The mesocortical dopamine (DA) system within the prefrontal cortex (PFC) is implicated in the regulation of cognitive processing like attention and working memory (Jones, 2002). Hypo-DA activity within the medial PFC (mPFC) contributes to the major symptoms of schizophrenia, including deficits in sensory gating, attention and working memory (Castner et al. 2004). Nicotine improves the attentional processes associated with working memory in laboratory animals (Levin et al. 1998) and in schizophrenic patients (Harris et al. 2004), possibly by facilitating DA release. Accordingly, the modulation of DA release by nicotinic acetylcholine receptors (nAChR) has been demonstrated in various brain regions, including the accumbens and striatum (Marshall et al. 1997). The present study characterized nAChR-mediated DA release in the mPFC using in vivo microdialysis in freely moving rats. Adult male Sprague-Dawley rats (300-320 g) were anaesthetized with ketamine (75 mg/kg, i.p.) and medetomidine (0.5 mg/kg, i.p.) and implanted with unilateral microdialysis probes (AN69, 4 mm active membrane) into the mPFC using standard stereotaxic surgery procedures. Buprenorphine (0.05 mg/kg, s.c.) was administered as analgesic and anaesthesia reversed with atipamezole (1 mg/kg, s.c.). After 24 h, the probes were perfused with artificial cerebrospinal fluid (aCSF, 2 μl/min) and 15 min fractions were collected and analyzed for DA by HPLC–amperometry. Local perfusion of nicotine produced a concentration-dependent increase in extracellular DA levels which was blocked by the nonspecific nAChR antagonist chlorisondamine (CHL) given by continuous local infusion (100 μM), or systemic administration (10mg/kg, i.p.). Nicotine-evoked DA release was partially attenuated by continuous local infusion of the β2*-selective nAChR antagonist dihydro-beta-erythroidine (DHβE, 10 μM). The involvement of α4β2* nAChR was supported by the ability of the more selective agonist 5-IA-85380 to increase extracellular DA levels in mPFC. This response was completely abolished by continuous local infusion of DHβE (10 μM). Local infusion of the specific α7 nAChR agonist Compound A also facilitated DA release within the mPFC concentration dependently. This effect was attenuated by the α7-specific antagonist methylcaconitine (MLA) administered locally (100 μM) or systemically (3mg/kg, i.p.). Further the α7 nAChR allosteric modulator PNU-120596 (10 μM) on co-infusion with Compound A, potentiated its DA facilitating effect. PNU-120596 alone on systemic (1mg/kg, s.c.) but not local administration (10 μM) produced DA release within mPFC. This suggests tonic cholinergic control of DA release in mPFC by extra cortical α7 receptors. These data demonstrate that local α7 and β2* nAChR within the mPFC can facilitate DA release.