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Rational: Stress is a major trigger for drug relapse in humans and animal models, even after prolonged abstinence. However, animal models for stress-induced relapse were criticized for the lack of predictive and face validity. Objectives: Here we investigated the effect of acute food deprivation stress in a novel stress-induced relapse model using voluntary, punishment-imposed abstinence from heroin. We also performed a detailed characterization of the development of punishment-imposed abstinence. Methods: Male rats were trained to self-administered heroin (0.1 mg/kg/infusion) for 2 weeks, using the seeking-taking chained schedule. Pressing the 'seeking' lever led to the insertion of the 'taking' lever and pressing the take lever resulted in heroin infusion. Following self-administration training, rats were exposed to 8 or 21 days of heroin-seeking punishment. During punishment, 30% of the completed seek links resulted in a mild escalating footshock instead of take lever presentation. Next, rats were tested for heroin seeking under extinction conditions after 24 h of food deprivation and sated conditions. Results: Probabilistic punishment of seeking lever responses resulted in gradual suppression of heroin seeking and taking. Exposure to food-deprivation stress induced a robust relapse to heroin seeking after short and long punishment-imposed abstinence periods, without significant effects of time, i.e., no incubation of heroin seeking. Individual differences were observed in the development of punishment-induced abstinence and stress-induced relapse. Conclusions: These results suggest that stress is a reliable trigger to relapse even after a prolonged period of punishment-induced, voluntary abstinence. [ABSTRACT FROM AUTHOR]

Rationale: Greater availability of cannabis in the USA has raised concerns about adverse effects of the drug, including possible amotivational states. Lack of motivation may be assessed by examining acute effects of cannabinoids on reward processing. Objectives: This study examined single doses of delta-9-tetrahydrocannabinol (∆9-THC; 7.5, 15 mg oral) in healthy adults using a version of the monetary incentive delay (MID) task adapted for electroencephalography (EEG; e-MID) in a within-subjects, double blind design. Methods: Two phases of reward processing were examined: anticipation, which occurs with presentation of cues that indicate upcoming reward, punishment, or neutral conditions, and outcome, which occurs with feedback indicating hits or misses. During anticipation, we measured two event-related potential (ERP) components: the P300, which measures attention and motivation, and the LPP, which measures affective processing. During outcome processing, we measured P300 and LPP, as well as the RewP, which measures outcome evaluation. Results: We found that ∆9-THC modulated outcome processing, but not reward anticipation. Specifically, both doses of ∆9-THC (7.5 and 15 mg) reduced RewP amplitudes after outcome feedback (hits and misses) relative to placebo. ∆9-THC (15 mg) also reduced P300 and LPP amplitudes following hits compared to misses, relative to both placebo and 7.5 mg ∆9-THC. Conclusions: These findings suggest that ∆9-THC dampens responses to both reward and loss feedback, which may reflect an "amotivational" state. Future studies are needed to determine generalizability of this effect, such as its pharmacological specificity and its specificity to monetary vs other types of reward. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol use disorder (AUD) is a complex, heterogeneous disorder that only occurs in a minority of alcohol users. Various behavioral constructs, including excessive intake, habit formation, motivation for alcohol and resistance to punishment have been implicated in AUD, but their interrelatedness is unclear. Objective: The aim of this study was therefore to explore the relation between these AUD-associated behavioral constructs in rats. We hypothesised that a subpopulation of animals could be identified that, based on these measures, display consistent AUD-like behavior. Methods: Lister Hooded rats (n = 47) were characterised for alcohol consumption, habit formation, motivation for alcohol and quinine-adulterated alcohol consumption. The interrelation between these measures was evaluated through correlation and cluster analyses. In addition, addiction severity scores were computed using different combinations of the behavioral measures, to assess the consistency of the AUD-like subpopulation. Results: We found that the data was uniformly distributed, as there was no significant tendency of the behavioral measures to cluster in the dataset. On the basis of multiple ranked addiction severity scores, five animals (~ 11%) were classified as displaying AUD-like behavior. The composition of the remaining subpopulation of animals with the highest addiction severity score (9 rats; ~ 19%) varied, depending on the combination of measures included. Conclusion: Consistent AUD-like behavior was detected in a small proportion of alcohol drinking rats. Alcohol consumption, habit formation, motivation for alcohol and punishment resistance contribute in varying degrees to the AUD-like phenotype across the population. These findings emphasise the importance of considering the heterogeneity of AUD-like behavior. [ABSTRACT FROM AUTHOR]

Rationale: Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males. Objectives: The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males. Methods: Motivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and after 7, 14, or 60 days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions. Results: Motivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14 days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes, although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine punishment by 14 days of withdrawal. Conclusions: Female rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal. [ABSTRACT FROM AUTHOR]

RationaleAppetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions.ObjectivesIn this pharmacological functional magnetic resonance imaging study, we investigated the contribution of the dopaminergic system to reward and punishment processing in humans.MethodsTwo groups of participants received either placebo or the dopamine precursor levodopa and were scanned during alternating reward and punishment anticipation blocks.ResultsLevodopa administration increased striatal activations for cues presented in punishment blocks. In an interaction with individual personality scores, levodopa also enhanced striatal activation for punishment-predictive compared with neutral cues in participants scoring higher on the novelty-seeking dimension.ConclusionsThese data support recent indications that dopamine contributes to punishment processing and suggest that the novelty-seeking trait is a measure of susceptibility to drug effects on motivation. These findings are also consistent with the possibility of an inverted U-shaped response function of dopamine in the striatum, suggesting an optimal level of dopamine release for motivational processing.

