ABSTRACT
Repeated cocaine administration induces behavioral sensitization and modifications in the phosphorylation pattern of dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32), characterized by a tonic increase in the Thr75 phosphorylated form, and a decrease in the Thr34 phosphorylated form. This study further investigated the correlations between cocaine sensitization and modifications in the DARPP-32 phosphorylation pattern, cAMP-dependent protein kinase (PKA) activity, and mGluR5 tone in the medial prefrontal cortex and nucleus accumbens. Behavioral sensitization and modifications in these neurochemical markers followed a similar temporal pattern. Moreover, in sensitized rats acute cocaine administration modified phosphorylation levels of Thr75- and Thr34-DARPP-32, GluR1, and NR1 subunits in the nucleus accumbens only at a dose double the efficacious dose in control rats. These results suggest that the high levels of phospho-Thr75 DARPP-32 maintain PKA in a prevalent inhibited state. Furthermore, in sensitized rats the acute administration of 6-methyl-2-(phenylethynyl)-pyridine, a mGluR5 antagonist, reinstated the phosphorylation levels of Thr75- and Thr34-DARPP-32, GluR1, and NR1 to control values, and a subsequent cocaine challenge did not elicit a sensitized response. These data suggest that a tonic increase in mGluR5 transmission in cocaine-sensitized rats sustains both the increase in phospho-Thr75 DARPP-32 levels and the expression of behavioral sensitization.
Subject(s)
Brain/drug effects , Cocaine-Related Disorders/metabolism , Cocaine/pharmacology , Cyclic AMP-Dependent Protein Kinases/drug effects , Dopamine and cAMP-Regulated Phosphoprotein 32/drug effects , Receptors, Metabotropic Glutamate/drug effects , Signal Transduction/drug effects , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain/metabolism , Brain/physiopathology , Cocaine-Related Disorders/physiopathology , Cyclic AMP-Dependent Protein Kinases/metabolism , Cyclin-Dependent Kinase 5/drug effects , Cyclin-Dependent Kinase 5/metabolism , Disease Models, Animal , Dopamine Uptake Inhibitors/pharmacology , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Male , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Phosphorylation/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, AMPA/drug effects , Receptors, AMPA/metabolism , Receptors, Metabotropic Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction/physiology , Up-Regulation/drug effects , Up-Regulation/physiologyABSTRACT
Mirtazapine is a widely used antidepressant and the aim of this study was to further investigate its antidepressant activity in rats. Thus, the efficacy of long-term mirtazapine treatment was assessed in three models of depressive symptoms induced by stress exposure: the acute escape deficit, the chronic escape deficit, and the stress-induced disruption of the acquisition of an appetitive behaviour sustained by a palatable food (vanilla sugar). Administration of mirtazapine for 2 wk prevented the escape deficit development induced by acute exposure to unavoidable stress. This protective effect was antagonized by the administration of a beta-adrenergic or a 5-HT1A receptor antagonist just before stress exposure; that is, mirtazapine effect was dependent on functional beta-adrenergic and 5-HT1A receptor systems. Repeated stress exposure indefinitely prolongs the condition of escape deficit and a 40-d mirtazapine treatment reversed this model of chronic escape deficit. In a Y-maze satiated rats learn to choose the arm baited with vanilla sugar, and exposure to stress during Y-maze training prevents this learning. Repeated mirtazapine administration completely antagonized the disrupting effect of chronic stress on the acquisition of this instrumental behaviour. We consider these effects to be crucial in the definition of antidepressant activity.
