LgA Rats Research Articles

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

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 self-administration. 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.

Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats

Evidence is accumulating that metabotropic glutamate 5 (mGlu5) receptors play an important role in regulating the reinforcing actions of drugs of abuse. We examined the effects of the mGlu5 receptor antagonist MPEP on cocaine consumption and cocaine-enhanced brain reward function in rats. Cocaine consumption was measured in rats with 1 h (short-access; ShA) or 6 h (long-access; LgA) daily access to intravenous cocaine (0.25 mg/infusion) self-administration. Cocaine-enhanced brain reward function was measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. Cocaine consumption remained stable and unaltered over successive self-administration sessions in ShA rats. In contrast, cocaine consumption progressively "escalated" in LgA rats. MPEP (1--9 mg/kg) dose-dependently decreased responding similarly in ShA and LgA rats. These data suggest that mGlu5 receptors regulate the reinforcing properties of cocaine, and that this action of mGlu5 receptors is independent of the escalation in consumption associated with extended access to cocaine self-administration. MPEP doses (1--9 mg/kg) that decreased cocaine self-administration elevated brain reward thresholds to a similar degree in cocaine- and vehicle-treated rats, indicating that MPEP induced a negative affective state. The additive effects of MPEP and cocaine on thresholds resulted in attenuation of the magnitude of cocaine-induced (10 mg/kg) lowering of ICSS thresholds. Overall, mGlu5 receptors appear to play an important role in regulating cocaine consumption, and also in regulating brain reward function. Further, it is likely that blockade of mGlu5 receptors may attenuate cocaine consumption, at least in part, by decreasing the baseline activity of brain reward circuitries.

Changes in response to a dopamine receptor antagonist in rats with escalating cocaine intake.

Prolonged access to cocaine self-administration (long access or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access or ShA). The present study tested the hypothesis that escalating use of cocaine is associated with chronic alterations in dopamine neurotransmission. After escalation of cocaine self-administration, ShA and LgA rats were challenged with different subcutaneous doses of cis-flupenthixol (10-270 micro g/kg), a highly selective dopamine receptor antagonist. In both groups, increasing doses of cis-flupenthixol first produced an increase in the number of cocaine injections and then a dramatic suppression of behavior. This biphasic dose-effect function-which replicates previous findings from this laboratory-was shifted to the left in LgA rats relative to ShA rats, thereby decreasing the threshold dose at which behavior was completely suppressed. These data support the hypothesis that alterations in dopamine neurotransmission contribute to escalation of cocaine self-administration.

Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels.

Previous studies showed that prolonged access to cocaine or heroin self-administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125-1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self-administration. Self-administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self-administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.

Long-lasting increase in the set point for cocaine self-administration after escalation in rats.

When access time to a continuous schedule of drug self-administration is restricted, animals tend to limit intake to a certain level over time and across doses. This observation suggests an endogenous constraint or set point that determines the individual's preferred level of pharmacological effects. To assess whether the transition to increased levels of drug intake is associated with a change in set point. Two groups of rats were trained on a 1-h continuous schedule of cocaine self-administration (250 microg/injection), after which access to cocaine was increased to 6 h in one group (Long Access or LgA rats) or kept to 1 h in the other group (Short Access or ShA rats). After 22 sessions on this regimen, different doses of cocaine were tested (31.25, 62.5, 125, and 250 microg/injection). For each dose, the post-response time-out period was reduced to 4 s to reduce any temporal limitations on self-injections and subjects were tested several times. In LgA rats, the first hour intake escalated over time and eventually reached a level 200% greater than that of ShA rats. Though all rats maintained relatively constant intake across doses, LgA rats took nearly two times as much cocaine than ShA rats. When access to cocaine for LgA rats was reduced to 1 h, intake returned very slowly toward pre-escalation levels but was still elevated even after 2 months of reduced availability. These data suggest that the transition to escalated levels of intake is associated with a long-lasting change in cocaine set point.