Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low-rate 72-second behavior.
Previous work in this laboratory has suggested that antagonist action of 5-hydroxytryptamine2 (5-HT2) receptors and agonist action of 5-HT1 receptors results in antidepressant-like effects (increased reinforcement rate and decreased response rate) in rats performing under the differential-reinforcement-of-low-rate 72-sec schedule (DRL 72-s) of reinforcement. Serotonergic mediation of antidepressant drug effects on DRL 72-s behavior was assessed with a series of 5-HT agonists, and blockade of the effects of the antidepressant drugs clorgyline and fluoxetine (which presumably indirectly stimulate 5-HT1 receptors) was attempted in separate experiments with the 5-HT1 and 5-HT2 antagonist methysergide and the 5-HT neurotoxin 5,7-dihydroxytryptamine. Direct 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine and the 5-HT precursor 5-hydroxytryptophan all increased the reinforcement rate. The 5-HT1B and 5-HT1C agonists m-chlorophenylpiperazine and 1-(m-trifluoromethylphenyl)piperazine did not increase the reinforcement rate. The 5-HT2 agonist and 5-HT3 antagonist quipazine also did not increase the reinforcement rate. The monoamine oxidase inhibitor clorgyline and the 5-HT uptake inhibitor fluoxetine increased the reinforcement rate and decreased the response rate as seen with other antidepressant drugs on the DRL 72-s schedule. Methysergide antagonized the reinforcement rate increasing effects of both clorgyline and fluoxetine. Depletion of brain 5-HT with i.v.t. 5,7-dihydroxytryptamine blocked the antidepressant-like effects of clorgyline. These results suggest that central 5-HT1A receptors are involved in mediating the antidepressant-like effects of some drugs on DRL 72-s behavior. These results provide evidence that stimulation of 5-HT1A receptors and antagonism of 5-HT2 receptors lead to an antidepressant-like effect on the DRL 72-s schedule and implies that these two receptors may be important in mediating clinical drug effects in depression.
Marek
G J
GJ
University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.
Li
A A
AA
Seiden
L S
LS
D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects*; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012054:Reinforcement, Psychology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013997:Time Factors
D001679:Biogenic Amines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003891:Desipramine