Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

Abstract

The transition from drug use to drug addiction is associated with a process of escalation, whereby drug use becomes excessive and difficult to control. Several mechanisms have been advanced to explain escalating patterns of drug use as opposed to nonescalating patterns. Although current evidence favors hedonic tolerance, there remains some dispute about the contribution of behavioral sensitization to cocaine intake escalation. Here, we concurrently assessed the ability of cocaine to induce psychomotor sensitization and drug-seeking behavior in animals with 1-h (short access or ShA) vs 6-h (long access or LgA) access to intravenous (i.v.) cocaine selfadministration. As expected, cocaine intake by LgA rats escalated over time and became excessive compared to cocaine intake by ShA rats, which remained low and stable. Despite escalated levels of cocaine consumption, however, LgA rats were not more sensitized to cocaine than ShA rats. The dose-effect function for cocaine-induced locomotion (0.125-1 mg, i.v.) was shifted to the left in LgA rats by the same amount as in ShA rats after cocaine self-administration. In contrast, LgA rats were much more responsive than ShA rats to the motivational effects of cocaine, as measured by the ability of i.v. cocaine to reinstate extinguished drug-seeking behavior. This study demonstrates a dissociation of psychomotor sensitization from the change in motivation underlying the transition to compulsive cocaine consumption, and therefore suggests that responsiveness to the motivational effects of the drug, not psychomotor sensitization, would represent a specific behavioral marker of the transition to and maintenance of compulsive cocaine use.

Heroin-Induced Reinstatement is Specific to Compulsive Heroin Use and Dissociable from Heroin Reward and Sensitization

“…During the screening phase, rats were allowed to self-administer heroin (15 mg per unit dose delivered in a volume of 74 ml) during only 1 h after which two balanced groups with the same mean body weight (ShA rats, 300.872.9 g; LgA rats, 297.074.0 g) and mean heroin self-administration (6.170.4 injections in both groups) were formed. This 1-day screening method of balancing groups was shown to be highly reliable in previous experiments on escalation of cocaine self-administration (Ahmed et al, 2002(Ahmed et al, , 2003Ahmed and Cador, 2006). During the escalation phase, one group had access to heroin self-administration for only 1 h/day (short-access or ShA rats, n ¼ 24) and the other group for 6 h/day (long-access or LgA rats, n ¼ 24).…”

“…We recently began to test the validity of the sensitization hypothesis of drug addiction in animals with differential access to cocaine self-administration (Ben-Shahar et al, 2004;Ahmed and Cador, 2006). We concurrently assessed the ability of cocaine to induce stimulation of locomotion and to reinstate drug seeking after extinction in both ShA rats and LgA rats.…”

“…After escalation of heroin intake by LgA rats, all animals were tested with different heroin doses (7.5-30 mg, i.v.) in a within-session reinstatement model of drug-induced craving (Ahmed and Cador, 2006). All tests were conducted in the environment paired with heroin selfadministration.…”

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…The regulation of mesolimbic Homer protein expression by cocaine has also been assessed in a "long access" animal model of addiction in which groups of animals are allowed to self-administer intravenous cocaine daily for either 1 hr or 6 hrs [e.g., [230][231][232]. These two self-administration paradigms elicit very different patterns of cocaine intake (stable vs. escalating, respectively) [e.g., 230] and result in very different neuroadaptations, as revealed by both behavioral and biochemical assays [230][231][232][233][234][235][236][237]. The effects of a history of cocaine self-administration upon corticoaccumbens CC-Homer expression are complex, dependent upon the duration of cocaine access, the duration of withdrawal and the region investigated (Table 2) [167,237].…”

Supply of a Nondrug Substitute Reduces Escalated Heroin Consumption

“…During the screening phase, rats had access to heroin (15 mg per unit dose delivered in a volume of 74 ml) during only 1 h. The goal of this phase was to measure the initial operant level of responding on each lever in each rat to form two balanced groups with similar mean levels of responding and mean body weight before differential access to the drug (eg Ahmed et al, 2002;Ahmed and Cador, 2006;. During the escalation phase, one group had access to heroin self-administration for only 1 h per day (ShA rats, n ¼ 12) and the other group for 6 h per day (LgA rats, n ¼ 12).…”