The role of impulsivity as predisposing behavioural trait in different aspects of alcohol self-administration in rats.

BACKGROUND: Therapeutic interventions to promote abstinence and prevent relapse in alcohol use disorder (AUD) are limitedly available. Therefore, targeting risk factors in the onset and maintenance of AUD could pose an interesting alternative treatment strategy. In this regard, over the last decade trait impulsivity has received considerable attention as such a risk factor predisposing substance dependence both in clinical populations and preclinical rodent studies. This study investigated whether different forms of impulsivity (action versus choice) predict distinct stages of instrumental alcohol self-administration, extinction and cue-induced relapse. METHODS: Two cohorts of n = 48 rats each were trained in an operant tasks for either impulsive action or impulsive choice. Subsequently, high and low impulsive rats were then tested in an alcohol self-administration and relapse model and following this retested in the impulsivity tasks to evaluate possible changes in impulsivity levels. RESULTS: The current data show that neither impulsive action, nor impulsive choice predict the extent to which rats consume alcohol and the extent to which rats are motivated to self-administer alcohol. Moreover, extinction of responding for alcohol and cue-induced relapse was not predicted by impulsivity. Interestingly, rats and most prominently low impulsive rats became more impulsive after the alcohol self-administration procedure. Although due to employed experimental design it is not clear whether this resulted from alcohol consumption or alcohol abstinence. CONCLUSION: Together, these findings lend further support for the notion of a unidirectional relationship between self-administration of the depressant drug alcohol and impulsivity.

Cannabinoids and value-based decision making: implications for neurodegenerative disorders.

In recent years, disturbances in cognitive function have been increasingly recognized as important symptomatic phenomena in neurodegenerative diseases, including Parkinson's Disease (PD). Value-based decision making in particular is an important executive cognitive function that is not only impaired in patients with PD, but also shares neural substrates with PD in basal ganglia structures and the dopamine system. Interestingly, the endogenous cannabinoid system modulates dopamine function and subsequently value-based decision making. This review will provide an overview of the interdisciplinary research that has influenced our understanding of value-based decision making and the role of dopamine, particularly in the context of reinforcement learning theories, as well as recent animal and human studies that demonstrate the modulatory role of activation of cannabinoid receptors by exogenous agonists or their naturally occurring ligands. The implications of this research for the symptomatology of and potential treatments for PD are also discussed.

Trait impulsive choice predicts resistance to extinction and propensity to relapse to cocaine seeking: a bidirectional investigation.

Despite the strong association between impulsivity and addiction in humans, it is still a matter of debate whether impulsive choice predisposes to, or results from, drug dependence. Furthermore, it is unknown whether treating impulsivity can protect against relapse propensity. Therefore, this study explored the bidirectional relationship between impulsive choice and cocaine taking and seeking in rat behavioral models. In experiment 1, to determine whether impulsive choice predisposes to cocaine taking or seeking, rats were selected based on trait impulsivity in a delayed reward task and subsequently compared on various stages of cocaine self-administration (SA). To examine the consequence of cocaine intake on impulsive choice, impulsivity was monitored once a week throughout various stages of cocaine SA. To determine whether treating impulsive choice can protect against relapse propensity, in experiment 2, impulsive choice was manipulated by pharmacological interventions and cocaine-associated contextual cues. Trait impulsive choice as determined in experiment 1 predicted high extinction resistance and enhanced propensity to context-induced relapse in the cocaine SA model, whereas cocaine intake did not alter impulsive choice. Furthermore, acute changes in impulsive choice were not related to rates of context-induced relapse. Taken together, the current data indicate that trait impulsive choice predicts persistent cocaine seeking during extinction and enhanced propensity to relapse, whereas acute manipulations of impulsive choice had no favorable outcomes on relapse measures. These observations suggest that trait impulsivity can be used as a predictive factor for addiction liability, but treating this impulsivity does not necessarily protect against relapse.

Poor impulse control predicts inelastic demand for nicotine but not alcohol in rats.

