Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors

Abstract

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 while 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 (TRN). We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal (VB) 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 VB 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 −/−. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in presynaptic TRN terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine.

Differential alterations of intracellular [Ca2+] dynamics induced by cocaine and methylphenidate in thalamocortical ventrobasal neurons

“…administered (3 injections, 15 mg/kg each, 1 hour apart; [26,29–32]). Control groups received saline injections similarly timed.…”

“…followed by transcardial perfusion with ice-cold low sodium/antioxidants solution, and then decapitated. Thalamocortical slices, including the somatosensory cortex (250–350 µm) were obtained using a stage with 55° vertical inclination as previously described [26,29–31]. Slices were then allowed to recover at 35 °C for at least 30 min in a psychostimulant-free ACSF solution.…”

“…Pipettes also contained the low-affinity ratiometric Ca 2+ -sensitive indicator Bis-fura 2 (Final intracellular concentration100 µM; stock solutions: 50 mM in DMSO, 1:500 ratio DMSO vs intracellular saline solution). Single 500 ms square pulses were used to evoke voltage dependent calcium currents, changing from a −70 mV holding potential to −30 mV step voltage (i.e., to generate maximum amplitude of mibefradil and 2-octanol sensitive T-type mediated currents; [26,29–31]), or to −10 mV step voltage (i.e., to generate maximum amplitude of ω-agatoxin-IVA sensitive P/Q-type currents; [30,31]). Pulses to −30 mV always preceded pulses to −10 mV.…”

“…In the somatosensory VB thalamus, cocaine is known to rapidly increase synaptic NE and 5-HT [24], while MPH was able to increase DA levels in the thalamic reticular nucleus (i.e., origin of GABAergic afferents to VB neurons, [25]). A recent work using transgenic mouse has described a specific 5-HT modulatory role on GABA release onto VB neurons, modulated by a cocaine binge [26]. Using transgenic mice bypassed previously described collateral effects of SERT inhibitors like fluoxetine on voltage-gated calcium channels [27,28].…”

Arousal and drug abuse

“…In rodents, an enhancement of spontaneous GABA release from thalamic reticular nucleus neurons was described after repetitive cocaine administration (i.e., binge-like administration: 3 cocaine injections at 15 mg/kg; i.p., one hour apart) [75–78]. Higher levels of GABA release at thalamic levels were correlated with abnormally high levels of low frequency oscillations in the cortical EEG [75].…”