The anorexic agents, sibutramine and fenfluramine, depress GABA(B)-induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells.
OBJECTIVE
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.


METHODS
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.


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
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.
Ledonne
Ada
A
Università della Calabria, Dipartimento Farmaco-Biologico, Arcavacata di Rende, Cosenza, Italy.
Sebastianelli
Luca
L
Federici
Mauro
M
Bernardi
Giorgio
G
Mercuri
Nicola Biagio
NB
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D003503:Cyclobutanes / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D001067:Appetite Depressants; D003503:Cyclobutanes; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D044302:Receptor, Serotonin, 5-HT1B; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D058825:Serotonin 5-HT1 Receptor Agonists; D005277:Fenfluramine; D001418:Baclofen; D004298:Dopamine; C058254:sibutramine