The anorexic agents, sibutramine and fenfluramine, depress GABAB‐induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells

Background and purpose: Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells. Experimental approach: Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABA A and GABA B receptors. Key results: Fenfluramine and sibutramine reduced, concentration-dependently, the GABA B IPSPs, without affecting the GABA A-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABA B receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT 1B) receptor antagonist, SB216641, blocked the reduction of GABA B IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT 1B. Conclusions and implications: Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT 1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. © 2009 The British Pharmacological Society.