The Influence of CNS stimulants, opioid antagonists and an NMDA antagonist on the reinforcing effect of cocaine using a progressive-ratio schedule

It has been hypothesized that there is a common dopaminergic pathway mediating the reward properties of abused drugs, and that dopamine is involved in tolerance to the reinforcing effect of cocaine. The progressive-ratio (PR) schedule can be used to test both potentiation and reduction of the reinforcing effects of cocaine by other factors. Under the PR schedule, an increasing number of responses is required to obtain each subsequent cocaine injection, and failure to complete the required number of responses within 1 h of the previous cocaine injection terminates the session. The number of total reinforcers obtained during a session is defined as “the breaking point” and was used as the primary dependent measure. Fisher F344 male rats acquired the self-administration task under the PR schedule within forty sessions and showed a stable daily acquisition baseline. The breaking point and inter-reinforcer time (ISRT) were positively correlated within each ratio. A motor-incapacitating side effect of a pretreatment can be determined by a change in the relationship between the ISRT and the breaking point. d-Amphetamine pretreatment (0.32-3.2 mg/kg, i.p., 30 min) potentiates the reinforcing effect of cocaine as demonstrated by a higher breaking point of self-administration without changing the ISRT. Morphine pretreatment (0.32-3.2 mg/kg, i.p., 30 min failed to change the breaking point of cocaine self-administration but it did increase the ISRT. These results support an additive reinforcing effect for amphetamines and cocaine, but do not support an additive reinforcing effect of morphine and cocaine. The reinforcing effect of cocaine was reduced by pretreatment with ketamine (0.032-0.32 mg/kg, i.p., 20 min) as indicated by a reduction in the breaking point. In a concurrent experiment, animals were trained to self-administer cocaine under a fixed ratio 2 schedule (FR2). Ketamine pretreatment did not modify the ISRT in FR2 trained animals except at the highest dose (0.32 mg/kg, i.p., 20 min), where significant motor incoordination was observed. Both chronic treatment with cocaine (20 mg/kg/ 8hr x 7 days, iv) or amphetamine (3.2 mg/kg /12 hr x 7 days, i.p.) resulted in a reduction in breaking point at any given dose, providing direct evidence of tolerance and cross-tolerance to the reinforcing effects of cocaine. Chronic treatment with ketamine (0.32 mg/kg/8hr x 7 days, i.v.) failed to modify either the breaking point under a PR schedule of reinforcement or the ISRT under a FR2 schedule of reinforcement. Co-administration of ketamine (0.32 mg/kg/8hr x 7 days, i.v.) with chronic cocaine (20 mg/kg/8hr x 7days, i.v.) failed to prevent tolerance to the reinforcing effect of cocaine as indicated by either the breaking point under a PR schedule of reinforcement of the ISRT under an FR2 schedule of reinforcement. These data indicate that the breaking point in the PR schedule is more sensitive to changes in the dopamine reward system, whereas changes in rate of response are not consistently related to the changes in the dopamine reward system. These data support the use of PR schedule as a better method than FR schedule for determining reward properties of drugs of abuse with fewer complications due to the central nervous system inhibitory effects of some drugs of abuse.