The current upswing in the abuse of methamphetamine, 3,4- methylenedioxymethamphetamine (MDMA; """"""""ecstacy"""""""") and related compounds follows closely on the heels of an epidemic of cocaine abuse. An increased incidence of adverse consequences associated with cocaine use has generated investigations of its mechanisms of action; one goal of such studies is to identify pharmacological agents which can block or reverse its psychotropic and toxic effects. Much of this research has focussed on the importance of dopamine (DA) and norepinephrine (NE) in mediating the many and varied physiological and psychological effects attributed cocaine. However, in addition to actions on DA and NE, cocaine also interferes with serotonin (5-hydroxytryptamine; 5-HT) function. Since cocaine abusers experience physiological disorders (anorexia and hyposomnia) as well as psychiatric disorders (anxiety, depression and psychoses) in which 5-HT has been implicated, specific alterations in 5-HT function may underlie some cocaine pharmacology. These psychiatric consequences probably are mediated in part by limbic structures, such as the amygdala and nucleus accumbens, which also receive significant afferent projections from 5-HT containing neurons of the dorsal raphe. Observational procedures will be used to study 5-HT receptor modulation of cocaine-induced hyperactivity and stereotypy and the hypothesis that repeated exposure to cocaine may elicit lasting alterations in 5-HT function will be measured using two behavioral models of 5HT stimulation. Groups of rats will also be trained to discriminate cocaine from saline in two- or three-lever drug discrimination tasks; in three-lever situations, the second drug will be pharmacologically similar to cocaine (e.g., DA reuptake inhibitor or local anesthetic). Substitution, potentiation and antagonism tests with selective 5-HT compounds will help to identify the importance of this system in the subjective state induced by cocaine. We will investigate the dorsal raphe and two limbic sites (amygdala, nucleus accumbens) as possible anatomical substrates of the cocaine cue using microinjection and neurotoxin lesion techniques. Importantly, these studies will provide new insights into the mechanisms responsible for the physiological and psychological effects of cocaine and how these compare to other stimulants. This knowledge is essential to the development of novel approaches to stimulant antagonism and pharmacological treatment strategies for abusers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA006511-01
Application #
3213128
Study Section
Special Emphasis Panel (SRCD (31))
Project Start
1990-05-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
O'Hayre, Morgan; Eichel, Kelsie; Avino, Silvia et al. (2017) Genetic evidence that ?-arrestins are dispensable for the initiation of ?2-adrenergic receptor signaling to ERK. Sci Signal 10:
Gendron, Louis; Cahill, Catherine M; von Zastrow, Mark et al. (2016) Molecular Pharmacology of ?-Opioid Receptors. Pharmacol Rev 68:631-700
Cunningham, Kathryn A; Anastasio, Noelle C (2014) Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76 Pt B:460-78
Herin, David V; Bubar, Marcy J; Seitz, Patricia K et al. (2013) Elevated Expression of Serotonin 5-HT(2A) Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine. Front Psychiatry 4:2
Anastasio, Noelle C; Gilbertson, Scott R; Bubar, Marcy J et al. (2013) Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior. J Neurosci 33:1615-30
Graves, Steven M; Viskniskki, Annika A; Cunningham, Kathryn A et al. (2013) Serotonin(2C) receptors in the ventral pallidum regulate motor function in rats. Neuroreport 24:605-8
Nielsen, David A; Huang, Wen; Hamon, Sara C et al. (2012) Forced Abstinence from Cocaine Self-Administration is Associated with DNA Methylation Changes in Myelin Genes in the Corpus Callosum: a Preliminary Study. Front Psychiatry 3:60
Anastasio, Noelle C; Stoffel, Erin C; Fox, Robert G et al. (2011) Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats. Behav Pharmacol 22:248-61
Lau, Elaine K; Trester-Zedlitz, Michelle; Trinidad, Jonathan C et al. (2011) Quantitative encoding of the effect of a partial agonist on individual opioid receptors by multisite phosphorylation and threshold detection. Sci Signal 4:ra52
Cunningham, Kathryn A; Fox, Robert G; Anastasio, Noelle C et al. (2011) Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues. Neuropharmacology 61:513-23

Showing the most recent 10 out of 66 publications