Propofol decreases stimulated dopamine release in the rat nucleus accumbens by a mechanism independent of dopamine D2, GABA(A) and NMDA receptors

Abstract

Although propofol (2,6-di-isopropylphenol) is a popular i.v. general anaesthetic, it has been suggested to have abuse potential. As many drugs of abuse act preferentially via release of dopamine in the limbic system, we investigated the action of propofol on stimulated dopamine release in the rat nucleus accumbens. Nucleus accumbens slices were superfused (1.6 ml min-1) with artificial cerebrospinal fluid at 32°C. Dopamine release was evoked by electrical stimulation (10 pulses, 0.1 ms, 10 mA, 10 Hz, every 10 min) and monitored by fast cyclic voltammetry. Propofol 100 μmol litre-1 reduced stimulated dopamine release over the 2 h after administration, relative to Intralipid controls, to mean 30 (SEM 2)% (P < 0.01). The dopamine D2 receptor antagonist metoclopramide 0.3 μmol litre-1 increased dopamine release but did not block the effect of propofol (38 (3)%). The selective GABA(A) antagonist bicuculline 24 μmol litre-1 also failed to antagonize the action of propofol (45 (3)%). The NMDA receptor antagonist dextromethorphan 10 μmol litre-1 decreased dopamine release to 57 (6)% (P < 0.01) but failed to block the inhibitory effect of propofol (46 (6)%). Although propofol has been reported to bind to D2, GABA(A) and NMDA receptors, failure of metoclopramide and bicuculline to block its effects suggests that an agonist action at D2 or GABA(A) receptors does not mediate the effects of propofol on dopamine release in the rat nucleus accumbens. The lack of effect of dextromethorphan makes an NMDA receptor antagonist action unlikely.