Attenuation of isobutylmethylxanthine-induced suppression of operant behavior by pretreatment of rats with clonidine.

Administration of 3-isobutyl-1-methylxanthine (IBMX) to rats performing a FR30 operant for food reinforcement produces a dose-dependent suppression of behavior. Operant behavior suppressed by 5 mg IBMX/kg is attenuated by pretreatment, 30 min before the operant session, with the alpha 2 adrenergic agonist clonidine (5-30 micrograms/kg). Clonidine itself causes a dose-dependent reduction in FR30 responding prior to the administration of IBMX. However, doses of clonidine which also suppressed responding were not more effective than lower doses in attenuating the suppression of operant behavior caused by IBMX, perhaps due to postsynaptic or nonspecific actions of clonidine. Methylxanthines, alone or in combination with the opiate antagonist naloxone, produce signs of opiate withdrawal. This quasi-morphine withdrawal syndrome may be useful in studies of either the development or expression of opiate withdrawal. Since clonidine attenuates the rate-suppressant effect of IBMX, it is likely that a significant component of IBMX's behavioral effects are due to increases in NE neurotransmission. These results are similar to those obtained with true opiate withdrawal in rats, strengthening the idea that suppression of operant behavior by IBMX involves mechanisms in common with opiate withdrawal. It may be a useful way of objectively studying the expression of the withdrawal syndrome in the absence of opiates and/or a way of determining if a drug can selectively block withdrawal.