Neurochemical changes associated with schedule-controlled behavior.

Studies of monoamine metabolites within the cerebrospinal fluid compartment have indicated that this approach may be useful in examining central metabolic changes in vivo. By combining the technologies of radioisotope chemistry, operant behavior control and modification, and brain perfusion with push-pull cannulas, we have been able to examine minute to minute changes in the disposition of radiolabeled monoamine transmitter candidates and their metabolites. These substances appear to co-vary with changes in complex behavior maintained by operant schedules of reinforcement and affected by changes in schedules or administration of psychotropic drugs. In agreement with other perfusion studies, we have observed changes in fractional distribution of radiolabeled urea, a so-called extracellular marker, along with shifts in monoamines; but the former appear more transient. These observations nevertheless support the concept of dynamic changes within the extracellular environment of the CNS that may be part of a hormone-like communicating system with functional significance. Furthermore, the presence of peaks and/or troughs, in perfusates of [14C]urea of similar substances should not be taken as a priori evidence for nonspecificity of the technic, since selective release or inhibition of release of monoamines can be shown with appropriate drugs that are thought to act through these aminergic systems. Destruction of catecholamine nerve terminals with 6-hydroxydopamine likewise attenuates the signal-locked release of radiolabeled norepinephrine by a conditioned stimulus after conditioning occurs. No such release is seen on presentation of the to-be-conditioned neutral stimulus in control or 6-hydroxydopamine treated rats. These initial studies indicate the availability of a powerful tool for the study of drug-neurochemical-behavioral interactions using subjects as their own controls for extended periods of time so that phenomena of plasticity, tolerance and dependence may likewise be examined.