COCAINE TIME ACTION PROFILE ON REGIONAL CEREBRAL BLOOD-FLOW IN THE RAT

Cocaine is a powerful psychostimulant the high abuse liability of which in man appears to be linked, at least in part, to its pharmacokinetic properties. For example, intravenous and inhalation routes of administration result in appreciably higher level of dependence than either the oral or intranasal route, while cocaine's behavioral and physiologic profile is both route- and time-dependent. Therefore, to determine if various aspects of the drug's profile of effects are due to alterations in regional neuronal activity, we measured the effects of cocaine on regional cerebral blood flow (rCBF) 1, 2, 5, 15 and 45 min after a single 1.0 mg/kg i.v. cocaine injection. rCBF is known to directly reflect the state of local neuronal activity and, when measured autoradiographically using the method of Sakurada et al., can be resolved with a very high temporal resolution (30 s). A heterogeneous pattern of cerebral activation was seen. Of those regions which responded to cocaine, all but three did so with a threshold to effect of less than 1 min. Several groups of structures were evident: (1) those regions where blood flow returned to baseline prior to the 5 min measurement group (including several amygdaloid nuclei and lateral septum); (2) those returning to baseline prior to the 15 min sacrifice point (including limbic cortex); (3) regions activated for at least 15 but less than 45 min (including such motor-related regions as the caudate, substantia nigra and globus pallidus); and (4) those demonstrating persistent rCBF alterations for the entire 45 min observation period (including nucleus accumbens, olfactory tubercle, hippocampus, various thalamic nuclei and medial prefrontal cort''). It thus appears that cocaine's duration of action varies heterogenously across both time and brain structure, with many limbic regions displaying either very brief or prolonged duration of action while many motor-related structures display intermediate times of action. This regionally distinct time-course may reflect the diverse behavioral profile seen after cocaine administration in the rat.