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The Journal of Neuroscience, November 23, 2005, 25(47):10831-10843; doi:10.1523/JNEUROSCI.2999-05.2005

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Neurobiology of Disease
Involvement of 5-HT_1A Receptors in Prefrontal Cortex in the Modulation of Dopaminergic Activity: Role in Atypical Antipsychotic Action

Llorenç Díaz-Mataix,^1 * M. Cecilia Scorza,^1 * Analía Bortolozzi,^1 * Miklos Toth,² Pau Celada,¹ and Francesc Artigas¹

¹Department of Neurochemistry, Institut d' Investigacions Biomèdiques de Barcelona Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain, and ²Department of Pharmacology, Weill Medical College, Cornell University, New York, New York 10021

Atypical antipsychotics increase dopamine (DA) release in the medial prefrontal cortex (mPFC), an effect possibly involved in the superior effects of atypical versus classical antipsychotics on cognitive/negative symptoms. We examined the role of 5-HT_1A receptors in the mPFC on the modulation of dopaminergic activity and the mesocortical DA release in vivo. The highly selective 5-HT_1A agonist BAY x 3702 (BAY; 10-40 µg/kg, i.v.) increased the firing rate and burst firing of DA neurons in the ventral tegmental area (VTA) and DA release in the VTA and mPFC. The increase in DA release in both areas was potentiated by nomifensine coperfusion. The selective 5-HT_1A antagonist WAY-100635 reversed the effects of BAY in both areas, and the changes in the VTA were prevented by frontocortical transection.

The application of BAY in rat and mouse mPFC by reverse dialysis increased local extracellular DA at a low concentration (3 µM) and reduced it at a higher concentration (30 µM). Both effects disappeared in 5-HT_1A knock-out mice. In the presence of bicuculline, BAY reduced DA release at all concentrations. The atypical antipsychotics clozapine, olanzapine, and ziprasidone (but not haloperidol) enhanced DA release in the mPFC of wild-type but not 5-HT_1A knock-out mice after systemic and local (clozapine and olanzapine) administration in the mPFC. Likewise, bicuculline coperfusion prevented the elevation of DA release produced by local clozapine or olanzapine application. These results suggest that the activation of mPFC 5-HT_1A receptors enhances the activity of VTA DA neurons and mesocortical DA release. This mechanism may be involved in the elevation of extracellular DA produced by atypical antipsychotics.

Key words: antipsychotic; dopamine; prefrontal cortex; schizophrenia; serotonergic1A receptor; ventral tegmental area

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Received Feb 24, 2005; revised October 3, 2005; accepted October 9, 2005.

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