Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors.
Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 μM) and high (100 μM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 μM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 μM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 μM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre-synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G-protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and thus facilitating GABA release.
Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado" (DFBMC) Facultad de Ciencias Exactas y Naturales, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET-UBA), Universidad de Buenos Aires, Ciudad Universitaria, Ciudad de Buenos Aires, Argentina.|Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
Belén
B
Goitia
Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado" (DFBMC) Facultad de Ciencias Exactas y Naturales, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET-UBA), Universidad de Buenos Aires, Ciudad Universitaria, Ciudad de Buenos Aires, Argentina.|Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
María Celeste
MC
Rivero-Echeto
Grupo de Neurociencia de Sistemas, Departamento de Fisiología, Facultad de Medicina, Instituto de Fisiología y Biofísica (IFIBIO), UBA, Ciudad de Buenos Aires, Argentina.
Noelia V
NV
Weisstaub
Division of Developmental Neuroscience, Columbia University and the NYSPI, Sackler Institute for Developmental Psychobiology, New York City, New York, USA.
Jay A
JA
Gingrich
Department of Neurobiology and Developmental Sciences, Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Edgar
E
Garcia-Rill
Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
Verónica
V
Bisagno
Departamento de Fisiología, Biología Molecular y Celular "Dr. Héctor Maldonado" (DFBMC) Facultad de Ciencias Exactas y Naturales, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET-UBA), Universidad de Buenos Aires, Ciudad Universitaria, Ciudad de Buenos Aires, Argentina.
Francisco J
FJ
Urbano
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D019256:Cadmium Chloride / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D013787:Thalamic Nuclei / Q000187:drug effects* / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D010726:Phosphodiesterase Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D012701:Serotonin; D002110:Caffeine; D005680:gamma-Aminobutyric Acid; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D003042:Cocaine; D019256:Cadmium Chloride
GABA; caffeine; cocaine; serotonin; thalamic reticular nucleus