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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Volman, Susan
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Scripps Research Institute
La Jolla
United States
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Sanchez-Alavez, Manuel; Chan, Sic L; Mattson, Mark P et al. (2007) Electrophysiological and cerebrovascular effects of the alpha-secretase-derived form of amyloid precursor protein in young and middle-aged rats. Brain Res 1131:112-7
Criado, Jose R; Sanchez-Alavez, Manuel; Conti, Bruno et al. (2005) Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis 19:255-65
Winsky-Sommerer, Raphaelle; Spier, Avron D; Fabre, Veronique et al. (2004) Overexpression of the human beta-amyloid precursor protein downregulates cortistatin mRNA in PDAPP mice. Brain Res 1023:157-62
Sanchez-Alavez, Manuel; Gombart, Lhys M; Huitron-Resendiz, Salvador et al. (2004) Physiological and behavioral effects of methamphetamine in a mouse model of endotoxemia: a preliminary study. Pharmacol Biochem Behav 77:365-70
Sanchez-Alavez, Manuel; Gallegos, Roger A; Kalafut, Mary A et al. (2002) Loss of medial septal modulation of dentate gyrus physiology in young mice overexpressing human beta-amyloid precursor protein. Neurosci Lett 330:45-8
Huitron-Resendiz, Salvador; Sanchez-Alavez, Manuel; Gallegos, Roger et al. (2002) Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice. Brain Res 928:126-37
Thomas, E A; Sautkulis, L N; Criado, J R et al. (2001) Apolipoprotein D mRNA expression is elevated in PDAPP transgenic mice. J Neurochem 79:1059-64
Bourgin, P; Huitron-Resendiz, S; Spier, A D et al. (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20:7760-5