Tobacco and alcohol dependence are characterized by continued use despite deleterious health, social and occupational consequences, implying that addicted individuals pay a high price for their use. In behavioral economic terms, such persistent consumption despite increased costs can be conceptualized as inelastic demand. Recent animal studies demonstrated that high-impulsive individuals are more willing to work for nicotine or cocaine infusions than their low-impulsive counterparts, indicating that this trait might be causally related to inelastic drug demand. By employing progressive ratio schedules of reinforcement combined with a behavioral economics approach of analysis, we determined whether trait impulsivity is associated with an insensitivity of nicotine or alcohol consumption to price increments. Rats were trained on a delayed discounting task, measuring impulsive choice. Hereafter, high- and low-impulsive rats were selected and trained to nose poke for intravenous nicotine or oral alcohol. Upon stable self-administration on a continuous reinforcement schedule, the price (i.e. response requirement) was increased. Demand curves, depicting the relationship between price and consumption, were produced using Hursh's exponential demand equation. Similar to human observations, nicotine and alcohol consumption in rats fitted this equation, thereby demonstrating the validity of our model. Moreover, high-impulsive rats displayed inelastic nicotine demand, as their nicotine consumption was less sensitive to price increments as compared with that in low-impulsive rats. Impulsive choice was not related to differences in alcohol demand elasticity. Our model seems well suited for studying nicotine and alcohol demand in rats and, as such, might contribute to our understanding of tobacco and alcohol dependence.

Disruption of Long-Term Alcohol-Related Memory Reconsolidation: Role of ß-Adrenoceptors and NMDA Receptors.

Disrupting reconsolidation of drug-related memories may be effective in reducing the incidence of relapse. In the current study we examine whether alcohol-related memories are prone to disruption by the ß-adrenergic receptor antagonist propranolol (10 mg/kg) and the NMDA receptor antagonist MK801 (0.1 mg/kg) following their reactivation. In operant chambers, male Wistar rats were trained to self-administer a 12% alcohol solution. After 3 weeks of abstinence, the animals were placed in the self-administration cages and were re-exposed to the alcohol-associated cues for a 20-min retrieval period, immediately followed by a systemic injection of either propranolol, MK801 or saline. Rats were tested for cue-induced alcohol seeking on the following day. Retrieval session, injection and test were repeated on two further occasions at weekly intervals. Both propranolol and MK801 administration upon reactivation did not reduce alcohol seeking after the first reactivation test. However, a significant reduction of alcohol seeking was observed over three post-training tests in propranolol treated animals, and MK801 treated animals showed a strong tendency toward reduced alcohol seeking (p = 0.06). Our data indicate that reconsolidation of alcohol-related memories can be disrupted after a long post-training interval and that particularly ß-adrenergic receptors may represent novel targets for pharmacotherapy of alcoholism, in combination with cue-exposure therapies.

Trait impulsivity predicts escalation of sucrose seeking and hypersensitivity to sucrose-associated stimuli.

Poor impulse control has been associated with compulsive drug seeking and an enhanced risk of relapse, suggesting that impulsivity is causally related to addiction proneness and relapse vulnerability. However, whether this association is specific to drugs of abuse or whether heightened impulsivity relates to a general increase in sensitivity to rewards and reward-associated stimuli is unknown. To address this issue, the authors selected rats on the basis of individual differences in impulsive action in the 5-choice serial reaction time task, after which they were subjected to an operant sucrose self-administration paradigm. High-impulsive rats displayed a progressive increase in responding on the active hole (including responses emitted during the time-out period) in comparison with low-impulsive rats, which reflects escalation of sucrose-seeking behavior. Once sucrose and sucrose-associated stimuli were omitted (extinction training), nose-poke responding ceased rapidly, an effect that was independent of impulsivity level. In contrast, on reintroduction of sucrose-associated stimuli, sucrose seeking was successfully reinstated in high-impulsive but not in low-impulsive rats. Collectively, the results suggest that impaired response inhibition is associated with enhanced responsiveness to reward-associated stimuli. As such, elevated impulsivity might constitute a risk factor for the initiation and maintenance of addictive behaviors.

Pharmacological manipulation of memory reconsolidation: towards a novel treatment of pathogenic memories.

