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Rationale: The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or "PACO" (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system., Objectives: Our aim was to study ion conductances that have important implications regulating sleep-wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples ("PACO"-like binge") using mice., Methods: We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle., Results: Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine ("PACO"-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic "PACO"-like administrations. Furthermore, intracellular basal [Ca 2+ ] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type "window currents." As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca 2+ transients, regulated the membrane excitability, and altered sleep-wake transitions., Conclusion: Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca 2+ ].

Rationale: In previous studies, we have demonstrated that seized samples of a smokable form of cocaine, also known as coca paste (CP), induced behavioral sensitization in rats. Interestingly, this effect was accelerated and enhanced when the samples were adulterated with caffeine. While the cocaine phenomenon is associated with persistent functional and structural alterations in the prefrontal cortex (PFC) and nucleus accumbens (NAc), the molecular mechanisms underlying the CP sensitization and the influence of caffeine remains still unknown., Objective: We examined the gene expression in NAc and mPFC after the expression caffeine-adulterated and non-adulterated CP locomotor sensitization., Methods: The locomotor sensitization was established in C57BL/6 mice, repeatedly treated with a CP-seized sample adulterated with caffeine (CP-2) and a non-adulterated one (CP-1). We then assessed the mRNA expression of receptor subunits of the dopaminergic and glutamatergic systems in the medial PFC (mPFC) and NAc. Other molecular markers (e.g., adenosinergic, endocannabinoid receptor subunits, and synaptic plasticity-associated genes) were also analyzed., Results: Only CP-2-treated mice expressed locomotor sensitization. This phenomenon was associated with increased Drd1a, Gria1, Cnr1, and Syn mRNA expression levels in the NAc. Drd3 mRNA expression levels were only significantly increased in mPFC of CP-2-treated group., Conclusions: Our results demonstrated that caffeine actively collaborates in the induction of the molecular changes underlying CP sensitization. The present study provides new knowledge on the impact of active adulterants to understand the early dependence induced by CP consumption.

Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca 2+ -dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity.