Serotonin, (5-HT3) receptors are found in high density in the mesocorticolimbic dopamine (DA) system (Kilpatrick et al., 1987). It has been suggested that 5-HT3 antagonists inhibit mesolimbic portions of this DA system involved in brain-stimulation reward and drug-induced reward, and that this inhibitory interaction may form the basis for novel and clinically useful approaches in the treatment of drug addiction (Costall et al., 1987). Similarly, other studies have shown that 5-HT3 agonists enhance DA release in striatal slices (Blandina et al., 1988) and nucleus accumbens (Jiang et al., 1990;Chen et al., 1991). Another DA-rich forebrain locus believed by some workers to be involved in mediating the reward engendered by habit-forming drugs [i.e., capable of supporting self-administered electrical brain-stimulation reward (Routtenberg and Sloane, 1971) and capable of supporting self-administered microinjections of cocaine (Goeders and Smith, 198311 is the prefrontal cortex. However, little is known regarding the modulating function of 5-HT, receptors on mesocortical portions of the mesocorticolimbic DA pathway. In the present preliminary study, we examined the effect of 5-HT3 receptor activation on DA release in the medial prefrontal cortex, using in vivo microdialysis in conjunction with direct local application of a relatively 5-HT3-selective agonist (1-phenylbiguanide) and a highly 5-HT3-selective antagonist (zacopride).
Male Sprague-Dawley rats (250-300 g) were implanted under pentobarbital anesthesia with microdialysis probes in the DA-terminal region of the medial prefrontal cortex, with probe tips at stereotaxic coordinates (Paxinos and Watson, 1982): A t-2.7 (from bregma), L 0.5 (from midline), and V -5.5 (from skull). The concentric microdialysis probes used had 4-mm exposed cellulose membranes (SpectraRor hollow cellulose fiber, MWCO 5000, Spectrum Medical Industries) and mean relative recovery rates of 7.2% for DA, 5.9% for 3,4-dihydroxyphenylacetic acid (DOPAC), and 9.3%