The primary goal of this research is to characterize the effects of long-term opiate administration on central adrenoceptor function, with an overall effort aimed at clarifying the role of noradrenergic mechanisms in the mediation of the physiological and behavioral changes associated with chronic opiate abuse. This work is predicated on previous demonstrations of alterations in presynaptic alpha2 and postsynaptic beta-adrenoceptor function in hippocampus in chronic morphine-treated animals.
The specific aims are to delineate events at the cellular and molecular level which underlie these receptor adaptations and to determine whether similar alterations in adrenoceptor function can be generalized to the amygdala. Much of the work will involve intracellular recording from hippocampal pyramidal cells (HPCs) and amygdala neurons in brain slice preparations during bath superfusion of test substances in known concentration. Changes in postsynaptic beta-adrenoceptor function will be assessed by comparing the concentration-effect relationship of agonists for inhibiting calcium-activated potassium responses in HPCs in slices from control and chronic morphine-treated rats. Similar measurements will be taken during administration of agents which act beyond the beta-adrenoceptor to effect closure of the underlying conductance to reveal alterations in post-receptor events. Assessments will be made of changes in postsynaptic alpha2-adrenoceptor function by comparing the hyperpolarizing effect of alpha2-adrenergic agonists in neurons recorded in amygdala slices form control and experimental animals. In a second aspect of the work, chronic opiate effects on presynaptic alpha2-adrenoceptor function will be examine by comparing the inhibitory effects of agonists on electrically-evoked release of 3H-NE in hippocampal and amygdala slices in vitro and on synaptic release of NE in the dentate gyrus in situ. These measurements of alpha2 and beta-adrenoceptor-mediated physiological action will be conducted at multiple time points after chronic treatment with morphine or the kappa-agonist U50,488H to examine the relationship between alterations in presynaptic and postsynaptic adrenoceptor function and the emergence or expression of opiate dependence. The proposed research, in contributing to our understanding of the adaptations in central noradrenergic function that accompany prolonged opiate exposure, might help to promote effective new strategies in the treatment of narcotic dependency in man.
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