Desensitization of the D1 dopamine receptors in rats reproduces a model of escape deficit reverted by imipramine, fluoxetine and clomipramine.
1. The present study investigated the effect of long-term D1 dopamine receptor stimulation on an animal model of depression derived from the learned helplessness paradigm. 2. The model used is based on the escape deficit produced by a series of unavoidable shocks administered to rats 24 h before the test session. SKF 38393 administered acutely, completely prevented the development of animal hyporeactivity, while given repeatedly produced tolerance to its own protective effect. Moreover it also reduced the spontaneous escape reactivity of rats not exposed to the inescapable shocks. Animals chronically receiving SKF 38393 and showing a clearcut escape deficit, were treated daily with either imipramine, fluoxetine, or clomipramine. After 21 days of combined treatment the 3 antidepressants appeared equally effective in reverting the behavioral deficit. Moreover, long term administration of both imipramine or SKF 38393 down regulated D1 dopamine receptor number in the prefrontal cortex, while the association of the two drugs resulted in a receptor density similar to that of control rats. 3. The present results further support the crucial role played by D1 dopamine receptors in the control of animal reactivity to stressful stimuli and in the mechanism of action of imipramine. Moreover they show that the D1 dopamine receptor related escape deficit is sensitive also to compounds selectively acting through the serotonergic neuronal system.
Institute of Pharmacology, University of Siena, Italy.
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Gambarana
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Ghiglieri
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Graziella de Montis
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D002997:Clomipramine / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D013997:Time Factors
D017447:Receptors, Dopamine D1; D005473:Fluoxetine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D002997:Clomipramine; D007099:Imipramine