Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

The transition from controlled drug use to drug addiction depends on an interaction between a vulnerable individual, their environment and a drug. Here we tested the hypothesis that conditions under which individuals live influence behavioral vulnerability traits and experiential factors operating in the drug taking environment to determine the vulnerability to addiction. The role of behavioral vulnerability traits in mediating the influence of housing conditions on the tendency to acquire cocaine self-administration was characterized in 48 rats housed in either an enriched (EE) or a standard (SE) environment. Then, the influence of these housing conditions on the individual vulnerability to develop addiction-like behavior for cocaine or alcohol was measured in 72 EE or SE rats after several months of cocaine self-administration or intermittent alcohol drinking, respectively. The determining role of negative experiential factors in the drug taking context was further investigated in 48 SE rats that acquired alcohol drinking to self-medicate distress in a schedule-induced polydipsia procedure. The environment influenced the acquisition of drug intake through its effect on behavioral markers of resilience to addiction. In contrast, the initiation of drug taking as a coping strategy or in a negative state occasioned by the contrast between enriched housing conditions and a relatively impoverished drug taking setting, facilitated the development of compulsive cocaine and alcohol intake. These data indicate that addiction vulnerability depends on environmentally determined experiential factors, and suggest that initiating drug use through negative reinforcement-based selfmedication facilitates the development of addiction in vulnerable individuals.

BackgroundN-acetylcysteine (NAC) has been suggested to prevent relapse to cocaine seeking. However, the psychological processes underlying its potential therapeutic benefit remain largely unknown.MethodsWe investigated the hallmark features of addiction that were influenced by chronic NAC treatment in rats given extended access to cocaine: escalation, motivation, self-imposed abstinence in the face of punishment, or propensity to relapse. For this, Sprague Dawley rats were given access either to 1 hour (short access) or 6 hours (long access [LgA]) self-administration (SA) sessions until LgA rats displayed a robust escalation. Rats then received daily saline or NAC (60 mg/kg, intraperitoneal) treatment and were tested under a progressive ratio and several consecutive sessions in which lever presses were punished by mild electric foot shocks.ResultsNAC increased the sensitivity to punishment in LgA rats only, thereby promoting abstinence. Following the cessation of punishment, NAC-treated LgA rats failed to recover fully their prepunishment cocaine intake levels and resumed cocaine SA at a lower rate than short access and vehicle-treated LgA rats. However, NAC altered neither the escalation of SA nor the motivation for cocaine. At the neurobiological level, NAC reversed cocaine-induced decreases in the glutamate type 1 transporter observed in both the nucleus accumbens and the dorsolateral striatum. NAC also increased the expression of Zif268 in the nucleus accumbens and dorsolateral striatum of LgA rats.ConclusionsOur results indicate that NAC contributes to the restoration of control over cocaine SA following adverse consequences, an effect associated with plasticity mechanisms in both the ventral and dorsolateral striatum.

The alarming increase in heroin overdoses in the USA is a reminder of the need for efficacious and novel treatments for opiate addiction. This may reflect the relatively poor understanding of the neural basis of heroin, as compared to cocaine, seeking behaviour. While cocaine reinforcement depends on the mesolimbic system, well-established cocaine seeking is dependent on dorsolateral striatum (aDLS) dopamine-dependent mechanisms which are disrupted by N-acetylcysteine, through normalisation of corticostriatal glutamate homeostasis. However, it is unknown whether a functional recruitment of aDLS dopamine-dependent control over instrumental responding also occurs for heroin seeking, even though heroin reinforcement does not depend on the mesolimbic dopamine system. Lister Hooded rats acquired heroin self-administration and were subsequently trained to seek heroin daily over prolonged periods of time under the control of drug-paired cues, as measured under a second-order schedule of reinforcement. At different stages of training, that is, early on and when heroin seeking behaviour was well established, we measured the sensitivity of drug-seeking responses to either bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (5, 10 and 15 μg/side) or systemic administration of N-acetylcysteine (30, 60 and 90 mg/kg). The results demonstrate that control over heroin seeking behaviour devolves to aDLS dopamine-dependent mechanisms after extended training. Further aDLS-dependent well-established, cue-controlled heroin seeking was disrupted by N-acetylcysteine. Comparison with previous data on cocaine suggests that the development of drug seeking habits and the alteration of corticostriatal glutamate homeostasis, which is restored by N-acetylcysteine, are quantitatively similar between heroin and cocaine.

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