Well-consolidated memories, when retrieved, may return to a transiently fragile state, and need to be consolidated again in order to be maintained. This process has been referred to as memory reconsolidation and presumably serves to modify or strengthen memory traces. In recent years, our understanding of the neurobiological mechanisms underlying this phenomenon has increased rapidly. Here, we will briefly review some of the pharmacological evidence, stressing a crucial role for the brain's major neurotransmitter systems, such as glutamate and noradrenaline, in memory reconsolidation. Pharmacological intervention of reconsolidation processes may have clinical relevance, especially for the treatment of psychiatric disorders that are characterized by pathological memories, including post-traumatic stress disorder and addictive behaviour.

Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats.

BACKGROUND: Although heavy smoking has been associated with impulsivity in humans, it is not clear whether poor impulse control represents a risk factor in the etiology of nicotine dependence. METHODS: To address this issue, rats were selected on the basis of individual differences in impulsivity in the delayed reward task (impulsive choice) and the 5-choice serial reaction time task (impulsive action). Subsequently, rats were subjected to a nicotine self-administration (SA) paradigm tailored to measure the motivational properties of nicotine and nicotine-associated stimuli. In separate groups, differences in electrically evoked dopamine release in slice preparations obtained from several mesolimbic brain regions were determined. RESULTS: Impulsive action was associated with an enhanced motivation to initiate and maintain nicotine SA. In contrast, impulsive choice predicted a diminished ability to inhibit nicotine seeking during abstinence and an enhanced vulnerability to relapse upon re-exposure to nicotine cues. Impulsive action was associated with reduced dopamine release in the accumbens core and impulsive choice with reduced dopamine release in accumbens core, shell, and medial prefrontal cortex. CONCLUSIONS: The strong association between sub-dimensions of impulsivity and nicotine SA implies that interventions aimed to improve impulse control might help to reduce susceptibility to nicotine dependence and/or lead to successful smoking cessation.

Beta-adrenoceptor mediated inhibition of long-term reward-related memory reconsolidation.

Well-consolidated fear-related memories, once retrieved, are susceptible to disruption and require reconsolidation in order to be maintained. We examined whether reactivated reward-related memories are also susceptible to interference by evaluating the effect of propranolol (PROP), a beta-adrenergic antagonist known to impair reconsolidation of fear-related memories, on context-induced sucrose seeking. PROP administration upon reactivation reduced sucrose seeking behaviour 3 weeks post-training, indicating that reconsolidation of reward-related memories can be disrupted after a long post-training interval.

Neonatal amygdala lesions affect appetitive motivational and consummatory aspects of social behavior in the rat.

In the present study, rats received amygdala lesions (AMX) on either Postnatal Day 7 (PD 7; immature brain) or PD 21 (almost mature brain), and adult social activity was studied after short-term isolation housing. Sham-operated rats demonstrated increased following and approaching behavior after 7 days of isolation compared with after 4 days of isolation, an effect that was absent in AMX-PD 7 and AMX-PD 21 rats. Furthermore, AMX-PD 7 rats, but not AMX-PD 21 rats, displayed a reduction in investigatory behavior after prolonged isolation. This indicates that in AMX-PD 21 rats, mainly appetitive motivational aspects of social behavior were affected, whereas in AMX-PD 7 rats both motivational and consummatory aspects were disturbed. Finally, the reported deficits in AMX-PD 7 rats may reflect neurodevelopmental deficits of structures connected with the amygdala.

Neonatal amygdala lesions and juvenile isolation in the rat: differential effects on locomotor and social behavior later in life.

Pervasive developmental disorders such as autism are characterized by deficits in social interaction and communication. Disturbed development of limbic structures such as the amygdala might underlie these deficits. The authors examined the effects of amygdala lesions on Postnatal Day 7 and juvenile isolation (2 weeks of individual housing during Weeks 4 and 5 of life) on rat locomotor and social activity later in life. Before puberty, but more pronounced after puberty, lesioned rats displayed enhanced locomotor activity. Adult social behavior was selectively disturbed by the lesion and the isolation procedure. In particular, the combination of neonatal lesions and juvenile isolation severely disrupted social interaction. These results suggest that a combination of neonatal amygdala damage and juvenile isolation may serve as an animal model of certain psychopathological neurodevelopmental disorders, such as autism.