Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine

Abstract

Chronic sequential exposure to a variety of mild stressors has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions, associated with abnormalities of dopaminergic neurotransmission in the nucleus accumbens. In the present study, 5 weeks of treatment with imipramine (10 mg/kg b.i.d.) reversed the decreased sucrose intake of rats exposed to chronic mild stress. Stress also caused a decrease in D2-receptor binding in the limbic forebrain (but not the striatum), which was completely reversed by imipramine. In nonstressed animals, imipramine decreased D1-receptor binding in both regions. However, in stressed animals, imipramine did not significantly alter D1-receptor binding in either area. Stress alone slightly increased D1-receptor binding, in striatum only. Scatchard analysis showed that all changes in receptor binding resulted from changes in receptor number (Bmax) rather than receptor affinity (KD). The results support the hypothesis that changes in D2-receptor function in the nucleus accumbens are responsible for chronic mild stress-induced anhedonia and its reversal by antidepressant drugs. They do not support the hypothesis that the sensitization of D2-receptors seen following chronic antidepressant treatment is caused by a down-regulation of D1-receptors.

Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress

“…Firstly, direct cannabinoid agonists produce antidepressant-like responses in both CMS (Onaivi et al 2006) and forced swim tests (Jiang et al 2005). Secondly, as documented in the present report, chronic treatment with URB597 elevates anandamide levels in brain regions, such as midbrain and striatum, which are thought to participate in the induction of CMS-related behaviors (Bekris et al 2005;Dziedzicka-Wasylewska et al 1997;Papp et al 1994).…”

“…Since acute or subchronic treatment with URB597 enhances firing of serotonergic and noradrenergic neurons in the midbrain (Gobbi et al 2005), it is possible that persistent anandamide accumulation in this region might contribute to the antidepressant-like effects of URB597 in CMS (Haidkind et al 2003;Liu et al 2003;Papp et al 1994). Testing this hypothesis will require, however, further experimentation.…”

The role of stress in the pathophysiology of the dopaminergic system

“…58 CMS causes a decrease in the number of D2 receptors, but not affinity, in the rat limbic forebrain (nor in the striatum), which is completely reversed by chronic imipramine. 59 Changes in D2 receptor function in the NAc produced after CMS are similar to those observed after footshock stress. 60 These conditions seem to be preserved during evolution up to the levels of primates.…”

Chronic imipramine treatment-induced changes in acetylcholinesterase (EC 3.1.1.7) activity in discrete rat brain regions

“…Imipramine, one of the most extensively studied tricyclic antidepressants, inhibits 5-hydroxytryptamine (5-HT) uptake both in vitro and in vivo and chronic treatment induces adaptive changes in brain monoamin-ergic neurotransmission (7)(8)(9)(10)(11)(12). Janowsky et al (6) proposed that depression in humans may be associated with overactive cholinergic and decreased monoaminergic neurotransmission.…”