Rationale: Strategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists. Objectives: The effects of KOR agonists (U50488, nalfurafine) on fentanyl-vs.-food choice were compared under conditions where the KOR agonists were added to the intravenously self-administered fentanyl (contingent delivery) or administered as subcutaneous pretreatments (non-contingent delivery) in male and female rats. Methods: Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32–10 μg/kg/infusion) and food reinforcement. In experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In experiment 2, U50488 (1–10 mg/kg) and nalfurafine (3.2–32 μg/kg) were administered as acute pretreatments (non-contingent administration). The selective KOR antagonist, nor-BNI (32 mg/kg), was administered prior to contingent and non-contingent KOR-agonist treatment in experiment 3. Results: Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. However, evidence for punishment corresponded with an elimination of operant responding in the majority of rats. Non-contingent U50488 and nalfurafine administration only decreased the number of choices made during the behavioral session without altering fentanyl choice. Contingent and non-contingent KOR-agonist effects on fentanyl choice were both attenuated by nor-BNI. Conclusions: These results illustrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered. [ABSTRACT FROM AUTHOR]

Rationale: Compulsive cocaine use, defined as the continued use despite the dire consequences, is a hallmark of cocaine addiction. Thus, understanding the brain mechanism regulating the compulsive cocaine-seeking and cocaine-taking behaviors is essential to understand cocaine addiction and the key to identification of the molecular targets for the development of medications against this condition. Objective: This study aimed to determine how the GABAa and GABAb receptors of the central nucleus of the amygdala (CeA) regulate the compulsive cocaine-seeking behavior. Methods: Male Wistar outbred rats were trained to self-administer intravenous cocaine (0.4 mg/kg/infusion) under a chained schedule. The compulsive cocaine-seeking behavior was measured as the cocaine-seeking behavior in the face of footshock punishment. The role of the GABA receptors of CeA in the regulation of such behavior was determined by measuring the dose-dependent effects of the GABAa agonist muscimol or the GABAb agonist baclofen bilaterally microinjected into the CeA on the punished cocaine-seeking behavior. Results: The cocaine-seeking behavior was inhibited by footshock punishment in an intensity-dependent manner. Both muscimol and baclofen dose-dependently increased the punished cocaine-seeking behavior. However, the potency of muscimol but not baclofen was negatively correlated with the effects of punishment. Conclusion: These data indicate that the CeA GABAa receptors play a key role in the regulation of the compulsive cocaine-seeking behavior and suggest that an increase in the function of the GABAa receptors possibly induced by cocaine or genetic factors may be an important mechanism involved in the development of or vulnerability to the compulsive cocaine use and addiction. [ABSTRACT FROM AUTHOR]

Rationale: Excessive intake of rewards, such as food and drugs, often has explicit negative consequences, including the development of obesity and addiction, respectively. Thus, choosing not to pursue reward is the result of a cost/benefit decision, proper execution of which requires inhibition of behavior. An extensive body of preclinical and clinical evidence implicates dopamine in certain forms of inhibition of behavior, but it is not fully known how it contributes to behavioral inhibition under threat of explicit punishment. Objectives: To assess the involvement of midbrain dopamine neurons and their corticostriatal output regions, the ventral striatum and prefrontal cortex, in control over behavior under threat of explicit (foot shock) punishment in rats. Methods: We used a recently developed behavioral inhibition task, which assesses the ability of rats to exert behavioral restraint at the mere sight of food reward, under threat of foot shock punishment. Using in vivo fiber photometry, chemogenetics, c-Fos immunohistochemistry, and behavioral pharmacology, we investigated how dopamine neurons in the ventral tegmental area, as well as its output areas, the ventral striatum and prefrontal cortex, contribute to behavior in this task. Results: Using this multidisciplinary approach, we found little evidence for a direct involvement of ascending midbrain dopamine neurons in inhibitory control over behavior under threat of punishment. For example, photometry recordings suggested that VTA DA neurons do not directly govern control over behavior in the task, as no differences were observed in neuronal population activity during successful versus unsuccessful behavioral control. In addition, chemogenetic and pharmacological manipulations of the mesocorticolimbic DA system had little or no effect on the animals' ability to exert inhibitory control over behavior. Rather, the dopamine system appeared to have a role in the motivational components of reward pursuit. Conclusions: Together, our data provide insight into the mesocorticolimbic mechanisms behind motivated behaviors by showing a modulatory role of dopamine in the expression of cost/benefit decisions. In contrast to our expectations, dopamine did not appear to directly mediate the type of behavioral control that is tested in our task. [ABSTRACT FROM AUTHOR]

Rationale: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement. Methods: In separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01–0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001–0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine's effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.). Results: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. Conclusions: These results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine's punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability. [ABSTRACT FROM AUTHOR]

Rationale: During value-based decision-making, organisms make choices on the basis of reward expectations, which have been formed during prior action-outcome learning. Although it is known that neuronal manipulations of different subregions of the rat prefrontal cortex (PFC) have qualitatively different effects on behavioral tasks involving value-based decision-making, it is unclear how these regions contribute to the underlying component processes. Objectives: Assessing how different regions of the rodent PFC contribute to component processes of value-based decision-making behavior, including reward (or positive feedback) learning, punishment (or negative feedback) learning, response persistence, and exploration versus exploitation. Methods: We performed behavioral modeling of data of rats in a probabilistic reversal learning task after pharmacological inactivation of five PFC subregions, to assess how inactivation of these different regions affected the structure of responding of animals in the task. Results: Our results show reductions in reward and punishment learning after PFC subregion inactivation. The prelimbic, infralimbic, lateral orbital, and medial orbital PFC particularly contributed to punishment learning, and the prelimbic and lateral orbital PFC to reward learning. In addition, response persistence depended on the infralimbic and medial orbital PFC. As a result, pharmacological inactivation of the infralimbic and lateral orbitofrontal cortex reduced the number of reversals achieved, whereas inactivation of the prelimbic and medial orbitofrontal cortex decreased the number of rewards obtained. Finally, using simulated data, we explain discrepancies with a previous study and demonstrate complex, interacting relationships between conventional measures of probabilistic reversal learning performance, such as win-stay/lose-switch behavior, and component processes of value-based decision-making. Conclusions: Together, our data suggest that distinct components of value-based learning and decision-making are generated in medial and orbital PFC regions, displaying functional specialization and overlap, with a prominent role of large parts of the PFC in negative feedback processing. [ABSTRACT FROM AUTHOR]

