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Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

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Abstract

Rationale

Serotonin in the dorsal periaqueductal gray (DPAG) through the activation of 5-HT1A and 5-HT2A receptors inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with antipanic drugs that nonselectively or selectively blocks the reuptake of serotonin (e.g., imipramine and fluoxetine, respectively) enhances the inhibitory effect on escape caused by intra-DPAG injection of 5-HT1A and 5-HT2A receptor agonists. It has been proposed that these compounds exert their effect on panic by facilitating 5-HT-mediated neurotransmission in the DPAG.

Objectives

The objective of this study was to investigate whether facilitation of 5-HT neurotransmission in the DPAG is also observed after treatment with alprazolam, a pharmacologically distinct antipanic drug that acts primarily as a high potency benzodiazepine receptor agonist.

Materials and methods

Male Wistar rats, subchronically (3–6 days) or chronically (14–17 days) treated with alprazolam (2 and 4 mg/kg, i.p.) were intra-DPAG injected with (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), (±)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI), and midazolam, respectively, 5-HT1A, 5-HT2A/2C, and benzodiazepine receptor agonists. The intensity of electrical current that needed to be applied to the DPAG to evoke escape behavior was measured before and after the microinjection of these agonists.

Results

Intra-DPAG injection of the 5-HT agonists and midazolam increased the escape threshold in all groups of animals tested, indicating a panicolytic-like effect. The inhibitory effect of 8-OH-DPAT and DOI, but not midazolam, was significantly higher in animals receiving long-, but not short-term treatment with alprazolam.

Conclusions

Alprazolam as antidepressants compounds facilitates 5-HT1A- and 5-HT2A-receptor-mediated neurotransmission in the DPAG, implicating this effect in the mode of action of different classes of antipanic drugs.

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Acknowledgment

The authors thank Prof Neil McNaughton and Robert Munn for valuable suggestions to the manuscript and Afonso Paulo Padovan for expert technical assistance. This is study was funded by FAPESP and CNPq, Brazil.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, University of São Paulo, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Valquíria Camin de Bortoli & Hélio Zangrossi Jr.

  2. Laboratory of Comparative Psychology, University Estácio de Sá, 20260-060, Rio de Janeiro, Rio de Janeiro, Brazil

    Regina Lúcia Nogueira

  3. School of Psychology, University of Ribeirão Preto, 14096-380, Ribeirão Preto, São Paulo, Brazil

    Regina Lúcia Nogueira

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  1. Valquíria Camin de Bortoli
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  2. Regina Lúcia Nogueira
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  3. Hélio Zangrossi Jr.
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Correspondence to Hélio Zangrossi Jr..

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de Bortoli, V.C., Nogueira, R.L. & Zangrossi, H. Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray. Psychopharmacology 198, 341–349 (2008). https://doi.org/10.1007/s00213-008-1134-7

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  • DOI: https://doi.org/10.1007/s00213-008-1134-7

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