the role of cannabis in relation to false memory production, i.e., memories of events that were not experienced, is less well-understood. Objective The aim of the current field study was to examine the impact of cannabis use on false memory production. Methods The Deese/Roediger-McDermott (DRM) paradigm was used to induce false memories. In this paradigm, participants study word lists that are associatively related to a non-presented word, termed the critical lure. In a later memory test, true recognition rates and false alarm rates toward critical lures and unrelated items are assessed. Memory performance was compared between three groups: regular cannabis consumers who were acutely intoxicated (n = 53), regular cannabis consumers who were sober (n = 50), and cannabis-naïve controls (n = 53). The participants were approached in Dutch coffee shops (cannabis outlets) and cafes and asked to participate in our study. After collecting general information on their cannabis use, they were subjected to the DRM procedure. Results Although false memory rates for critical lures did not statistically differ between groups, both intoxicated and sober cannabis consumers falsely recognized more unrelated items than control participants. Also, individuals without a history of cannabis use demonstrated higher memory accuracy compared with the intoxicated group. Conclusion It is concluded that cannabis intoxication and history of cannabis use induce a liberal response criterion for newly presented words for which the level of association with previously learned words is low and uncertainty is high.

CB1 receptor antagonism in capuchin monkeys alters social interaction and aversive memory extinction Abstract Rationale The endocannabinoid system (eCS) is an important modulator of social anxiety and social reward, as well as memory functions. Objectives The present study evaluated the role of eCS in social interactions and aversive memory extinction in capuchin monkeys (Sapajus spp.) by blocking the cannabinoid type 1 receptor (CB1r). Methods In experiment 1, spontaneous social and non-social behaviors of five capuchin males, each one living in triads with two other females, were observed after AM251 treatment (vehicle, 0.3, 1.0, and 3.0 mg/kg; i.m.). In experiment 2, seven male capuchin monkeys were trained to reach for a reward inside a wooden box. After training, they were given either vehicle or a 3.0-mg/kg i.m. dose of AM251 before a single aversive encounter with a live snake in the box. The latency to return to reach the reward inside the box in subsequent trials was measured. Results The 3.0-mg/kg dose significantly increased the time spent performing self-directed behaviors, while decreasing that of social interactions. No changes were observed in vigilance or locomotion. AM251 increased the latency to reach the reward after the aversive encounter. Conclusion Taken together, these results suggest that CB1r antagonism induces social deficits without increasing anxiety levels and impairs the extinction of aversive memories. This behavioral profile in monkeys underscores the potential involvement of eCS signaling in the deficits observed in autism spectrum disorders.

L-DOPA improves extinction memory retrieval after successful fear extinction Abstract Rationale A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction. Methods In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session. Results In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction. Conclusion The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session.

Preconception maternal cocaine self-administration increases the reinforcing efficacy of cocaine in male offspring Abstract Rationale Although the influence of gestational cocaine exposure on offspring has been the focus of a sustained research effort, the effect of preconception cocaine self-administration by dams on progeny has received far less attention. Method In the current study, adult female rats were allowed to self-administer cocaine 2 h a day for 60 days and then after a 10-day wash out period, bred to naïve males. Maternal behavior was measured in dams until weaning. When male and female progeny reached adulthood, anxiety-like behavior, memory, and cocaine self-administration were assessed in separate cohorts of rats. Results Despite a total of at least 30 days of cocaine abstinence, the quality of maternal behaviors was negatively affected by previous cocaine exposure as reflected by less time spent with pups as well as an excess of other maladaptive maternal behaviors. Measures of anxiety-like behavior and memory were not affected by maternal cocaine intake in either male or female offspring. In contrast, male, but not female, the progeny of dams exposed to cocaine showed increased reinforcing efficacy of cocaine as measured by cocaine self-administration under a progressive ratio schedule. The fact that cocaine self-administration was influenced only in the male offspring of cocaine-exposed dams argues against this phenotype being linked to altered maternal behavior, although this possibility cannot be ruled out completely. Conclusions Collectively, these results indicate that preconception cocaine self-administration by dams results in the relatively selective enhancement of cocaine addiction-like behavior in male offspring.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com