Rationale: Control of reward-seeking behavior under conditions of punishment is an important function for survival. Objectives and methods: We designed a task in which rats could choose to either press a lever and obtain a food pellet accompanied by a footshock or refrain from pressing the lever to avoid footshock, in response to tone presentation. In the task, footshock intensity steadily increased, and the task was terminated when the lever press probability reached < 25% (last intensity). Rats were trained until the last intensity was stable. Subsequently, we investigated the effects of the pharmacological inactivation of the ventromedial prefrontal cortex (vmPFC), lateral orbitofrontal cortex (lOFC), and basolateral amygdala (BLA) on task performance. Results: Bilateral inactivation of the vmPFC, lOFC, and BLA did not alter lever press responses at the early stage of the task. The number of lever presses increased following vmPFC and BLA inactivation but decreased following lOFC inactivation during the later stage of the task. The last intensity was elevated by vmPFC or BLA inactivation but lowered by lOFC inactivation. Disconnection of the vmPFC-BLA pathway induced behavioral alterations that were similar to vmPFC or BLA inactivation. Inactivation of any regions did not alter footshock sensitivity and anxiety levels. Conclusions: Our results demonstrate a strong role of the vmPFC and BLA and their interactions in reward restraint to avoid punishment and a prominent role of the lOFC in reward-seeking under reward/punishment conflict situations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction in a different context (B) and reinstate (or relapse to) drug seeking after exposure to the original drug-associated context (A). In a more recent version of the model introduced in 2013, the experimental conditions in context A are identical to those used in the classical model, but drug-reinforced responding in context B is suppressed by probabilistic punishment. The punishment-based ABA renewal model is proposed to resemble abstinence in humans, which is often initiated by the desire to avoid the negative consequences of drug use. The goal of our review is to discuss similarities and differences in mechanisms that play a role in suppression of drug seeking in context B and context-induced relapse to drug seeking in context A in the two models. We first describe psychological mechanisms that mediate extinction and punishment of drug-reinforced responding in context B. We then summarize recent findings on brain mechanisms of context-induced relapse of drug seeking after extinction, or punishment-imposed abstinence. These findings demonstrate both similarities and differences in brain mechanisms underlying relapse in the two variations of the ABA renewal model. We conclude by briefly discussing clinical implications of the preclinical studies. [ABSTRACT FROM AUTHOR]

Rationale: The adverse consequences of human addictive drug use could be the result of either addictive drug consumption resulting in punishment (e.g., incarceration) or failure to engage in negative-reinforced behaviors that might compete with drug-maintained behaviors (e.g., contingency management strategies that reset payment amounts for drug free urines)., Objective: The goal of the present study was to establish a discrete-trial cocaine-vs-negative reinforcer (S NR ) choice procedure where rats were presented with a simplified model of this conflict: choose negative reinforcement (i.e., escape or avoid foot shock) or choose an intravenous (IV) cocaine infusion followed by an inescapable shock., Methods: Responding was maintained in male and female rats by IV cocaine infusions (0.32-1.8 mg/kg/inf) and a S NR (0.1-0.7 mA shock) under a discrete-trial concurrent "choice" schedule during daily sessions. Following parametric reinforcer magnitude and response requirement experiments, the effects of 12 h extended access cocaine self-administration and acute diazepam (0.32-10 mg/kg, IP) pretreatment were determined on cocaine-vs-S NR choice., Results: Negative reinforcement was chosen over all cocaine doses. Lowering shock magnitude or increasing S NR response requirement failed to promote behavioral reallocation towards cocaine. Extended access cocaine self-administration sessions resulted in high daily cocaine intakes but failed to significantly increase cocaine choice in all (19) but one rat. Acute diazepam pretreatment also did not alter choice behavior up to doses that produced behavioral depression., Conclusions: These results suggest that S NR s may be a source of reinforcement that effectively compete with and mitigate maladaptive addictive drug-maintained behaviors in the general population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Approach and avoidance decisions are made when an animal experiences a state of motivational conflict inflicted by stimuli imbued with both positive and negative valences. The nucleus accumbens (NAc), a site where valenced information and action selection converge, has recently been found to be critically involved in the resolution of approach-avoidance conflict. However, the individual roles of the region’s dopamine receptor D1 (D1R)- and D2 (D2R)-expressing medium spiny neurons (MSNs) in regulating conflict resolution have not been well established.Objectives: Here, we examined the roles of NAc D1R and D2R in cue-elicited approach-avoidance decision-making.Methods: Using a conditioned mixed-valence conflict paradigm, rats were initially trained in a radial maze to associate separate visuotactile cues with sucrose reward, foot shock punishment, and no outcome. Following acquisition of the cue-outcome associations, rats were subjected to a conditioned approach-avoidance conflict scenario, in which they were presented with a maze arm containing a superimposition of the reward and punishment cues, and another arm containing neutral cues.Results: Post-training intra-NAc D1R antagonism (SCH23390) led to an avoidance of the arm containing the mixed-valence cue over the neutral arm, whereas intra-NAc D2R antagonism (sulpiride) resulted in rats exhibiting a preference for the mixed-valence arm.Conclusion: Our results suggest that NAc D1R and D2R exert differential control over decision-making involving cue-elicited approach-avoidance conflict resolution. [ABSTRACT FROM AUTHOR]

Background Current diagnosis of drug addiction like other mental disorders is based on clinical symptoms not on neural pathophysiology and consequently, does not provide useful information on the underlying pathophysiology and may impede the efforts to identify the underlying mechanisms. Identifying the functional deficits that are relevant to addiction and can be traced to the neural systems will greatly facilitate our understanding of the heterogeneity of the condition and improve future diagnosis and treatment. Cocaine addiction is characterized by the continued use despite the dire consequences, and the deficit in inhibitory control may play a key role in this process. This study aimed to develop a paradigm to measure the punishmentinduced inhibitory regulation of reward-seeking behavior. Methods Rats were first trained to self-administer sucrose pellets under a chained schedule and then the breaking points (BPs) under the progressive-ratio schedule, and the intensity-response effects of footshock punishment on sucrose SA were measured. Subsequently, the rats went on to self-administer intravenous cocaine, and the BPs and the punishment intensity-response effects were similarly determined. Results The areas under the punishment intensity-response curves (AUCs) were calculated and used as an indicator of the sensitivity of the inhibitory system. The BPs for cocaine were not correlated with the AUCs. Furthermore, the change in the BPs for cocaine induced by changing cocaine dose did not predict the change in the AUCs. Conclusion The intensity-response effects of punishment can be used to measure the function or sensitivity of the inhibitory system independent of the motivational state. [ABSTRACT FROM AUTHOR]

