Cracking the Molecular Code of Cocaine Addiction

Abstract

Cocaine addiction is a behavioral disorder defined by behavioral symptoms that set it apart from nondisordered forms of drug use. Here we review evidence in rats (the most frequently used animal model in the field) that it is possible, after extended (but not after limited) access to cocaine for self-administration, to selectively induce some of these behaviors: gradual escalation of cocaine intake, enhanced motivation for the drug despite increased costs (or negative consequences), and increased sensitivity to drug- and stress-primed craving-like behavior. Animals with extended drug use also present selective neurocognitive deficits (e.g., compromised working memory) that may impair their ability to regulate cocaine intake. In some rats, extended access to cocaine for self-administration is associated with loss of control over cocaine intake, as assessed by continued drug use despite the opportunity to make a different choice and to the exclusion of more natural and rewarding activities. These rats may represent the most advanced and severe stage on the path to cocaine addiction. Finally, comparisons of rats with extended versus limited access to cocaine for self-administration have recently revealed the existence of a new molecular pathway in the dorsal striatum (a brain region altered in cocaine-addicted humans) that causally and selectively controls cocaine intake. This pathway involves unforeseen homeostatic interactions between microRNAs (a class of nonprotein-coding RNAs) and some key molecular regulators of neuronal plasticity (e.g., MeCP2 and BDNF). This discovery provides an entirely new direction for the development of effective antiaddiction treatments.

Cocaine self‐administration induces changes in synaptic transmission and plasticity in ventral hippocampus

“…Escalation of the initial drug intake was evident in the taker rats, as the number of cocaine infusions during the first hour of the self‐administration averaged over the last 3 days of LgA sessions (27.3 ± 1.2, days 20–22) was significantly enhanced when compared with the infusions during the first hour of self‐administration averaged over the last 3 days of the ShA sessions (23.5 ± 1.1, days 13–15; paired t ‐test, P < 0.05). Protocols similar to the current one have been shown to generate rats that exhibited typical characteristics of psychostimulant addiction, such as (1) compulsive binging, (2) drug seeking under aversive conditions and (3) propensity for reinstatement upon presentation of drug associated cues, context or priming with the drug itself (Ahmed & Kenny ). All recordings were obtained 3–5 weeks following the last day of LgA self‐administration, a time by which incubation‐dependent changes have occurred in the NAc (see Loweth et al for review).…”

Effects of Conditional Central Expression of HIV-1 Tat Protein to Potentiate Cocaine-Mediated Psychostimulation and Reward Among Male Mice

“…As such, the present data support the notion that exposure to HIV-Tat protein may exert important effects over already established patterns of drug use. Although challenging to execute in mice, future investigations will aim to utilize self-administration (Ahmed and Kenny, 2011) to parse out the reinforcing effects of Tat on cocaine use.…”

Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence

“…In Exp. an extended-access relative to short-access self-administration are distinct [60] and that juvenile onset and adult onset self-administration are associated with different physiological and behavioral changes [61,62].…”