Tolerance to N6-(l-phenylisopropyl) adenosine Contribution of behavioral mechanisms and cross-tolerance profile

The contribution of behavioral mechanisms to tolerance to N6-(l-rmphenylisopropyl)adenosine (l-PIA) was studied, along with the degree of cross-tolerance to other drugs active in the CNS. Rats were stabilized on a fixed-ratio of a 20 lever-pressing schedule for food reward and were then assigned to three daily-treatment groups. One group (saline-behavior associated) was injected with saline 15 min before the session, another (l-PIA-behavior associated) was injected with l-PIA (0.08 mg/kg) 15 min before the session and the last (l-PIA-behavior dissociated) was injected with l-PIA (0.08 mg/kg) immediately after the session. Tolerance developed to the decreasing effects of l-PIA on response rate in both groups, l-PIA-behavior associated and l-PIA-behavior dissociated. Behavioral mechanisms were thus not important in tolerance to l-PIA. In subsequent cross-tolerance tests, l-PIA-tolerant rats were crosstolerant to the adenosine A1 receptor agonist, N6-cyclohexyladenosine. The drugs 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), diazepam, pentobarbital, ketamine, clonidine, d-amphetamine and caffeine did not produce differential effects in l-PIA-tolerant and non-tolerant subjects; however, l-PIA-tolerant subjects were more sensitive to the suppressive effects of chlorpromazine on the response-rate.