Background and rationale: Steven R. Goldberg was a pioneering behavioral pharmacologist whose intravenous drug self-administration studies advanced the understanding of conditioned stimuli and schedules of reinforcement as determinants of pattern and persistence of drug-seeking behavior, and in particular, the importance of nicotine in tobacco use. His passing in 2014 led to invitations to contribute articles to psychopharmacology dedicated to his work. Objectives: The objectives of this review are to summarize and put into historical perspective Goldberg's contributions to elucidate the reinforcing effects of nicotine and to summarize the implications of his research for medication development, tobacco regulation, and potential tobacco control policy options. This includes a review of intravenous nicotine self-administration research from the 1960s to 2016. Results: Goldberg's application of behavioral pharmacology methods to investigate nicotine reinforcement and the influence of schedule of reinforcement and conditioned stimuli on nicotine administration contributed to the conclusions of the US National Institute on Drug Abuse, and the Surgeon General, that nicotine met the criteria as a dependence-producing drug and cigarette smoking as a prototypic drug dependency or 'addiction.' Equally important, this work has been systematically extended to other species and applied to address a range of factors relevant to tobacco use, medication development, regulation, and public health policy. Conclusions: Steven R. Goldberg was a pioneering scientist whose systematic application of the science of behavioral pharmacology advanced the understanding of tobacco and nicotine use and contributed to the scientific foundation for tobacco product regulation and potential public health tobacco control policy development. [ABSTRACT FROM AUTHOR]

Rationale: Dopaminergic therapy improves some cognitive functions and worsens others in patients with Parkinson's disease (PD). These paradoxical effects are explained by the dopamine overdose hypothesis, which proposes that effects of dopaminergic therapy on a cognitive function is determined by the baseline dopamine levels in brain regions mediating that function. Objectives: We directly tested this prevalent hypothesis, evaluating the effects of levodopa on stimulus-reward learning in healthy young adults, who presumably have optimal baseline dopamine levels and dopamine regulation. Methods: Twenty-six healthy, young adults completed a probabilistic reversal learning task in a randomized, double-blind, placebo-controlled, crossover design. Participants completed one session on levodopa 100 mg/carbidopa 25 mg and another session on placebo. Results: We found that levodopa impaired reversal learning relative to placebo. Further analyses revealed that levodopa impaired learning from both punishment and reward. Conclusions: Exogenous dopamine impairs stimulus-reward learning, independent of PD pathology and prior to sensitization through repeated exposure, in healthy adults with normal cognition and baseline dopamine function. Our findings support the dopamine overdose hypothesis and caution clinicians about detrimental effects of levodopa in all clinical populations (e.g., early PD, restless leg syndrome) regardless of baseline cognitive and dopaminergic system function. [ABSTRACT FROM AUTHOR]

Rationale: Studies employing the Iowa Gambling Task (IGT) demonstrated that areas of the frontal cortex, including the ventromedial prefrontal cortex, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and anterior cingulate cortex (ACC), are involved in the decision-making process. However, the precise role of these regions in maintaining optimal choice is not clear. Objectives: We used the rat gambling task (rGT), a rodent analogue of the IGT, to determine whether inactivation of or altered dopamine signalling within discrete cortical sub-regions disrupts decision-making. Methods: Following training on the rGT, animals were implanted with guide cannulae aimed at the prelimbic (PrL) or infralimbic (IL) cortices, the OFC, or the ACC. Prior to testing, rats received an infusion of saline or a combination of baclofen and muscimol (0.125 μg of each/side) to inactivate the region and an infusion of a dopamine D2 receptor antagonist (0, 0.1, 0.3, and 1.0 μg/side). Results: Rats tended to increase their choice of a disadvantageous option and decrease their choice of the optimal option following inactivation of either the IL or PrL cortex. In contrast, OFC or ACC inactivation did not affect decision-making. Infusion of a dopamine D2 receptor antagonist into any sub-region did not alter choice preference. Conclusions: Online activity of the IL or PrL cortex is important for maintaining an optimal decision-making strategy, but optimal performance on the rGT does not require frontal cortex dopamine D2 receptor activation. Additionally, these results demonstrate that the roles of different cortical regions in cost-benefit decision-making may be dissociated using the rGT. [ABSTRACT FROM AUTHOR]

Rationale: A bidirectional relationship between alcohol use disorder (AUD) and deficits in impulse control and decision making has been suggested. However, the mechanisms by which neurocognitive impairments predispose to, or result from AUD remain incompletely understood. Objectives: The aim of this study is to gain more insight in the effects of alcohol exposure on decision making and impulse control. We used two modified versions of the rat gambling task (rGT) that differ in the net gain and the punishment magnitude associated with the different response options. Methods: In experiment 1, we assessed the effects of acute alcohol treatment (0-0.8 g/kg) on rGT performance. In experiment 2, we determined the effects of alcohol on rGT acquisition (15 sessions, 0.6 g/kg). Next, these animals were challenged with alcohol (0-1.0 g/kg) prior to rGT sessions. Results: Acute alcohol treatment suppressed baseline performance in both rGT versions but only modestly altered decision making. Treatment with alcohol during acquisition increased risky choices in the rGT version that involved larger punishment and blunted the reduction in win-shift behavior during acquisition in both rGT versions. Moreover, rats treated with alcohol during acquisition showed an increase in premature and perseverative responding upon subsequent alcohol challenges (0-1.0 g/kg) and were less sensitive to the behavioral suppressant effects of alcohol. Conclusions: Our results show that repeated alcohol exposure alters decision making during rGT acquisition and reduces the ability to adjust choice behavior on the basis of feedback. In addition, repeated alcohol exposure unmasks its behavioral disinhibitory effects in the rGT. Impaired responsiveness to choice feedback and behavioral disinhibition may contribute to the development of AUD. [ABSTRACT FROM AUTHOR]

