The major objective of the proposed research is to determine the effects of chronic exposure to cocaine (in rats) on the function of neural circuitry involving the substantia nigra. In particular, dynamic in vivo interactions between dopaminergic transmission and GABA-containing outputs from the basal ganglia will be examined in order to define how chronic exposure to cocaine modifies these interactions. For these studies, we will make measurements indicative of the turnover rate a) of GABA in specific pathways (nigrotectal and nigrotegmental) which are known to mediate the expression of certain behaviors elicited by dopamine stimulants such as cocaine and b) of dopamine in the nigrostriatal pathway. The neurotransmitter turnover in these pathways will be manipulated using the following probes: a) directly and indirectly-acting dopamine agonists given either systemically or directly applied to specific intracerebral sites and b) serotonergic agonists and antagonists applied directly into substantia nigra. The effect of these probes on transmitter turnover will be evaluated in rats chronically exposed to cocaine in comparison to drug-naive rats. Using turnover as an index of the functional responsiveness of the nigral outputs to selected neurotransmitters in the nigrostriatal circuit, we hope to identify those synaptic links that are functionally altered by chronic exposure to cocaine. An attempt will be made to relate neurochemical changes observed to each other and to changes in behavioral responses. In particular, we hope to identify functional neurochemical alterations that may account for the behavioral sensitization to cocaine in chronically exposed animals. As sensitization to psychomotor stimulants in animals may be a model of exaggerated psychotogenic actions of these drugs in chronic stimulant abusers (8), it is possible that the information we obtain may provide insights into the neuropathological basis for behavioral disorders induced by stimulant abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002206-09
Application #
3207193
Study Section
Special Emphasis Panel (SRCD (25))
Project Start
1988-01-01
Project End
1992-08-31
Budget Start
1990-08-01
Budget End
1991-08-31
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Dentistry
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Karstaedt, P J; Kerasidis, H; Pincus, J H et al. (1994) Unilateral destruction of dopamine pathways increases ipsilateral striatal serotonin turnover in rats. Exp Neurol 126:25-30
Meloni, R; Gale, K (1991) Cocaine-induced turning behavior in rats with 6-hydroxydopamine lesions: effect of transplants of fetal substantia nigra. Eur J Pharmacol 209:113-7
Segovia, J; Castro, R; Notario, V et al. (1991) Transplants of fetal substantia nigra regulate glutamic acid decarboxylase gene expression in host striatal neurons. Brain Res Mol Brain Res 10:359-62
Meloni, R; Gale, K (1990) Pharmacological evidence for feedback regulation of dopamine metabolism in solid fetal substantia nigra transplants. J Pharmacol Exp Ther 253:1259-64
Bachus, S E; Gale, K (1988) Differential effects of chronic treatment with chlorpromazine versus cocaine on behavioral responsiveness to nigral GABA receptor stimulation. Psychopharmacology (Berl) 95:56-62
Garant, D S; Gale, K (1987) Substantia nigra-mediated anticonvulsant actions: role of nigral output pathways. Exp Neurol 97:143-59
Piredda, S; Gale, K (1986) Anticonvulsant action of 2-amino-7-phosphonoheptanoic acid and muscimol in the deep prepiriform cortex. Eur J Pharmacol 120:115-8
Garant, D S; Iadarola, M J; Gale, K (1986) Substance P antagonists in substantia nigra are anticonvulsant. Brain Res 382:372-8
Bachus, S E; Gale, K (1986) Muscimol microinfused into the nigrotegmental target area blocks selected components of behavior elicited by amphetamine or cocaine. Naunyn Schmiedebergs Arch Pharmacol 333:143-8
Gale, K (1985) Mechanisms of seizure control mediated by gamma-aminobutyric acid: role of the substantia nigra. Fed Proc 44:2414-24

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