European Journal of Pharmacology , 199 (1991) 247-253 0 1991 Elsevier Science Publishers B.V. 0014-2999/91/$03.50 ADONIS 0014299991004355 EJP 51917 247 Sandra Sigala, Paola Rizzonelli, Emanuela Zanelli, Angelo Forgione l, Cristina Missale and PierFranco Spano Institute of Pharmacology and Experimental Therapeutics, School of Medicine, Unirrrsity of Brescia, Brescia, 11rly and ’ Institute of Pharmacology, I SchooI of Medicine, Utkersity of Napoli, Napoli. Italy Received 17 December 1990, revised MS received 13 March 1991, accepted 2 April 1991 There is now clinical evidence that I-sulpiride has antidepressant effects when administered at low, non-neuroleptic doses. Down-regulation of P-receptor-linked adenylate cyclase is a well-documented adaptive response to chronic administration of antidepressant drugs. In this study, we investigated dopamine receptor and fi-adrenoceptor changes induced by chronic administration of low doses of I-sulpiride. The data indicate that striatal D, and D, receptor function was desensitized by the treatment, which suggests that at low doses I-sulpiride preferentially blocks D, autoreceptors, leading to increased dopamine release. 1Bulpiride also induced a selective down-regulation of &receptor-associated adenylate cyclase activity in the frontal cortex, but not in the striatum, which does not receive norepinephrine projections. Taken together these data suggest that cortical noradrenergic terminals may be endowed with dopamine D, receptors controlling norepinephrine release and that blockade of this dopaminergic inhibitory modulation may be involved in the antidepressant effects of I-sulpiride. I-Sulpiride; Depression; Dopamine Dz receptors; P-Adrenoceptors; Frontal cortex 1. Intruhction Brain dopamine (DA) receptors have been classified into D, and D, subtypes (Spano et al., 1978; 1983; Kebabian and Caine, 1979) according to their phar- macological properties and their association with stim- ulation or inhibition (Onali et al., 1985) of adenylate cyclase (AC). Recently, the existence of different D, receptor subtypes has been suggested by the observation of multiple transduction mechanisms (Memo et al., 1986; Freedman and Weight, 1988; Castelletti et al., 1989; Vallar and Meldolesi, 1989) and by the discovery that the D, receptor gene produces two receptor isoforms by alternative mRNA splicing (Dal Toso et al., 1989; Giros et al., 1989; Monsma et al., 1989). DA receptors are present in those brain regions where neuroleptics are presumed to act to cause either the antipsychotic effects or the extrapyramidal side-effects (Chase and Tamminga, 1980; Crow et al., 1980; Davis, 1980). One of the most prominent features of these receptor popu- Correspondence to: S. Sigala, Institute of Pharmacology and Experi- mental Therapeutics, School of Medicine, University of Brescia, Via Valsabbina 19, 25124 Brescia, Italy. lations is their ability to adapt to changes In neuronal inputs. It has been shown that chronic treatment with neu- roleptic drugs results in D, receptor supersensitivity. as measured in binding studies TJith different ligands (Owen et al., 1978; Seeman et ai., 1984; MacKenzie and Zigmond, 1985). In line with this, we have shown that chronic treatment with the selective D, antagonist I-sulpiride induces a selective up-regulation of striatal D, receptors, without changing the functional activity of D, receptors (Memo et al., 1987). There is increas- ing evidence that the selective D, antagonist I-sulpiride has antidepressant activity when administered at low, non-neuroleptic doses (Corsini et al., 1979; Del Zompo et al., 1990). The molecular mechanisms of this effect, however, are still unknown. Down-regulation of j?- adrenoceptors and desensitization of the B-receptor- linked AC in the frontal cortex is a well-documented adaptive response to chronic administration of antide- pressants (Vetulani and Sulser, 1975; Vetulani et al., 1976; Minneman et al., 1979; Okada et al., 1986). This effect is common to a number of drugs and requires the presence of intact noradrenergic and serotoniner- gic neurons (Brunello et al., 1982; Janowsky et al., 1982). In addition to the noradrenergic terminals from the locus coeruleus, the rat frontal cortex receives