The amygdala is a collection of anatomically, biochemically and functionally heterogeneous nuclei and is a major component of the limbic system. This proposal will test two general hypotheses: that different amygdaloid nuclei have markedly different roles in mediating the actions of antipsychotic drugs and; that the dopamine (DA) neurons terminating in these nuclei, and their postsynaptic elements, exhibit characteristics unusual to neurons of other DA systems. While DA will be the primary neurochemical focus, emphasis will be placed on the role of interactions between DA and norepinephrine (NE) and DA and neurotensin in the expression of antipsychotic drug effects on DA synthesis or turnover in the individual amygdaloid nuclei and other brain nuclei. The role of end-product inhibition and presynaptic DA autoreceptors in regulating the synthesis of DA in mesoamygdaloid neurons will be determined, and the functional significance of conventional postsynaptic DA mechanisms (e.g., adenylate cyclase) will also be assessed. The biochemically estimated in vivo synthesis and turnover of DA in amygdaloid neurons and midbrain cell bodies will be examined as relates to the compensatory response to DA receptor blockade by acute and chronic administration of """"""""typical"""""""" and """"""""atypical"""""""" antipsychotics. The role of selective dosage regimen and drug subclass differences on NE and neurotensin mechanisms in influencing drug effects on DA function will be determined, and the significance of static or dynamic (drug-induced) bilateral asymmetries of amygdaloid DA, NE or neurotensin will be examined. The tools to be used include tissue micropunching from coronal brain slices, sensitive trace enrichment HPLC with electrochemical detection, in vitro adenylate cyclase and radioligand binding techniques optimized for microdeterminations and radioimmunoassay of neurotensin. To complement these methods, site specific microinjections, selective brain lesions and the administration of antipsychotics with differentiated neuropharmacological properties will be used. From these experiments a further understanding of the role of DA, perhaps as a function of interrelated neuromodulators, in the neurobiology and pharmacotherapy of schizophrenia will be obtained.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH039967-01
Application #
3377781
Study Section
(BPNA)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Leonard, Sarah K; Anderson, Carl M; Lachowicz, Jean E et al. (2003) Amygdaloid D1 receptors are not linked to stimulation of adenylate cyclase. Synapse 50:320-33
Kilts, C D; Knight, D L; Nemeroff, C B (1996) The simultaneous determination of neurotensin and its major fragments by on-line trace enrichment HPLC with electrochemical detection. Life Sci 59:911-20
Dunn, L A; Atwater, G E; Kilts, C D (1993) Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioral model of clinical drug action. Psychopharmacology (Berl) 112:315-23
Scibilia, R J; Lachowicz, J E; Kilts, C D (1992) Topographic nonoverlapping distribution of D1 and D2 dopamine receptors in the amygdaloid nuclear complex of the rat brain. Synapse 11:146-54
Cain, S T; Bissette, G; Kilts, C D et al. (1992) A commentary on methods in peptide neurobiology: focus on neurotensin. Crit Rev Neurobiol 6:233-41
Coco, M L; Kuhn, C M; Ely, T D et al. (1992) Selective activation of mesoamygdaloid dopamine neurons by conditioned stress: attenuation by diazepam. Brain Res 590:39-47
Christison, G W; Atwater, G E; Dunn, L A et al. (1988) Haloperidol enhancement of latent inhibition: relation to therapeutic action? Biol Psychiatry 23:746-9
Kilts, C D; Anderson, C M; Ely, T D et al. (1988) The biochemistry and pharmacology of mesoamygdaloid dopamine neurons. Ann N Y Acad Sci 537:173-87
Kilts, C D; Anderson, C M; Bissette, G et al. (1988) Differential effects of antipsychotic drugs on the neurotensin concentration of discrete rat brain nuclei. Biochem Pharmacol 37:1547-54
Kilts, C D; Anderson, C M (1987) Mesoamygdaloid dopamine neurons: differential rates of dopamine turnover in discrete amygdaloid nuclei of the rat brain. Brain Res 416:402-8

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