In this week’s issue of Journal of Neuroscience, a worldwide group of neuroscientists characterized rapid neuronal tolerance to a single-time injection of cocaine, specifically at GIRK channels and related dopaminergic and glutamatergic cascades.  GIRK channels are inhibitory receptors, which, in this case, were less active during the first, but no consecutive cocaine challenge.  What this means is that a cocaine-induced reduction of inhibition would actually increase neuronal activity, which most likely explains the increased dopaminergic signaling arising from the VTA that subsequently projects onto integrative reward areas, and elicits physiologic and behavioral hedonism during cocaine use. As shown in this series of figures, the tolerance effects of cocaine on reward system signaling are really compelling as there is an immediate reversal of cocaine-induced GIRK channel hypoactivation by the second ResearchBlogging.orgcocaine challenge as well as dose-dependent responses.

Devinder Arora,1* Matthew Hearing,1* Desirae M. Haluk,1* Kelsey Mirkovic,1 Ana Fajardo-Serrano,3, & Martin W. Wessendorf,2 Masahiko Watanabe,4 Rafael Luja´n,3 and Kevin Wickman1 (2011). Acute Cocaine Exposure Weakens GABAB Receptor-
Dependent G-Protein-Gated Inwardly Rectifying K
Signaling in Dopamine Neurons of the Ventral Tegmental
Area Journal of Neuroscience : 10.1523/JNEUROSCI.0494-11.2011

I have an invested interest in this transient, electrophysiologic tolerance effect because a few years ago we found that the circadian clock shows rapid tolerance (within 5 minutes!!!) to ethanol in that a few minutes of ethanol application to the SCN prior to a photic (glutamate) or nonphotic (serotonin) “pulse” completely reverses ethanol’s impairing actions on the clock.

Further, this research recognizes the dangerous consequences of even single-time drug use. In individuals with a family history of hedonism (like mine), a fast-acting, long-lasting drug  linked to an intense state of euphoria and mania like cocaine or heroine could rapidly send someone into a downward spiral of further abuse since the re-wiring of the major reward pathways is so immediate.