Integrated channel plasticity contributes to alcohol tolerance in neurohypophysial terminals.
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. I(A,) 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 I(A) 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.
Knott
Thomas K
TK
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Dopico
Alejandro M
AM
Dayanithi
Govindan
G
Lemos
José
J
Treistman
Steven N
SN
D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004361:Drug Tolerance; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology*; D006728:Hormones / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010904:Pituitary Gland, Posterior / Q000187:drug effects* / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020746:Calcium Channels, L-Type; D002492:Central Nervous System Depressants; D006728:Hormones; D024681:Potassium Channels, Calcium-Activated; D000431:Ethanol