Conditioning and learning processes are known to play a key role in drug addiction. The pedunculopontine tegmental nucleus (PPT) and the ventral tegmental area (VTA) are considered critical components of the neural circuit involved in the motivational effects of opiates and are also known to modulate cognitive processes. However, very little is known regarding the effects of heroin on the modulatory roles of these subcortical inputs on brain regions critically involved in cognitive function, such as the hippocampus. The hippocampus plays a role in aversive conditioning to contextual cues and in drug-associated conditioned reward. The main goal of this research project is to characterize the modulatory effects of the PPT and the VTA on hippocampal function during non-dependent opiate states and during periods of opiate dependence and withdrawal. The rationale of this research proposal is based on the view that understanding the interactions among brain circuits involved in cognitive and rewarding processes during opiate reinforcement, dependence and withdrawal will facilitate the development of more effective pharmacological treatment strategies for opiate addiction. The principal investigator of this research proposal is a newer, less experienced investigator and the relevant priority category is #1 (NIDA Small Grants Program). The proposed studies will test the hypothesis that the effects of heroin on PPT- and VTA-modulation of hippocampal dentate physiology are distinct and dependent on the history of heroin administration. Field potentials and electroencephalographic activity will be recorded to determine the effects of heroin on PPT- and VTA-induced modulation of perforant path-to-dentate responses and their induction of dentate theta rhythm. To determine the roles of the PPT and VTA on heroin-induced changes in dentate activity, this study will investigate the effects of heroin treatment following excitotoxic lesions of either the PPT or the VTA. These data will provide information on the cellular neuropharmacology of the PTA and the VTA in critical septohippocampal circuits important in learning and memory and drug abuse. Findings obtained in the proposed studies will be used as a building block in the development of a future research proposal that will test the hypothesis that opiate-induced changes in PPT- and VTA-septohippocampal transmission are critical for the modulatory role of cognitive and reward processes on opiate addiction.
