ELSEVIER European Neuropsychopharmacology 5 (1995) 43-48 EUROPEANNEURO. PSYCHOPHARMACOLOGY The effect of chronic treatment with imipramine on the responsiveness of hippocampal CA1 neurons to phenylephrine and serotonin in a chronic mild stress model of depression M. Bijak, M. Papp* Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Cracow, Poland Received 9 May 1994; revision received 17 August 1994; accepted 6 September 1994 Abstract The effect of chronic mild stress (CMS) and chronic treatment with the tricyclic antidepressant drug imipramine (10 mg/kg/day for 5 weeks) on neuronal responsiveness to the al-noradrenergic agonist phenylephrine and serotonin (5-HT) was examined ex vivo, in the CA1 cell layer of the rat hippocampal slice preparation. We corroborated some previous findings that CMS, which had been used as an animal model of depression, decreased the consumption of a 1% sucrose solution and that that effect was reversed by chronic administration of imipramine. Imipramine did not change the sucrose consumption in control animals. In both control and stressed animals, phenylephrine (5/zM) and 5-HT (10/zM) attenuated the amplitude of the population spikes evoked in the CA1 pyramidal cell layer by stimulation of Schaffer collateral/commissural fibers. Those inhibitory effects of phenylephrine and 5-HT were significantly potentiated by chronic treatment with imipramine. The imipramine-induced potentiation was similar in slices from control and stressed animals. These results suggest that the imipramine-induced functional changes in al-noradrenergic and serotonergic receptors in the hippocampus are not involved in the anti-anhedonic effect of chronic imipramine administration in the CMS model of depression. Keywords: Chronic mild stress; Imipramine; al-Adrenergic receptor; 5-HT1A receptor; Hippocampal slice 1. Introduction There exists a considerable body of literature re- porting that long-term administration of antidepres- sants results in functional changes in many neurotrans- mitter systems in the brain of experimental animals (cf. Caldecott-Hazard et al., 1991). It is well known that antidepressants are devoid of mood-elevating effects in non-depressed individuals (Pillard and Fisher, 1978); therefore it has been postulated that studies into the action of antidepressants should be carried out on animal models of depression. One of these models, developed by Willner and his colleagues (Willner et al., 1992), is chronic mild stress (CMS). In this model, rats subjected to a variety of mild stressors show a gradual and long-lasting decrease in their response to rewarding stimuli (Papp et al., 1991; Moreau et al., 1992). This phenomenon seems to * Corresponding author. Tel.: (48 12) 37 40 22; Fax: (48 12) 37 45 00. 0924-977X/95/$09.50 © 1995 Elsevier Science B,C. All rights reserved SSDI 0924-977X(94)00132-4 reflect anhedonia, which is regarded as a core symp- tom of major depression (APA, 1987). The CMS- induced deficit in responsiveness to reward is usually monitored by a substantial decrease in the consump- tion of a palatable, weak (1%) sucrose solution, which has been proved to be a simple measure of the animal's sensitivity to reward (cf. Willner et al., 1992). This effect of prolonged stress is reversed by long-term treatment with antidepressant drugs. Recent bio- chemical and binding studies have shown that CMS affects the noradrenergic and serotonergic systems (Willner et al., 1991; Papp et al., 1994). Both these systems are involved in a reaction to acute and chronic stress, and are regarded as potential targets of the antidepressant action (Joseph and Kennett, 1983; Stone et al., 1986; Kennett et al., 1987; Caldecott- Hazard et al., 1991; Kawahara et al., 1993; Watanabe et al., 1993). Previous in vivo and ex vivo electro- physiological studies demonstrated in normal animals that prolonged treatment with different antidepressant drugs significantly changed the responsiveness of hip-