Knowledge concerning the pharmacology, biochemistry, physiology and regulatory control of mesotelencephalic dopamine (DA) neurons is crucial for obtaining a better understanding of their role in both normal and abnormal behavior and the mechanisms through which antipsychotic drugs (APDs) partially ameliorate psychotic symptoms. Both the therapeutic and neurological side effects of APDs are believed to be due, in part, to actions on mesotelencephalic DA systems. We will therefore continue our studies which have focused on the biochemical, anatomical, and pharmacological heterogeneity of the mesotelencephalic neurons, with particular emphasis on the mesoprefrontal cortical DA system. This cortical DA system has a number of unique properties, and has been hypothesized to be critically involved in the pathogenesis of schizophrenia. We will examine the involvement of DA autoreceptors in the regulation of different DA systems. We will also investigate the modulation of specific DA neurons by heteroceptors (e.g. benzodiazepine/GABA, excitatory amino acid, neuropeptide, serotonin) responding to specific afferents to midbrain DA neurons; these studies will utilize both in vivo and ex vivo biochemical methods, and histochemical approaches. A particular focus will be the investigation of the role of neurotensin in the regulation of mesoprefrontal DA neurons. We will determine whether the activation of the mesoprefrontal DA system by various behavioral stressors and anxiogenic beta-carboline treatment are mediated by similar or divergent mechanisms. The adaptive responses of meso-corticolimbic DA neurons to prolonged or repeated stressors will be evaluated in normal rats and rats in which DA function has been altered by perinatal diazepam exposure. In addition, we will investigate the biochemical effects of stress on DA systems following acute and chronic treatment with typical and atypical APDs. Since the extrapyramidal side effects as well as therapeutic actions of APDs are thought to be related to the induction of depolarization block (DPB) following chronic administration of APDs, we will examine the biochemical correlates of DPB, using post-mortem and in vivo dialysis methods. In light of the importance of relating our findings to man, we plan to extend our rodent findings to the primate. We will investigate the role of autoreceptors in regulation of DA function in a primate species. We will also evaluate which central catecholamine systems are functionally influenced by anxiogenic beta-carbolines, using biochemical and histochemical measurements of monoamine function and c-fos expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH014092-32
Application #
2890106
Study Section
Special Emphasis Panel (NSS)
Program Officer
Brady, Linda S
Project Start
1977-05-01
Project End
2001-04-30
Budget Start
1999-05-15
Budget End
2000-04-30
Support Year
32
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Jentsch, J David; Sanchez, Diana; Elsworth, John D et al. (2008) Clonidine and guanfacine attenuate phencyclidine-induced dopamine overflow in rat prefrontal cortex: mediating influence of the alpha-2A adrenoceptor subtype. Brain Res 1246:41-6
Zachariou, V; Caldarone, B J; Weathers-Lowin, A et al. (2001) Nicotine receptor inactivation decreases sensitivity to cocaine. Neuropsychopharmacology 24:576-89
George, T P; Picciotto, M R; Verrico, C D et al. (2001) Effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in rats: dissociation of biochemical and behavioral effects. Biol Psychiatry 49:300-6
George, T P; Verrico, C D; Picciotto, M R et al. (2000) Nicotinic modulation of mesoprefrontal dopamine neurons: pharmacologic and neuroanatomic characterization. J Pharmacol Exp Ther 295:58-66
Goldstein, L E; Rasmusson, A M; Bunney, B S et al. (1994) The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat. J Neurosci 14:4937-50
Youngren, K D; Moghaddam, B; Bunney, B S et al. (1994) Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment. Neurosci Lett 165:41-4
Rasmusson, A M; Goldstein, L E; Deutch, A Y et al. (1994) 5-HT1a agonist +/-8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine. Synapse 18:218-24
Iyer, R N; Sprouse, J S; Aghajanian, G K et al. (1994) Tryptophan pretreatment augmentation of p-chloroamphetamine-induced serotonin and dopamine release and reduction of long-term neurotoxicity. Biochem Pharmacol 48:1501-8
Horger, B A; Taylor, J R; Elsworth, J D et al. (1994) Preexposure to, but not cotreatment with, the neurotensin antagonist SR 48692 delays the development of cocaine sensitization. Neuropsychopharmacology 11:215-22
Morrow, B A; Clark, W A; Roth, R H (1993) Stress activation of mesocorticolimbic dopamine neurons: effects of a glycine/NMDA receptor antagonist. Eur J Pharmacol 238:255-62

Showing the most recent 10 out of 78 publications