During the past decade, cocaine abuse has become this nation's most devastating drug problem. The potent rewarding effect of cocaine, more than any other variable, probably accounts for the meteoric rise in cocaine abuse. Animal studies have demonstrated that the dopamine (DA)-containing neuronal tracts arising from the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) and medial prefrontal cortex (MPC) are intricately involved in the rewarding efficacy of cocaine. The objectives of this research program are to identify the neuronal mechanisms by which cocaine alters activity within these systems, the neuronal circuitry affected by cocaine's actions and the influence of repeated administration of cocaine on such circuits. Electrophysiological studies from this laboratory have determined that cocaine only partially inhibits the firing of A1O DA neurons within the VTA while potently inhibiting the activity of target neurons within the NAc and MPC. This profile is unlike that of other DA agonists and indicates a poor compensatory decrease of DA activity following enhanced activation of postsynaptic DA receptors resulting from cocaine administration. These findings have lead to the hypothesis that the poor compensatory response results in exaggerated dopaminergic activity which may be related to cocaine's reward efficacy. The present proposal outlines a research plan which will utilize single-cell recording, microiontophoresis, electrical stimulation and radiolabelled dopamine uptake techniques to identify the mechanisms, including the DA receptor subtypes and serotonergic interactions, by which cocaine exerts this unusual profile of effects. In addition, experiments using antidromic stimulation techniques are proposed which should identify the efferent neuronal pathways affected by cocaine's actions within the mesoaccumbens and mesocortical DA pathways. Upon identification of such circuits, additional experiments will determine the extent to which other drugs of abuse affect the same pathways. Finally, experiments will attempt to identify the alterations occurring in the mesoaccumbens and mesocortical DA pathways as a result of repeated cocaine administration. It is hoped that the results of these experiments will define the neurobiological concomitants of cocaine use, particularly as they relate to reward mechanisms and will provide information regarding the consequences of long-term

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA004093-05
Application #
3209178
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1988-02-01
Project End
1993-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Cass, Daryn K; Thomases, Daniel R; Caballero, Adriana et al. (2013) Developmental disruption of gamma-aminobutyric acid function in the medial prefrontal cortex by noncontingent cocaine exposure during early adolescence. Biol Psychiatry 74:490-501
Perez, Mariela F; Ford, Kerstin A; Goussakov, Ivan et al. (2011) Repeated cocaine exposure decreases dopamine D?-like receptor modulation of Ca(2+) homeostasis in rat nucleus accumbens neurons. Synapse 65:168-80
Tseng, Kuei Y; Caballero, Adriana; Dec, Alexander et al. (2011) Inhibition of striatal soluble guanylyl cyclase-cGMP signaling reverses basal ganglia dysfunction and akinesia in experimental parkinsonism. PLoS One 6:e27187
Heng, Li-Jun; Markham, Julie A; Hu, Xiu-Ti et al. (2011) Concurrent upregulation of postsynaptic L-type Ca(2+) channel function and protein kinase A signaling is required for the periadolescent facilitation of Ca(2+) plateau potentials and dopamine D1 receptor modulation in the prefrontal cortex. Neuropharmacology 60:953-62
McCutcheon, James E; Loweth, Jessica A; Ford, Kerstin A et al. (2011) Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism. J Neurosci 31:14536-41
Ferrario, Carrie R; Loweth, Jessica A; Milovanovic, Mike et al. (2011) Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca²?-permeable AMPA receptors during the incubation of cocaine craving. Neuropharmacology 61:1141-51
Blume, Shannon R; Cass, Daryn K; Tseng, Kuei Y (2009) Stepping test in mice: a reliable approach in determining forelimb akinesia in MPTP-induced Parkinsonism. Exp Neurol 219:208-11
Ford, Kerstin A; Wolf, Marina E; Hu, Xiu-Ti (2009) Plasticity of L-type Ca2+ channels after cocaine withdrawal. Synapse 63:690-7
Hu, Xiu-Ti; Nasif, Fernando J; Zhang, Jianhua et al. (2008) Fos regulates neuronal activity in the nucleus accumbens. Neurosci Lett 448:157-60
Hu, Xiu-Ti (2007) Cocaine withdrawal and neuro-adaptations in ion channel function. Mol Neurobiol 35:95-112

Showing the most recent 10 out of 69 publications