Blockade of MK-801-Induced Heat Shock Protein 72/73 in Rat Brain by Antipsychotic and Monoaminergic Agents Targeting D2, 5-HT1A, 5-HT2A and α1-Adrenergic Receptors
Tamara Romon, Anna M. Planas and Albert Adell
Affiliation: Department of Neurochemistry and Neuropharmacology, Instituto de Investigaciones Biomedicas de Barcelona, CSIC, IDIBAPS, Carrer Rossello 161, 6th floor, room 630, 08036 Barcelona, Spain.
Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative
symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats,
these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced
glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats,
which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work,
we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block
immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK-
801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors
responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone -
and to a lesser extent haloperidol-reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the
administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2A (M100907) and α1-
adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced
number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest
that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2A, 5-HT1A and
α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism.
Keywords: MK-801, antipsychotic drugs, dopamine D2 receptor, 5-HT2A receptor, 5-HT1A receptor, α1-adrenoceptor.
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