Sigma receptors, a novel class of putative neurotransmitter receptors, have been extensively characterized in binding studies, but relatively less is known about their functions in the central nervous system. Indeed, establishment of the function of these sites would greatly strengthen the argument that they serve as a signalling mechanism in the brain. Previous work and work from the investigators laboratories has supported the hypothesis that one function of sigma receptors is to regulate dopamine neurotransmission. The study of sigma-dopamine interactions is important for several reasons: (1) dopamine activity has been hypothesized to be involved in the expression of schizophrenic symptoms, (2) the motor side effects of antipsychotic drug treatment, such as tardive dyskinesia may be related to alterations in dopamine neurotransmission, (3) antipsychotic drugs that produce tardive dyskinesia, such as haloperidol, have high affinity for both dopamine and sigma receipts, (4) sigma ligands have been shown to affect dopamine neurotransmission. The proposed studies will analyze the role of sigma receptors in dopamine neurotransmission within the nigrostriatal system. These studies will address the nature of the interaction from three perspectives: (1) behavioral, using the rat turning model, (2) neurochemical, using microdialysis with electrochemical detection to measure in vivo dopamine release; and (3) electrophysiological, with measurements of firing rate and pattern following administration of sigma ligands. The proposed studies aims to elucidate the sites and mechanisms of action of sigma ligands within the nigrostriatal dopamine system. The proposed research examines the effects of putative sigma antagonists and the possibility of interactions between sigma and NMDA receptors in the nigrostriatal system These issues will be addressed in both cell body and terminal regions by examining the effects of dopamine and NMDA antagonists, and the effects of sigma ligands on NMDA-evoked changes in physiology or neurochemistry. The results of these experiments may provide a better understanding of the role of sigma receptors as a signalling mechanism within the nigrostriatal system and the possible mechanisms by which sigma-active antipsychotics produce movement disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010043-06
Application #
2654383
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1996-05-01
Project End
1999-01-31
Budget Start
1998-05-01
Budget End
1999-01-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Brown University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Sanudo-Pena, M C; Tsou, K; Walker, J M (1999) Motor actions of cannabinoids in the basal ganglia output nuclei. Life Sci 65:703-13
Strangman, N M; Walker, J M (1999) Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses. J Neurophysiol 82:472-7
Sanudo-Pena, M C; Force, M; Tsou, K et al. (1999) Dopaminergic system does not play a major role in the precipitated cannabinoid withdrawal syndrome. Zhongguo Yao Li Xue Bao 20:1121-4
Hohmann, A G; Tsou, K; Walker, J M (1999) Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. J Neurophysiol 81:575-83
Sanudo-Pena, M C; Walker, J M (1998) A novel neurotransmitter system involved in the control of motor behavior by the basal ganglia. Ann N Y Acad Sci 860:475-9
Strangman, N M; Patrick, S L; Hohmann, A G et al. (1998) Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity. Brain Res 813:323-8
Hohmann, A G; Tsou, K; Walker, J M (1998) Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212-2. Neurosci Lett 257:119-22
Sanudo-Pena, M C; Walker, J M (1998) Effects of intrapallidal cannabinoids on rotational behavior in rats: interactions with the dopaminergic system. Synapse 28:27-32
Sanudo-Pena, M C; Force, M; Tsou, K et al. (1998) Effects of intrastriatal cannabinoids on rotational behavior in rats: interactions with the dopaminergic system. Synapse 30:221-6

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