Lorcaserin bidirectionally regulates dopaminergic function site-dependently and disrupts dopamine brain area correlations in rats

Philippe De Deurwaerdère, Marta Ramos, Rahul Bharatiya, Emilie Puginier, Abdeslam Chagraoui, Julien Manem, Eleonora Cuboni, Massimo Pierucci, Gabriele Deidda, Maurizio Casarrubea, Giuseppe Di Giovanni
Neuropharmacology. 2020-04-01; 166: 107915
DOI: 10.1016/j.neuropharm.2019.107915

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De Deurwaerdère P(1), Ramos M(2), Bharatiya R(3), Puginier E(3), Chagraoui A(4), Manem J(3), Cuboni E(2), Pierucci M(2), Deidda G(2), Casarrubea M(5), Di Giovanni G(6).

Author information:
(1)Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5287), Bordeaux Cedex, France. Electronic
(2)Neurophysiology Laboratory, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta – Msida, Malta.
(3)Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5287), Bordeaux Cedex, France.
(4)Normandie University, UNIROUEN, INSERM, U1239, CHU Rouen, Neuronal and Neuroendocrine Differentiation and Communication Laboratory, Institute for Research and Innovation in Biomedicine of Normandy (IRIB), Rouen, France;
Department of Medical Biochemistry, Rouen University Hospital, Rouen, France.
(5)Laboratory of Behavioral Physiology, Department of Biomedicine Neurosciences and Advanced Diagnostics (Bi.N.D.) – Human Physiology Section “Giuseppe Pagano”, University of Palermo, Palermo, Italy.
(6)Neurophysiology Laboratory, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta – Msida, Malta; School of Biosciences, Cardiff University, Cardiff, UK.

Lorcaserin, which is a selective agonist of serotonin2C receptors (5-HT2CRs), is a new FDA-approved anti-obesity drug that has also shown therapeutic promise in other brain disorders, such as addiction and epilepsy. The modulation of dopaminergic function might be critical in the therapeutic effect of lorcaserin, but its exact effect is unknown. Here, we studied the effect of the peripheral administration of lorcaserin on the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) dopaminergic neural activity, dopamine (DA) dialysis levels in the nucleus accumbens and striatum and on DA tissue levels in 29 different rat brain regions. Lorcaserin (5-640 μg/kg, i.v.) moderately inhibited only a subpopulation of VTA DA neurons, but had no effect on the SNc neurons. Lorcaserin (0.3, 3 mg/kg, i.p.) did not change VTA and SNc DA population neural activity but slightly decreased the firing rate and burst firing of the spontaneously active VTA neurons, without altering DA extracellular dialysate levels in both the nucleus accumbens and the striatum. Quantitative analysis of DA and metabolites tissue contents of the 29 areas studied revealed that lorcaserin (0.3 or 3 mg/kg, i.p.) only affected a few brain regions, i.e., increased DA in the central amygdala, ventral hypothalamus and nucleus accumbens core and decreased it in the ventromedial striatum. On the other hand, lorcaserin dramatically changed the direction and reduced the number of correlations of DA tissue content among several brain areas. These effects on DA terminal networks might be significant in the therapeutic mechanism of lorcaserin.

 


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