Rationale: The relatively weak reinforcing effects of nicotine in experimental studies have been attributed to possible aversive effects or the need to space nicotine administrations over time to expose reinforcing effects. Objective: This study was designed to determine if the response-maintaining effects of nicotine are increased when availability is spaced through time, and whether nicotine is an effective punisher of remifentanil-maintained responding. Methods: Compared to a cocaine reference dose, nicotine dose and timeout (TO) value were varied in eight rhesus monkeys responding for intravenous (i.v.) nicotine on varying fixed-ratio (FR) schedules of reinforcement.The aversive effects of nicotine were evaluated in four animals choosing between a standard dose of remifentanil alone or in combination with one of several doses of nicotine. Results: In three of eight self-administration monkeys, 0.01 mg/kg/inj nicotine did not maintain responding at any FR value. In the other five animals, nicotine-maintained response rates increased with either FR or TO values to a certain point, and then slowed. Maximum nicotine-maintained response rates were much slower than those maintained by cocaine, and demand for nicotine was less than demand for cocaine. Nicotine was an effective punisher of remifentanil-maintained responding at doses ranging from 0.01 to 0.3 mg/kg/inj. Lower punishing dose seemed to be related to the absence of reinforcing effects within subject. Conclusion: There are an order of magnitude individual differences in sensitivity to both the reinforcing and punishing effects of nicotine, and this drug may be unique in being a weak positive reinforcer in small doses and aversive in large doses. [ABSTRACT FROM AUTHOR]

Rationale: Drugs can function as punishers. However, work on the study of drugs as punishers is limited, as is the range of compounds known to function as punishers. Kappa opioid agonists, which have received much experimental attention as potential therapeutics for drug abuse, reportedly produce aversive effects. However, kappa agonists have yet to be tested as punishers of behavior. Objective: The goal of the current study was to determine if a kappa agonist could function as a punisher of drug self-administration. Method: In separate experiments, monkeys were allowed to choose in a two-lever choice design between intravenous injections of equal doses of either cocaine (0.1 mg/kg/injection on each lever) or remifentanil (0.1 μg/kg/injection on each lever) when one of the two options was mixed with various doses of the kappa agonist, salvinorin A. Results: Choice for the cocaine and remifentanil options that were combined with salvinorin A decreased as a function of salvinorin A dose in all monkeys. However, operant response rates were not systematically affected by salvinorin A administration. Conclusion: The present findings demonstrate that the kappa agonist, salvinorin A, can punish self-administration of a psychotimulant, cocaine, and a mu opioid, remifentanil. In consideration of these findings, it may be possible to curtail the abuse of some drugs by contingently delivering kappa agonists (e.g., as combination formularies for prescription medications). [ABSTRACT FROM AUTHOR]

Rationale: The serotonin (5-HT) system has been reported to be involved in decision-making. A key component of this neurotransmitter system is the 5-HT receptor, and research is beginning to show how this receptor can influence decision-making. However, this relationship has rarely been studied in humans. Objectives: This study assessed whether individual variability in 5-HT availability correlates with decision-making in healthy volunteers. Methods: We measured regional availability of the 5-HT receptor in the hippocampal complex and striatum using positron emission tomography and correlated this with performance on two decision-making tasks measuring sensitivity to probability, rewards and punishments and temporal discounting, respectively. Results: No relationship between decision-making behaviour and 5-HT availability in the striatum was found. However, a positive correlation was detected between participants' 5-HT availability in the hippocampal complex and their sensitivity to the probability of winning. Furthermore, there was a negative correlation between the degree to which participants discounted future rewards and 5-HT availability in the hippocampal complex. Conclusions: These data support a role for the 5-HT receptor in the aberrant decision-making that can occur in neuropsychiatric disorders such as depression. [ABSTRACT FROM AUTHOR]

Rationale: Recent research has demonstrated that the drug, histamine, can function as a punisher of cocaine self-administration. However, little is known about how drug punishers affect the maximum reinforcing effectiveness of drugs as reinforcers. Objective: The goal of the present study was to determine if histamine, when self-administered as a mixture with cocaine, could reduce cocaine's maximum reinforcing effectiveness using two procedures designed for measuring reinforcing effectiveness. Methods: In the first experiment, rhesus monkeys were allowed to self-administer cocaine (0.1 mg/kg/inj) alone or as a mixture with histamine (0.012-0.05 mg/kg/inj) in a behavioral economic design. In the second experiment, monkeys were allowed to self-administer cocaine alone (0.006-0.56 mg/kg/inj) or as a mixture with histamine (0.025-0.1 mg/kg/inj) under a progressive-ratio schedule of reinforcement. Results: In Experiment 1, histamine decreased the reinforcing effectiveness of cocaine in a dose-dependent manner as evidenced by increases in cocaine's demand elasticity with increases in histamine dose. In Experiment 2, histamine decreased cocaine's potency and effectiveness as a reinforcer in a dose-dependent manner as indicated by rightward and downward shifts, respectively, in the dose-response functions. Conclusion: The reinforcing effectiveness of cocaine can be reduced by contingent self-administration of histamine. These results indicate that combining drug punishers with drug reinforcers reduces the maximum reinforcing effect of the drug reinforcer, which suggests a use for drug punishers as a deterrent to drug abuse (e.g., as mixtures with prescription medications with abuse potential). [ABSTRACT FROM AUTHOR]

Rationale: People often face decisions that pit self-interested behavior aimed at maximizing personal reward against normative behavior such as acting cooperatively, which benefits others. The threat of social sanctions for defying the fairness norm prevents people from behaving overly selfish. Thus, normative behavior is influenced by both seeking rewards and avoiding punishment. However, the neurochemical processes mediating the impact of these influences remain unknown. Several lines of evidence link the dopaminergic system to reward and punishment processing, respectively, but this evidence stems from studies in non-social contexts. Objectives: The present study investigates dopaminergic drug effects on individuals' reward seeking and punishment avoidance in social interaction. Methods: Two-hundred one healthy male participants were randomly assigned to receive 300 mg of l-3,4-dihydroxyphenylalanine (L-DOPA) or a placebo before playing an economic bargaining game. This game involved two conditions, one in which unfair behavior could be punished and one in which unfair behavior could not be punished. Results: In the absence of punishment threats, L-DOPA administration led to more selfish behavior, likely mediated through an increase in reward seeking. In contrast, L-DOPA administration had no significant effect on behavior when faced with punishment threats. Conclusions: The results of this study broaden the role of the dopaminergic system in reward seeking to human social interactions. We could show that even a single dose of a dopaminergic drug may bring selfish behavior to the fore, which in turn may shed new light on potential causal relationships between the dopaminergic system and norm abiding behaviors in certain clinical subpopulations. [ABSTRACT FROM AUTHOR]

