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The Journal of Neuroscience, September 22, 2004, 24(38):8214-8222; doi:10.1523/JNEUROSCI.1274-04.2004

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Cellular/Molecular
Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

Diego Centonze,^1,2 Alessandro Usiello,³ Cinzia Costa,^1,2 Barbara Picconi,^1,2 Eric Erbs,³ Giorgio Bernardi,^1,2 Emiliana Borrelli,^3 * and Paolo Calabresi^1,2 *

¹Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy, ²Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00179 Rome, Italy, and ³Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France

Reduced glutamate-mediated synaptic transmission has been implicated in the pathophysiology of schizophrenia. Because antipsychotic agents might exert their beneficial effects against schizophrenic symptoms by strengthening excitatory transmission in critical dopaminoceptive brain areas, in the present study we have studied the effects of acute and chronic haloperidol treatment on striatal synaptic plasticity. Repetitive stimulation of corticostriatal terminals in slices induced either long-term depression or long-term potentiation (LTP) of excitatory transmission in control rats, whereas it invariably induced NMDA receptor-dependent LTP in animals treated chronically with haloperidol. Haloperidol effects were mimicked and occluded in mice lacking both D2L and D2S isoforms of dopamine D2 receptors (D2R-/-), in mice lacking D2L receptors and expressing normal levels of D2S receptors (D2R-/-;D2L-/-), and in mice lacking D2L receptors and overexpressing D2S receptors (D2L-/-). These data indicate that the blockade of D2L receptors was responsible for the LTP-favoring action of haloperidol in the striatum. In contrast, overexpression of D2S receptors uncovered a facilitatory role of this receptor isoform in LTP formation because LTP recorded from D2L-/- mice, but not those recorded from wild-type, D2R-/-, and D2R-/-;D2L-/- mice, was insensitive to the pharmacological blockade of D1 receptors.

The identification of the cellular, molecular, and receptor mechanisms involved in the action of haloperidol in the brain is essential to understand how antipsychotic agents exert their beneficial and side effects.

Key words: antipsychotics; electrophysiology; LTD; LTP; synaptic transmission; transgenic mice

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Received April 5, 2004; revised August 3, 2004; accepted August 5, 2004.

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