A recent survey by NIDA indicates a significant increase in stimulant abuse. This evidence underscores the importance of characterizing in animals the behavioral profiles and corresponding neurochemical system(s) and mechanism(s) associated with different patterns of stimulant abuse. The primary objective of the proposed research is to extend previous work on the various behavioral and neurochemical effects induced by different doses and durations of exposure to amphetamine-like stimulants in rats. Assessments of the behavioral effects induced by single and repeated administration of low to moderate stimulant doses will be extended using our enhanced automated and observational monitoring systems to provide more accurate and thorough characterizations of the stimulant response. In addition to locomotion and focused sterotypies, behavioral measures are now available to evaluate our hypothesis that response perseveration and engagement with the environment represent important behavioral dimensions of the stimulant response. Specific roles for NE, DA, and 5-HT systems in these behavioral dimensions are proposed and studies are designed to test these hypotheses. In addition, a proposed neurochemical mechanism underlying the dose-related transition from stimulant-induced locomotor activation to focused stereotypies will also be assessed. Our previous studies revealed that different patterns and doses of repeated stimulant administration produce alterations in various components of the stimulant response in the form of behavioral augmentation, tolerance, and/or shortened response duration. These phenomena will be further investigated by examining age- and strain-related differences in response to repeated stimulant administration and by assessing the possible involvement of endogenous opioid and monoamine systems and mechanisms in the development of these effects. In addition, we will also examine """"""""emergent"""""""" behavioral syndromes produced by high, acute stimulant doses or continuous intoxication regimens and associated with CNS neurotoxicity, particularly with respect to determining the relationship of these syndromes to patterns of stimulant abuse in humans. The proposed research will utilize a variety of behavioral, pharmacological, neurochemical, and electrophysiological techniques to characterize the behaviors and underlying mechanisms associated with different patterns of stimulant administration. These studies may provide important information regarding persistent effects resulting from chronic stimulant administration, interactions between stimulants and other drugs of abuse, and potential treatments for specific adverse effects in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001568-10
Application #
3206955
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1976-06-29
Project End
1987-03-31
Budget Start
1986-01-01
Budget End
1987-03-31
Support Year
10
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
La?an, Goran; Hadamitzky, Martin; Kuczenski, Ronald et al. (2013) Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration. Synapse 67:476-88
Le Cozannet, Romain; Markou, Athina; Kuczenski, Ronald (2013) Extended-access, but not limited-access, methamphetamine self-administration induces behavioral and nucleus accumbens dopamine response changes in rats. Eur J Neurosci 38:3487-95
Hadamitzky, Martin; McCunney, Stanley; Markou, Athina et al. (2012) Development of stereotyped behaviors during prolonged escalation of methamphetamine self-administration in rats. Psychopharmacology (Berl) 223:259-69
Amitai, Nurith; Kuczenski, Ronald; Behrens, M Margarita et al. (2012) Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats. Neuropharmacology 62:1422-31
Hadamitzky, Martin; Markou, Athina; Kuczenski, Ronald (2011) Extended access to methamphetamine self-administration affects sensorimotor gating in rats. Behav Brain Res 217:386-90
Kuczenski, Ronald; Segal, David S; Melega, William P et al. (2009) Human methamphetamine pharmacokinetics simulated in the rat: behavioral and neurochemical effects of a 72-h binge. Neuropsychopharmacology 34:2430-41
Kuczenski, Ronald; Everall, Ian P; Crews, Leslie et al. (2007) Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat. Exp Neurol 207:42-51
Shilling, P D; Kelsoe, J R; Kuczenski, R et al. (2000) Differential regional zif268 messenger RNA expression in an escalating dose/binge model of amphetamine-induced psychosis. Neuroscience 96:83-90
Florin, S M; Kuczenski, R; Segal, D S (1994) Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment. Brain Res 654:53-62
Segal, D S; Kuczenski, R; Okuda, C (1992) Clorgyline-induced increases in presynaptic DA: changes in the behavioral and neurochemical effects of amphetamine using in vivo microdialysis. Pharmacol Biochem Behav 42:421-9

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