Effects of the antidepressant trazodone, a 5-HT sub(2A/2C) receptor antagonist, on dopamine-dependent behaviors in rats

• Published in: Psychopharmacology 2005-05, Vol.179 (3), p.597-605
• Main Authors: Balsara, Jehangir J, Jadhav, Sujata A, Gaonkar, Rajani K, Gaikwad, Ramona V, Jadhav, Jagdish H
• Format: Article
• Language: English
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-004-2095-0

Rationale: 5-Hydroxytryptamine, via stimulation of 5-HT sub(2C) receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT sub(2A) receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT sub(2A/2C) receptor antagonist. Objectives: 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 sub(2A) and 5-HT sub(2C) receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT sub(2C) receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.