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Effects of the antidepressant trazodone, a 5-HT2A/2C receptor antagonist, on dopamine-dependent behaviors in rats

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Abstract

Rationale

5-Hydroxytryptamine, via stimulation of 5-HT2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT2A/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-HT2A and 5-HT2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

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Acknowledgements

The authors are grateful to the Principal of Krishna Institute of Medical Sciences for providing them with the necessary facilities and to Protec Ltd., India, Endo Laboratories, USA, and Sun Pharmaceuticals, India for their generous gifts of trazodone HCl, molindone HCl and fluoxetine HCl, respectively.

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Authors and Affiliations

  1. Department of Pharmacology, Krishna Institute of Medical Sciences, Karad, Maharashtra, 415 110, India

    Jehangir J. Balsara, Sujata A. Jadhav, Rajani K. Gaonkar, Ramona V. Gaikwad & Jagdish H. Jadhav

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  1. Jehangir J. Balsara
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  2. Sujata A. Jadhav
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  3. Rajani K. Gaonkar
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  4. Ramona V. Gaikwad
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  5. Jagdish H. Jadhav
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Correspondence to Rajani K. Gaonkar.

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Balsara, J.J., Jadhav, S.A., Gaonkar, R.K. et al. Effects of the antidepressant trazodone, a 5-HT2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. Psychopharmacology 179, 597–605 (2005). https://doi.org/10.1007/s00213-004-2095-0

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