In vitro reinforcement of hippocampal bursting: Possible cellular and molecular mechanism of drug reward

Abstract

The spontaneous bursting activity of individual CA1 cells in hippocampal slices was progressively increased in a dose-related manner by burst-contingent microinjections of dopaminergic and cannabinoid receptor agonists, whereas the bursting responses of CA3 units were similarly increased by opioid receptor agonists. General pharmacological stimulation of bursting could be ruled out because the same injections administered independently of bursting were ineffective, and because burstcontingent applications of the excitatory transmitter glutamate failed to increase CA1 bursting. The findings suggested that individual neuronal responses may be reinforceable in vitro by a cellular operant conditioning mechanism analogous to that in behavioral reinforcement. As a possible molecular mechanism of in vitro reinforcement (IVR), we propose 1) that unreinforced CA1 bursting induces rapid dephosphorylation of L-type calcium channels through Ca 2+-dependent activation of calcineurin and phosphatase-1 and 2) that such calcium-channel dephosphorylation is prevented by burst-contingent applications of dopamine acting through D 1 receptors to activate cAMP kinase and DARPP-32.