Rationale: Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. Objective: This study examined whether a histamine injection could punish cocaine self-administration in a drug-drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Methods: Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37-50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. Results: When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to >80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the nonpreferred position, preference for that option increased with delay from ≤30% to >85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Conclusions: Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework. [ABSTRACT FROM AUTHOR]

Rationale: We have previously shown that tryptophan depletion enhances punishment but not reward prediction (Cools et al. in Neuropsychopharmacology 33:2291-2299, ). This provided evidence for a valence-specific role of serotonin (which declines under depleted tryptophan) in aversive processing. Recent theoretical (Dayan and Huys in PLoS Comput Biol 4:e4, ) and experimental (Crockett et al. in J Neurosci 29:11993-11999, ) approaches have, however, further specified this role by showing that serotonin is critical for punishment-induced inhibition. Objectives: We sought to examine the role of serotonin in punishment-induced inhibition. We also examined the impact of induced mood on this effect to assess whether effects of tryptophan depletion on affective inhibition are moderated by mood. Methods: Healthy females consumed a balanced amino acid mixture with ( N = 20) or without ( N = 21) the serotonin precursor tryptophan. Each subject completed either negative or neutral mood induction. All subjects completed the reward and punishment reversal learning task adopted in the previous study. Results: We demonstrate a punishment prediction impairment in individuals who consumed tryptophan which was absent in individuals who were depleted of tryptophan. This effect was impervious to mood state. Conclusions: Our results suggest that serotonin promotes the inhibition of responses to punishing outcomes. This may lead to reduced punishment prediction accuracy in the presence of tryptophan and may contribute to resilience to affective disorders. Reduction of serotonin via tryptophan depletion then removes this inhibition. As such, we highlight a mechanism by which reduced serotonin can contribute to disorders of impulsivity and compulsivity as well as disorders of emotion. [ABSTRACT FROM AUTHOR]

Rationale: Most individuals can accurately assess the risks and rewards associated with choice alternatives and decide accordingly; however, drug users often display maladaptive decision-making, such that choices are biased toward excessively risky options. Objective: The purpose of this study was to investigate the effects of a range of drugs of abuse on risky decision-making. Methods: Male Long-Evans rats were trained in the Risky Decision-Making Task, in which they chose between two levers, one which produced a small, 'safe' food reward and the other which produced a large, 'risky' food reward. The large reward was accompanied by the risk of a mild footshock, the probability of which increased over the course of each test session (0%, 25%, 50%, 75%, and 100%). Results: Nicotine (0.6 mg/kg) and amphetamine (1.5 mg/kg) caused a significant decrease in choice of the large risky reward (decreased risk taking). Diazepam (1.0 mg/kg) caused a significant increase in choice of the large risky reward (increased risk taking), whereas morphine (3.0 mg/kg) caused only a trend toward increased choice of the large risky reward. Ethanol had no effect on choice behavior. Conclusions: These results show that acute administration of drugs of abuse can modulate risk taking in a drug-specific manner, either increasing or decreasing preference for highly rewarding, but risky, options. [ABSTRACT FROM AUTHOR]

Rationale: Dysfunctional reward processing has been proposed as a main deficit in attention-deficit/hyperactivity disorder (ADHD), which could be modulated by treatment with methylphenidate (MPH). Objectives: We examined differences in reward processing in adulthood (independent of actual ADHD) depending on MPH treatment during childhood. Methods: Eleven males with childhood ADHD treated with MPH, 12 drug-naïve males with childhood ADHD, and 12 controls matched by age, handedness, and smoking behavior were studied drug-free using functional magnetic resonance imaging. BOLD-responses were compared during a monetary incentive delay task using an ANOVA design focusing on the ventral striatum during anticipation and the orbitofrontal cortex during outcome. Results: Controls, drug-naïve, and treated subjects did not differ significantly in their activations in the ventral striatum and orbitofrontal cortex. Explorative analyses revealed decreased insula activation during outcome of loss avoidance in drug-naïve subjects in comparison to both groups, while treated subjects did not differ from controls. Insula activation correlated significantly positive with harm avoidance in the treated group. Furthermore, comparing subjects with actual ADHD symptoms, remitters and controls we observed decreased putamen activition in ADHD persisters. Conclusions: Basal ganglia reward processing seemed to be unrelated to MPH pretreatment, but was related to remission. On the other hand, the revealed differences between treated and drug-naïve subjects with childhood ADHD, i.e., in the insula, give evidence for more pronounced abnormal activation in reward-associated brain regions in untreated subjects with childhood ADHD and underpin the need of prospective studies on long-term effects of psychostimulant treatment. [ABSTRACT FROM AUTHOR]

The neurotransmitter dopamine has frequently been implicated in reward processing but is also, increasingly, implicated in punishment processing. We have previously shown that both patients with Parkinson's disease and healthy individuals with low dopamine (DA) synthesis are better at reversal learning based on punishment than reward. Here, we extend these prior findings by examining the effects of artificially reducing DA synthesis in healthy individuals performing this previously employed task. In a double-blind, placebo-controlled crossover design, we applied the acute tyrosine and phenylalanine depletion (ATPD) procedure to reduce global DA synthesis in 15 female and 14 male subjects. Each subject performed the reward- and punishment-based reversal-learning paradigm. There was a significant three-way interaction between ATPD, the valence of the outcome signalling reversal and the gender of the participants. Examination of punishment and reward-based reversals separately revealed that this was driven by a significant improvement in punishment processing in female but not male subjects following DA depletion. Reducing DA synthesis in healthy individuals shifted sensitivity of performance from reward to punishment processing. Gender differences in DA synthesis might underlie the selectivity of this effect to female subjects. Such gender biases may go some way towards explaining the gender biases in certain psychiatric disorders such as depression and Parkinson's disease. [ABSTRACT FROM AUTHOR]

