Electrophysiological responsiveness to isoproterenol in rat hippocampal slices correlates with changes in β-adrenergic receptor density induced by chronic morphine treatment

Abstract

The effects of chronic morphine treatment and morphine withdrawal on β-adrenergic receptor density and electrophysiological responsiveness in rat hippocampus were examined. Chronic treatment of rats with morphine for 14 days resulted in a 19% increase in the number of β-adrenergic receptors in hippocampus, as measured by the binding of the specific antagonist [ 3H]dihydroalprenolol (DHA). In comparison, the number of specific binding sites for [ 3H]DHA was decreased 27% in hippocampus in morphine-withdrawn animals, compared to saline-treated controls. These alterations in β-adrenergic receptor density were not accompanied by a significant change in the dissociation constant ( K d) for [ 3H]DHA or in the inhibitory constants ( K i) for the displacement of the [ 3H]-antagonist by either norepinephrine or isoproterenol. Electrophysiological experiments in the in vitro hippocampal slice preparation revealed that responses to threshold as well as maximal concentrations of isoproterenol were significantly enhanced in morphine-dependent animals, compared to controls, whereas electrophysiological responsiveness to maximal concentrations of isoproterenol was decreased in slices from morphine-withdrawn rats. The results of this study indicate that β-adrenergic receptors in hippocampus are up-regulated during the development of morphine dependence and down-regulated during opiate withdrawal. These changes in hippocampal β-adrenergic receptor density are likely to be of functional relevance since they are manifested in a corresponding increase and decrease, respectively, in electrophysiological responsiveness to an exogenously administered β-adrenergic receptor agonist.