Research indicates that central 5-hydroxytryptamine(3) (5-HT3: serotonin) receptors regulate: (1) dopamine (DA) mediated behaviors, (2) mesocorticolimbic DA release, and (3) the withdrawal syndrome associated with drugs of abuse. The present application proposes to examine the role of 5-HT3 receptors in regulating the behavioral and neurochemical changes engendered by the continuous infusion of cocaine via an osmotic minipump. The continuous infusion of cocaine is an animal model of compulsive, binge-like, high-dose cocaine abuse. The proposal hypothesizes that continuous cocaine administration produces a decreased ability of 5-HT3 receptors to regulate DA neurotransmission and DA-mediated behaviors. This decreased regulatory capacity will be examined at several different levels of analyses to obtain an integrated picture of the changes in these receptors. Specifically, the present application will examine changes in the ability of 5-HT3 receptor agonists and antagonists to regulate DA release in brain slices from the striatum, nucleus accumbens, and prefrontal cortex, and changes in the ability of 5-HT3 receptor agonists and antagonists to regulate behavior. The present experiments will not only further elucidate the role of 5-HT3 receptors in cocaine abuse, but may also result in a fuller understanding of their functional significance for other psychiatric conditions. Cocaine abuse results in anxiety/mood disorders and depression, and psychosis. Central 5-HT have been implicated in all of these conditions. Thus, a fuller understanding of the behavioral neuropharmacology of 5-HT3 systems may not only aid in our understanding of other psychiatric conditions, but may also result in improved pharmacotherapies for a variety of psychiatric conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA008899-04
Application #
2700876
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1995-07-01
Project End
1999-02-28
Budget Start
1998-05-15
Budget End
1999-02-28
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Duke University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
King, George R; Hillburn, Craig; Pinto, Gail et al. (2004) The effects of continuous cocaine dose, treatment, and withdrawal duration on the induction of behavioral tolerance and dopamine autoreceptor function. Pharmacol Biochem Behav 78:293-300
Matell, Matthew S; King, George R; Meck, Warren H (2004) Differential modulation of clock speed by the administration of intermittent versus continuous cocaine. Behav Neurosci 118:150-6
King, George R; Pinto, Gail; Konen, Jennifer et al. (2002) The effects of continuous cocaine duration on the induction of behavioral tolerance and dopamine autoreceptor function. Eur J Pharmacol 446:111-8
King, George R; Pinto, Gail; Konen, Jennifer et al. (2002) The effects of continuous 5-HT(3) receptor antagonist administration on the subsequent behavioral response to cocaine. Eur J Pharmacol 449:253-9
King, G R; Xiong, Z; Douglass, S et al. (2000) Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT(3) receptor antagonist. Eur J Pharmacol 394:97-101
King, G R; Xiong, Z; Ellinwood Jr, E H (1999) Withdrawal from continuous cocaine administration: time dependent changes in accumbens 5-HT3 receptor function and behavioral tolerance. Psychopharmacology (Berl) 142:352-9
King, G R; Xiong, Z; Douglas, S et al. (1999) The effects of continuous cocaine dose on the induction of behavioral tolerance and dopamine autoreceptor function. Eur J Pharmacol 376:207-15
King, G R; Xiong, Z; Ellinwood Jr, E H (1998) Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine. Psychopharmacology (Berl) 135:263-9