European Neuropsychopharmacology 11 (2001) 343–349 www.elsevier.com / locate / euroneuro Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs a, a a a b * Laura Dazzi , Mariangela Serra , Francesca Spiga , M. Giuseppina Pisu , J. David Jentsch , a Giovanni Biggio a Department of Experimental Biology ‘B. Loddo’, University of Cagliari, 09123 Cagliari, Italy b Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA Received 5 January 2001; received in revised form 13 March 2001; accepted 3 April 2001 Abstract Use of antidepressant drugs in the treatment of anxiety disorders has recently increased due to the anxiolytic effect of some of these agents. Because dopaminergic transmission in the prefrontal cortex is sensitive to anxiogenic or stressful stimuli, the effects of two antidepressant drugs with different mechanisms of action, imipramine and mirtazapine, on the response of rat cortical dopaminergic neurons to stress were investigated. A 2-week (but not single dose) administration of imipramine (10 mg / kg, i.p., twice daily) or mirtazapine (10 mg / kg, i.p., once daily) reduced and completely antagonized, respectively, the increase in dopamine release in the prefrontal cortex elicited by footshock stress. Long-term administration of imipramine or mirtazapine had no marked effect on the stress-induced increases in the brain or plasma concentrations of neuroactive steroids or corticosterone. An attenuation of the response of mesocortical dopaminergic neurons to stress induced by long-term treatment with antidepressants might contribute to the anxiolytic effects of such drugs.  2001 Elsevier Science B.V. All rights reserved. Keywords: Antidepressant drugs; Stress; Dopamine release; Microdialysis; Neuroactive steroids 1. Introduction serotonin reuptake inhibitors (Stahl, 1999), and these agents have been used in the treatment of anxiety associ- The prescription of benzodiazepine drugs in the treat- ated with panic disorder (Falkai, 1999; Sheehan, 1999) or ment of anxiety disorders is limited by the ability of these of generalized anxiety disorders (Goodnick et al., 1999). drugs to produce dependence in a large proportion of Given that episodes of anxiety and / or depression are often patients (Lader, 1994; Griffiths and Weerts, 1997; preceded by stressful events, a modulation of the physio- Schweizer and Rickels, 1998). Benzodiazepines are rein- logical response to stressful stimuli by these drugs might forcing drugs that support self-administration (Ator and also be related to their therapeutic action. Griffiths, 1987; Woods et al., 1987). This problem has led Acute stressful stimuli markedly increase the extracellu- to a decrease in the number of prescriptions issued for lar concentration of dopamine in the prefrontal cortex benzodiazepines (Tyrer, 1986) and has provided impetus (Abercrombie et al., 1989; Imperato et al., 1991; Hama- for the use of non-benzodiazepine drugs in the treatment of mura and Fibiger, 1993; Dazzi et al., 1995; Finlay and anxiety disorders. Substantial evidence has recently shown Zigmond, 1997; Inglis and Moghaddam, 1999), and the that some antidepressant drugs exert an anxiolytic action, effects of stress on dopamine release in this brain region including tricyclic drugs, mirtazapine and specific are prevented by the acute administration of classical anxiolytic drugs, such as benzodiazepines or other positive allosteric modulators of GABA receptors (Ida et al., A *Corresponding author. Tel.: 139-070-675-4169; fax: 139-070-675- 1989; Kaneyuki et al., 1991; Dazzi et al., 1995; Hegarty 4166. E-mail address: dazzi@vaxca1.unica.it (L. Dazzi). and Vogel, 1995; Hutson and Barton, 1997). These effects 0924-977X / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0924-977X(01)00105-5