This proposal examines behavioral measures of the functional status of specific transmitter systems in the hippocampi of rats following chronic antidepressants to elucidate the neurochemical substrates of their therapeutic actions. Clinically, most antidepressant drugs take 3 weeks of adminstration to alleviate depression. In animals, chronic antidepressants alter neurochemical, electrophysiological and, most consistently, ligand-binding measures of the functioning of central noradrenergic, serotonergic, and cholinergic systems. To more directly and specifically assess the behavioral relevance of these reported changes, I propose to examine the effects of acute and chronic antidepressants on the behavioral effects of hippocampal microinfusions of norepinephrine, serotonin, and the cholinergic agonist carbachol. Using a new behavioral pattern monitor which reveals quantitative and qualitative changes in locomotor activity and investigation, my laboratory has described dose-dependent behavioral effects specifically reflective of the activation of either beta-adrenergic or muscarinic-cholinergic synapses in the dentate gyrus of the hippocampus. Studies are proposed here to similarly characterize the effects of serotonin infusions with neurotoxin lesions of the raphe nuclei being used to confirm their specificity. The distribution of infusate and the extent of lesions will be assessed with fluorescence histochemistry and liquid chromatography with electrochemical detection. The functional status of the serotonergic, beta-adrenergic, and muscarinic-cholinergic inputs to the hippocampus will be assessed behaviorally after 1 or 21 daily oral treatments with 4 disparate antidepressants: desmethylimipramine; imipramine; tarzodone; and mianserin. Appropriate ligand-binding studies will be done on the hippocampi from the same rats to confirm the expected changes due to the antidepressants. These studies should establish the functional significance at a behavioral level of the ligand-binding changes induced by antidepressants, and increase our understanding of the brain mechanisms responsible for their therapeutic actions in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH000188-04
Application #
3069615
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1983-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
4
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
Geyer, M A; Krebs, K M (1994) Serotonin receptor involvement in an animal model of the acute effects of hallucinogens. NIDA Res Monogr 146:124-56
Markou, A; Matthews, K; Overstreet, D H et al. (1994) Flinders resistant hypocholinergic rats exhibit startle sensitization and reduced startle thresholds. Biol Psychiatry 36:680-8
Sipes, T A; Geyer, M A (1994) Multiple serotonin receptor subtypes modulate prepulse inhibition of the startle response in rats. Neuropharmacology 33:441-8
Paulus, M P; Geyer, M A; Braff, D L (1994) The assessment of sequential response organization in schizophrenic and control subjects. Prog Neuropsychopharmacol Biol Psychiatry 18:1169-85
Geyer, M A; Wilkinson, L S; Humby, T et al. (1993) Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol Psychiatry 34:361-72
Paulus, M P; Callaway, C W; Geyer, M A (1993) Quantitative assessment of the microstructure of rat behavior: II. Distinctive effects of dopamine releasers and uptake inhibitors. Psychopharmacology (Berl) 113:187-98
Krebs, K M; Geyer, M A (1993) Behavioral characterization of alpha-ethyltryptamine, a tryptamine derivative with MDMA-like properties in rats. Psychopharmacology (Berl) 113:284-7
Swerdlow, N R; Geyer, M A (1993) Clozapine and haloperidol in an animal model of sensorimotor gating deficits in schizophrenia. Pharmacol Biochem Behav 44:741-4
Paulus, M P; Geyer, M A (1993) Quantitative assessment of the microstructure of rat behavior: I, f(d), the extension of the scaling hypothesis. Psychopharmacology (Berl) 113:177-86
Swerdlow, N R; Benbow, C H; Zisook, S et al. (1993) A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33:298-301

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