Simultaneous administration of cocaine and caffeine dysregulates HCN and T-type channels.

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 [Ca2+] 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 Ca2+ 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 [Ca2+].

Auditory Feedback Differentially Modulates Behavioral and Neural Markers of Objective and Subjective Performance When Tapping to Your Heartbeat.

Interoception, the perception of our body internal signals, plays a key role in maintaining homeostasis and guiding our behavior. Sometimes, we become aware of our body signals and use them in planning and strategic thinking. Here, we show behavioral and neural dissociations between learning to follow one's own heartbeat and metacognitive awareness of one's performance, in a heartbeat-tapping task performed before and after auditory feedback. The electroencephalography amplitude of the heartbeat-evoked potential in interoceptive learners, that is, participants whose accuracy of tapping to their heartbeat improved after auditory feedback, was higher compared with non-learners. However, an increase in gamma phase synchrony (30-45 Hz) after the heartbeat auditory feedback was present only in those participants showing agreement between objective interoceptive performance and metacognitive awareness. Source localization in a group of participants and direct cortical recordings in a single patient identified a network hub for interoceptive learning in the insular cortex. In summary, interoceptive learning may be mediated by the right insular response to the heartbeat, whereas metacognitive awareness of learning may be mediated by widespread cortical synchronization patterns.