This application seeks renewal of research support for five years to continue studies of the sites and mechanisms of action of amphetamine, one of several widely and increasingly abused psychomotor stimulant drugs. The research will approach these questions with three lines of experimental and methodological inquiry. In one line of research effort, single and ultimately multiple single neuron recording will be done in chronically implanted, behaving animals prior to and following various doses of systemically administered amphetamine while changes in neuronal firing rate and pattern are characterized simultaneously with various behavioral components of the amphetamine response. Both neostriatal and reticular formation neuronal activity will be characterized and the effects of acute as well as long-term administration of the drug will be studied initially. In a second line of inquiry, the presynaptic influence of amphetamine on the dopaminergic neuron and the influence of long-term amphetamine administration, as well as other treatments on the excitability of dopaminergic synaptic endings in the neostriatum will be further defined and the mechanisms underlying changes in terminal excitability presumed to result from presynaptic autoreceptor stimulation will be sought. Finally, the morphological basis for amphetamine actions on the brain will be further studied, especially morphological characteristics of the ventral tegmental area of rat brain, which has been implicated in both the behavioral effects of acute and chronic amphetamine administration as well as the reinforcement mechanisms underlying the maintenance of self-administration and abuse of amphetamine. Changes in various anatomical features of neostriatal neurons, especially changes in the size and shape of dendritic spines where dopaminergic inputs affected by amphetamine are known to terminate, will also be studied in animals given repeated amphetamine treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002854-07
Application #
3207591
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1980-06-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
7
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
Giardino, William J; Mark, Gregory P; Stenzel-Poore, Mary P et al. (2012) Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine. Psychopharmacology (Berl) 219:1055-63
Giardino, W J; Pastor, R; Anacker, A M J et al. (2011) Dissection of corticotropin-releasing factor system involvement in locomotor sensitivity to methamphetamine. Genes Brain Behav 10:78-89
Bierut, Laura Jean; Stitzel, Jerry A; Wang, Jen C et al. (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165:1163-71
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
Clark, Robert E; Kuczenski, Ronald; Segal, David S (2007) Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats. Synapse 61:515-22
Shilling, Paul D; Kuczenski, Ronald; Segal, David S et al. (2006) Differential regulation of immediate-early gene expression in the prefrontal cortex of rats with a high vs low behavioral response to methamphetamine. Neuropsychopharmacology 31:2359-67
O'Neil, Meghan L; Kuczenski, Ronald; Segal, David S et al. (2006) Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge. Synapse 60:465-73
Segal, David S; Kuczenski, Ronald (2006) Human methamphetamine pharmacokinetics simulated in the rat: single daily intravenous administration reveals elements of sensitization and tolerance. Neuropsychopharmacology 31:941-55
Segal, David S; Kuczenski, Ronald; O'Neil, Meghan L et al. (2005) Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization. Psychopharmacology (Berl) 180:501-12
Kuczenski, Ronald; Segal, David S (2005) Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol Psychiatry 57:1391-6

Showing the most recent 10 out of 51 publications