Previously, we have shown that DA neurons which innervate both the prefrontal or cingulate cortices are devoid of both synthesis-modulating nerve terminal and somatodendritic impulse-regulating dopamine (DA) autoreceptors. In addition, the basal electrophysiological characteristics of these mesoprefrontal and mesocingulate DA neurons are dramatically different from that of other DA cells within the midbrain. Moreover, the lack of autoreceptors on these neurons was correlated with a dramatic decrease in the responsiveness of these cells to DA agonists such as apomorphine and amphetamine. The studies proposed are devoted to increasing both our basic understanding of the electrophysiological characteristics of several antidromically identified populations of midbrain DA neurons as well as examining the effects of DA agonists administered acutely upon these cells. Given the relevance of DA agonist-induced psychoses in our current hypotheses regarding the biology of schizophrenia (as well as other disorders), we will also examine the effects of their chronic administration on these identified populations. In this initial proposal, we will focus on the effects of chronic agonist treatment on both the electrophysiological characteristics of subclasses of DA neurons and the sensitivity of somatodendritic DA autoreceptors (if present). The agonists chosen for these studies include not only direct and indirect acting agonists which have clinical relevance, but also the D1, D2, and autoreceptor specific agonists which have both preclinical and clinical importance. It is hoped that this detailed investigation of the """"""""basic"""""""" electrophysiological and pharmacological characteristics of specifically identified populations of midbrain DA neurons, together with an examination of the effects of chronic agonist administration upon these characteristics, will lead to a better understanding of the physiology of midbrain DA neurons and the actions of agonists upon them. Ultimately, it is hoped that such knowledge, combined with additional clinical trials with some of the newer specific agonists, will lead to a better understanding of the etiology of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH041557-03
Application #
3380235
Study Section
(BPNA)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Sinai Hospital of Detroit
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48235
Liu, L X; Monsma Jr, F J; Sibley, D R et al. (1996) D2L, D2S, and D3 dopamine receptors stably transfected into NG108-15 cells couple to a voltage-dependent potassium current via distinct G protein mechanisms. Synapse 24:156-64
Parikh, H N; Chiodo, L A; Koss, J et al. (1995) Cholecystokinin mobilizes intracellular Ca2+ in hybrid N18TG2 X mesencephalon (MES-23.5) cells. Synapse 21:278-80
Shen, R Y; Hannigan, J H; Chiodo, L A (1995) The effects of chronic amphetamine treatment on prenatal ethanol-induced changes in dopamine receptor function: electrophysiological findings. J Pharmacol Exp Ther 274:1054-60
Pitts, D K; Wang, L; Kelland, M D et al. (1995) Repeated stimulation of dopamine D2-like receptors: reduced responsiveness of nigrostriatal and mesoaccumbens dopamine neurons to quinpirole. J Pharmacol Exp Ther 275:412-21
Liu, L; Shen, R Y; Kapatos, G et al. (1994) Dopamine neuron membrane physiology: characterization of the transient outward current (IA) and demonstration of a common signal transduction pathway for IA and IK. Synapse 17:230-40
Kelland, M D; Chiodo, L A (1994) Effect of ketamine-anesthesia on N-methyl-D-aspartate-induced activation of type I nucleus accumbens neurons. Life Sci 54:PL35-8
Shen, R Y; Chiodo, L A (1993) Acute withdrawal after repeated ethanol treatment reduces the number of spontaneously active dopaminergic neurons in the ventral tegmental area. Brain Res 622:289-93
Pitts, D K; Kelland, M D; Freeman, A S et al. (1993) Repeated amphetamine administration: role of forebrain in reduced responsiveness of nigrostriatal dopamine neurons to dopamine agonists. J Pharmacol Exp Ther 264:616-21
Zhang, J; Chiodo, L A; Freeman, A S (1993) Effects of phencyclidine, MK-801 and 1,3-di(2-tolyl)guanidine on non-dopaminergic midbrain neurons. Eur J Pharmacol 230:371-4
Castellano, M A; Liu, L X; Monsma Jr, F J et al. (1993) Transfected D2 short dopamine receptors inhibit voltage-dependent potassium current in neuroblastoma x glioma hybrid (NG108-15) cells. Mol Pharmacol 44:649-56

Showing the most recent 10 out of 38 publications