Differential effects of methylphenidate and cocaine on GABA transmission in sensory thalamic nuclei

Abstract

Methylphenidate (MPH) is widely used to treat children and adolescents diagnosed with attention deficit/hyperactivity disorder. Although MPH shares mechanistic similarities to cocaine, its effects on GABAergic transmission in sensory thalamic nuclei are unknown. Our aim was to compare cocaine and MPH effects on GABAergic projections between thalamic reticular and ventrobasal (VB) nuclei. Mice (P18-30) were subjected to binge-like cocaine and MPH acute and sub-chronic administrations. Cocaine and MPH enhanced hyperlocomotion, though sub-chronic cocaine-mediated effects were stronger than MPH effects. Cocaine and MPH sub-chronic administration altered paired-pulse and spontaneous GABAergic input differently. The effects of cocaine on evoked paired-pulse GABA-A mediated currents changed from depression to facilitation with the duration of the protocols used, while MPH induced a constant increase throughout administration protocols. Thalamic reticular nucleus GAD67 and VB CaV3.1 protein levels were measured using Western blot in order to better understand their link to increased GABA release. Both proteins were increased by sub-chronic administration of cocaine. These results suggest that cocaine and MPH produced distinct presynaptic alterations on GABAergic transmission. MPH showed effects on GABAergic transmission that seems less disruptive than cocaine. Unique effects of cocaine on postsynaptic VB calcium currents might explain deleterious cocaine effects on sensory thalamic nuclei. These results might help to understand the impact of MPH repetitive administration on sensory thalamic nuclei.

Effects of methamphetamine on locomotor activity and thalamic gene expression in leptin-deficient obese mice

“…Mouse locomotor activity was recorded with an automated system (Ethovision XT 7.0, Noldus, The Netherlands) as previously described [15,18,19]. Total distance traveled (cm) was quantified for a total of 5 minutes prior to injections (basal), and 40 minutes following the last injection of METH/vehicle for days 1 and 7 (test).…”

“…Our group has described multiple METH-mediated alterations in mouse cortical and sub-cortical areas [13–16], including changes in mRNA levels of membrane receptors and voltage-gated ion channels in medial prefrontal neurons [17]. Repeated exposure to cocaine, a psychostimulant that can also increase DA neurotransmission, enhanced low threshold T-type calcium channel protein levels in mouse somatosensory thalamus neurons [18]. Selective targeting of T-type calcium channels using specific blockers reduced cocaine-mediated hyperlocomotion concomitantly with a reduction in GABAergic neurotransmission onto thalamic ventrobasal nucleus [19], thus suggesting the involvement of somatosensory ventrobasal thalamic nucleus in locomotor alterations.…”

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

“…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.…”

“…No clear effects on calcium channels of VB neurons were observed after acute MPH binge -like administration [31]. Although VB neurons can be considered key neurons to understand cocaine and MPH differential effects on thalamocortical networks, little is known about how cocaine and MPH administration can affect their intracellular [Ca 2+ ] dynamics.…”