The serotonin (5-HT) system is considered important for decision-making. However, its role in reward- and punishment-based processing has not yet been clearly determined. The present study examines the effect of 5-HTTLPR genotype and tryptophan depletion on reward- and punishment-related processing, using a task that considers decision-making in situations of subtlety of choice. Thus, it considers that response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or undesirable. It also considers that response choice is easier when the reinforcements associated with the options are far apart, rather than close, in value. Healthy volunteers underwent acute tryptophan depletion (ATD) or control procedures and genotyping of the 5-HTTLPR for long and short allele variants. We then examined the effects and interactions of ATD and the serotonin promoter polymorphism genotype on two aspects of decision-making: (a) decision form, choosing between two objects to gain the greater reward or lesser punishment and (b) between-object reinforcement distance, the difference in reinforcements associated with two options. ATD and LL homozygosity had comparable interactions with decision form and between-object reinforcement distance. Specifically, both modulated the effect of between-object reinforcement distance when deciding between objects both associated with punishment. Moreover, ATD and genotype interacted with ATD disproportionately affecting the performance of the LL homozygous group. These results suggest that serotonin is particularly associated with punishment, rather than reward-related processing, and that individual sensitivity to punishment-related information and tryptophan depletion varies with genotype. [ABSTRACT FROM AUTHOR]

Abstinence from drug occurs in human addicts for several reasons, including the avoidance of adverse consequences. To explore a model of drug use in the face of adverse consequences in rats through intermittent punishment of drug seeking and to investigate whether the ability to withhold seeking responses depends upon the duration of drug history. Rats were trained under a seeking–taking chained schedule with sucrose or cocaine as reinforcer. Pressing the seeking lever gave access to the taking lever, and a single press on this lever delivered the reinforcer after which the seeking–taking chain recycled. During punishment, half of the seeking links terminated with a mild foot shock without access to the taking link. After a moderate history of reinforcement, punishment of the terminal response in the seeking link suppressed both sucrose- and cocaine-seeking responses. By contrast, rats with an extended cocaine history were more resistant to punishment than those with a moderate cocaine history. This enhanced resistance to punishment was due to a sub-group of rats that showed minimal or no suppression of drug seeking. No differences in suppression of sucrose seeking were observed in animals with moderate versus extended sucrose histories. These results suggest that an extended drug self-administration history decreases the ability of vulnerable rats to suppress their drug seeking. [ABSTRACT FROM AUTHOR]

Previously, we reported that opiate users enrolled in methadone treatment made ‘risky’ choices on a decision-making task following a loss of points compared with heroin users and healthy volunteers. One possible explanation for this behaviour is that methadone users were less sensitive to punishment on immediately preceding unsuccessful trials. We sought to explore this finding from a neural perspective by performing a post hoc analysis of data from a previous % MathType!Translator!2!1!AMS LaTeX.tdl!TeX AMS-LaTeX! % MathType!MTEF!2!1!+- % feaaeaart1ev0aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbbjxAHX % garmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy0Hgip5wz % aebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbbf9v8qqaq % Fr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq-He9q8qq % Q8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaeaaakeaaca % WGibWaa0baaSqaaiaaikdaaeaacaaIXaGaaGynaaaakiaad+eaaaa!3B9E! $$ H^{{15}}_{2} O $$ positron emission tomography study. We restricted the analysis to the opiate groups and controls, assessing differences between opiate users on methadone and those on heroin. We found significant over-activation in the lateral orbitofrontal cortex (OFC) in methadone users compared with both heroin users and controls concomitant with the greatest overall tendency to ‘play risky’. Heroin users showed significant under-activation in this area compared with the other two groups whilst exhibiting the greatest overall tendency to ‘play safe’. Correlational analysis revealed that abnormal task-related activation of the left OFC was associated with the dose of methadone in methadone users and with the duration of intravenous heroin use in heroin users. ‘Playing safe’ following a loss of points was also negatively correlated with the activation of pregenual anterior cingulate and insula cortex in controls, but not in opiate users. Our findings suggest that the interplay between processes involved in integrating penalty information for the purpose of response selection may be altered in opiate users. This change was reflected differentially in task-related pattern of OFC activation depending on the opiate used. [ABSTRACT FROM AUTHOR]

Rationale: Punishment is widely used in an effort to control drug-taking behavior; however, only a few preclinical studies have investigated the effects of punishment on drug self-administration. Such studies may contribute to more rational use of punishment to control drug use. Objectives: To evaluate the effects of punishment on choice between cocaine and food in rhesus monkeys. Methods: Rhesus monkeys were trained under a concurrent- choice schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) or cocaine injections (0-0.1 mg/kg per injection, fixed-ratio 10 schedule). Full cocaine choice dose- effect curves were determined under baseline conditions and under test conditions in which a putative punisher (intravenous histamine injection; 0.0032-0.032 mg/kg per injection) was paired with either food or cocaine delivery. Results: Under baseline conditions, cocaine produced a dose-dependent increase in cocaine choice. Histamine functioned as a punisher of both food- and cocaine-maintained responding. Pairing histamine with food delivery reduced food choice, increased cocaine choice, and produced left shifts in the cocaine choice dose-effect curve. Conversely, pairing histamine with cocaine decreased cocaine choice, increased food choice, and produced right shifts in the cocaine choice dose-effect curve. The magnitude of histamine's punishing effects was directly related to histamine dose and probability of histamine delivery, and inversely related to the magnitude of the reinforcer. Conclusions: These results demonstrate that a primary effect of punishment in the context of food vs cocaine choice is not only a decrease in the behavior being punished, but also an increase in the unpunished alternative behavior. [ABSTRACT FROM AUTHOR]

Discusses a research on lorazepam that reinstates punishment-suppressed remifentanil self-administration in rats. Use of punishment schedules as a model of anxiety; Drugs with antipunishment properties that have been tested in the extinction-based reinstatement model; Discontinuation of shock during testing.

