Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats.
BACKGROUND
5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist.


OBJECTIVE
To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system.


METHODS
The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced oral stereotypies, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats.


RESULTS
Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies.


CONCLUSIONS
Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.
Balsara
Jehangir J
JJ
Department of Pharmacology, Krishna Institute of Medical Sciences, Karad, Maharashtra, 415 110, India.
Jadhav
Sujata A
SA
Gaonkar
Rajani K
RK
Gaikwad
Ramona V
RV
Jadhav
Jagdish H
JH
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology* / Q000633:toxicity; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D065127:Dopamine D2 Receptor Antagonists; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology; D014196:Trazodone / Q000494:pharmacology* / Q000633:toxicity
D018687:Antidepressive Agents, Second-Generation; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D004298:Dopamine; D014196:Trazodone