PT  - JOURNAL ARTICLE
AU  - Knott, Thomas K.
AU  - Dopico, Alejandro M.
AU  - Dayanithi, Govindan
AU  - Lemos, José
AU  - Treistman, Steven N.
TI  - Integrated Channel Plasticity Contributes to Alcohol Tolerance in Neurohypophysial Terminals
AID  - 10.1124/mol.62.1.135
DP  - 2002 Jul 01
TA  - Molecular Pharmacology
PG  - 135--142
VI  - 62
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/62/1/135.short
4100  - http://molpharm.aspetjournals.org/content/62/1/135.full
SO  - Mol Pharmacol2002 Jul 01; 62
AB  - Short-term ethanol challenge results in the reduction of peptide hormone release from the rat neurohypophysis. However, rats that have been maintained on an ethanol-containing diet for 3 to 4 weeks exhibit tolerance to this effect. Mechanistic underpinnings of this tolerance were probed by examining four ion channel conductances critical for neurohormone release. The voltage-gated L-type calcium channel and the functionally linked calcium-activated BK channel represent a functional dyad. Although these channels show opposite drug responses in the naive terminal (i.e., the L-type Ca2+ channel is inhibited whereas the BK channel is potentiated), the effect of long-term alcohol exposure is to decrease sensitivity to the short-term administration of drug in both instances. In addition to the shift in sensitivity, current density increased for the L-type Ca2+ current and decreased for the BK current, consistent with a compensatory change. Sensitivity to alcohol was also altered for two other channel types studied. Inhibition of the voltage-gated transient Ca2+current was lessened after long-term treatment. IA, which is not sensitive to the drug at clinically relevant concentrations in terminals from the naive rat, acquires sensitivity after long-term exposure, representing a potentially novel type of tolerance. However, neither the transient Ca2+ current nor IA shows a change in current density, demonstrating the selectivity of this aspect of tolerance. Overall, these results demonstrate that channel plasticity can explain at least a portion of the behavioral tolerance resulting from changes in sensitivity of peptide hormone release. Furthermore, they suggest that an understanding of tolerance requires the examination of dynamically coupled channel populations.