Postsynaptic 5-HT(1A) receptors mediate an increase in locomotor activity in the monoamine-depleted rat.
BACKGROUND
In animal models of reduced dopamine transmission, such as haloperidol-induced catalepsy or monoamine-depleted animals, serotonin (5-hydroxytryptamine; 5-HT) 5-HT(1A) agonists appear to enhance motor activity. However, the exact mechanism remains unclear.


OBJECTIVE
The objective of the present study was to demonstrate that 5-HT(1A) agonists can increase locomotor activity by activation of postsynaptic 5-HT(1A) heteroreceptors without the involvement of somatodendritic 5-HT(1A) autoreceptors which are known to regulate 5-HT neuronal activity.


METHODS
The effects of the 5-HT(1A) full agonist R-(+)-8-hydroxy-2-(di- n-propylamino)tertralin ( R-(+)-8-OHDPAT) on locomotor activity in reserpinized (i.e., monoamine-depleted) rats were studied.


RESULTS
The present data demonstrate that R-(+)-8-OHDPAT significantly increased locomotor activity in monoamine-depleted animals at a dose as low as 0.01 mg/kg. The partial 5-HT(1A) agonist/D(2) antagonist buspirone (3 mg/kg) also elevated locomotor activity. The effects of these 5-HT(1A) compounds were found to be similar to the locomotor-stimulating effect of the dopamine precursor 3,4-dihydroxyphenylalanine (150 mg/kg, 15 min after 50 mg/kg benserazide). The 5-HT(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635; 0.2 mg/kg) blocked the R-(+)-8-OHDPAT (0.03 mg/kg)-mediated increase in locomotion. Blockade of 5-HT synthesis with DL- p-chlorophenylalanine (pCPA), a tryptophan hydroxylase inhibitor, prior to reserpinization did not affect R-(+)-8-OHDPAT-induced locomotion.


CONCLUSIONS
The present data indicate that R-(+)-8-OHDPAT can increase motor activity in monoamine-depleted rats through postsynaptic 5-HT(1A) receptors and not necessarily through 5-HT(1A) autoreceptor-mediated alterations in 5-HT synthesis and release. A potential mechanism of 5-HT(1A)-mediated modulation of non-monoaminergic motor circuits in the brain is discussed. Taken together, the results suggest that 5-HT(1A) agonists would provide a novel approach to the amelioration of antipsychotic-induced side effects and the symptomatic treatment of Parkinson's disease.
Department of Pharmacology and Experimental Therapeutics, Loyola University, Stritch School of Medicine, Maywood, IL 60153, USA.
Laurence
L
Mignon
William A
WA
Wolf
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017661:Receptors, Presynaptic / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*
D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D017661:Receptors, Presynaptic; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine; D002065:Buspirone