Rationale. Converging evidence from studies with neurological patients and brain imaging studies with healthy volunteers suggests that the capacity to make choices between actions associated with probabilistic rewards and punishments depends upon a network of cortico-limbic systems including the orbitofrontal cortex, cingulate cortex, amygdala and striatum. The involvement of such structures highlights the emotional aspects of decision-making and suggests that decision-making may be sensitive to manipulations of the catecholamine systems that innervate these structures. In this study, we investigated the possible role of noradrenaline (NA). Objective. We examined the effects of a single oral 80 mg dose of the beta-adrenoceptor blocker, propranolol, on the decision-making of healthy volunteers in a double-blind, placebo-controlled, between-subjects design. Methods. Seventeen volunteers ingested a placebo while 15 volunteers ingested propranolol. Visual analogue scales, and self-reported positive and negative ratings, were used to assess subjective changes and mood. Vital signs were also monitored. Seventy-five minutes after treatment, volunteers were asked to make a series of choices between two simultaneously presented gambles, differing in the magnitude of possible gains (i.e. reward), the magnitude of possible losses (i.e. punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-cognitive biases in human decision-making, namely, risk-aversion when choosing between gains and risk-seeking when choosing between losses. Results. Propranolol treatment did not result in gross changes in subjective state or mood in comparison to placebo, but did slow heart rate significantly. Propranolol produced a selective change in volunteers’ decision-making; namely, it significantly reduced the discrimination between large and small possible losses when the probability of winning was relatively low and the probability of losing was high. Conclusions. These results suggest that NA modulates the processing of punishment signals when choosing between probabilistic rewards and punishments under conditions of increased arousal. [ABSTRACT FROM AUTHOR]

Rationale. Effects of compounds on punished responding have been predictive of anxiolytic efficacy in humans. The use of mice in these tests has been limited, but the utility of this species in drug discovery and for neurobiological inquiry would benefit from a rapid, reliable method. Objectives. The present experiments were designed to validate a new procedure in mice. Methods. Male, NIH Swiss mice were food deprived and placed in an experimental chamber with two nose-poke holes. Every nose poke (FR1) produced a 20 mg food pellet. On the following day, a drug vehicle was administered and the mice were again exposed to the FR1 schedule. On day 3, a compound was given and the mice were run under a mixed FR1 (food), FR1 (food+shock) schedule in alternating, unsignalled periods of 4 and 10 min for three cycles. In the 10-min periods, nose-pokes produced both food plus brief electrification of the grid floor (0.5 mA for 100 ms). Effects of compounds on food intake were also evaluated in separate groups of mice. Results. The introduction of shock substantially decreased responding during the 10-min punishment periods without significantly affecting responding during the non-punishment periods. The clinically effective anxiolytic agents chlordiazepoxide, pentobarbital, and bretazenil, but not buspirone, produced dose-dependent increases in suppressed responding, whereas d-amphetamine, chlorpromazine, and morphine were not effective. Chlordiazepoxide and bretazenil increased food consumption. Conclusions. The present method enables rapid and reliable evaluation of potential anxiolytic agents in mice with minimal training. Increases in food intake are not necessary for anxiolytic-like effects under these conditions. [ABSTRACT FROM AUTHOR]

Rationale. Despite a well-established relationship between alcohol and risky behavior in the natural environment, laboratory investigations have not reliably shown acute alcohol effects on human risk-taking. Objectives. The present study was designed to demonstrate a dose-response relationship between acute alcohol administration and human risk taking. Further, this investigation sought to delineate behavioral mechanisms that may be involved in alcohol-induced changes in the probability of risky behavior. Methods. Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.2, 0.4, and 0.8 g/kg alcohol in a within-subject repeated measures experimental design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and non-risky. Data analyses examined: breath alcohol level (BAL), subjective effects, response rates, distribution of choices between the risky and non-risky option, and trial-by-trial probabilities of making losing and winning risky responses. Results. The alcohol administration produced the expected changes in BAL, subjective effects, and response rate. Alcohol dose-dependently increased selection of the risky response option, and at the 0.8 g/kg dose, increased the probability of making consecutive losing risky responses following a gain on the risky response option. Conclusions. Acute alcohol administration can produce measurable changes in human risk-taking under laboratory conditions. Shifts in trial-by-trial response probabilities suggest insensitivity to past rewards and more recent losses when intoxicated, an outcome consistent with previous studies. This shift in sensitivity to consequences is a possible mechanism in alcohol-induced changes in risk taking. [ABSTRACT FROM AUTHOR]

A punishment discrimination was conditioned in pigs by simultaneously rewarding with food and punishing with electric shock all operant responses made in the presence of an odorous stimulus. Suppression of the punished responses did not develop after 5 days of training in pigs chronically treated with diazepam (1 mg/kg). Diazepam (0.25 to 2 mg/kg) consistently increased the number of punished responses on an already learned punished behaviour and decreased the latency of the first response during and after the odorous stimulus signalling the shock contingency. More marked effects were obtained with 1-2 mg/kg. The pig punishment procedure appears to be a useful technique in studying psychopharmacological agents of interest in veterinary therapeutics. [ABSTRACT FROM AUTHOR]

Clinical reports have suggested that propranolol, a Β-adrenergic blocker, has antianxiety properties. In the present laboratory experiments, this suggestion was explored by testing propranolol and chlordiazepoxide in rat lever-pressing conflict procedures that selectively identify antianxiety compounds. Chlordiazepoxide produced anticonflict effects in such a procedure at doses from 1.25 to 40 mg/kg. Propranolol, tested at doses of 2.5 to 80 mg/kg, did not produce the anticonflict pattern typical of standard antianxiety agents, which is characterized by progressive dose-related increases in punished responding that frequently are several 100% above control levels. In contrast, the largest increases produced by propranolol, which occurred in the 10-40 mg/kg dose range, were 18-26% above control; only the 26% increase observed at the 20 mg/kg dose was statistically significant. In a different conflict test, a 40 mg/kg dose of propranolol was found to have a slight, but not significant, anticonflict effect. When this dose level was combined with doses of 2.5, 5, or 10 mg/kg of chlordiazepoxide p.o., the combined treatments produced greater anticonflict effects than did the corresponding individual doses of chlordiazepoxide. [ABSTRACT FROM AUTHOR]