Tolerance to Acute Ethanol Inhibition of Peptide Hormone Release in the Isolated Neurohypophysis

Abstract

The altered component responsible for the tolerance to inhibition of release resides in the isolated terminal, because tolerance measured in vitro from intact neurohypophyses was similar to that seen in isolated terminals. The failure of EtOH-injected animals to exhibit reduced inhibition of release in response to an acute EtOH challenge indicates that short-term elevated blood alcohol level does not induce this tolerance. The finding of tolerance to EtOH-induced inhibition of release from the intact neurohypophysis and isolated terminals provides a physiological preparation in which to examine the molecular targets of acute drug action modified after chronic exposure to the drug.

Alcohol Tolerance in Large-Conductance, Calcium-Activated Potassium Channels of CNS Terminals Is Intrinsic and Includes Two Components: Decreased Ethanol Potentiation and Decreased Channel Density

“…The reduced potentiation was very rapid and evident within a few minutes of exposure, whereas the reduced current density did not near completion until 24 hr of exposure. Neither form of tolerance required the 3 week exposure period that was necessary to obtain stable blood alcohol levels in the ingesting animal (Knott et al, 2000). The rapid appearance of reduced potentiation suggests direct or indirect post-translational modifications of BK channels (e.g., phosphorylation) rather than genetic reorganization, especially because terminals from which BK currents were recorded are located in the neurohypophysis, whereas cell bodies lie in the hypothalamus a few millimeters away.…”

“…The use of the whole animal is limiting in a few important aspects. First, studies of the chronology of tolerance are impeded by the long period necessary for the buildup of blood alcohol levels, using the sucrose fade technique (Knott et al, 2000). Second, it is impossible to separate actions of the drug directly on channels within HNS neurons (intrinsic tolerance) from actions elsewhere in the intact animal and nervous system that secondarily affect neuronal function in HNS neurons (extrinsic tolerance).…”

“…The enhancement of BK activity by acute ethanol is linked to inhibition of AVP and OXT secretion (Knott et al, 2002). Chronic exposure of rats to an alcoholcontaining diet for 3 weeks results in the development of tolerance in the HNS, consisting of a reduced acute effect of ethanol on hormone secretion from the neurohypophysial (NH) terminal (Knott et al, 2000), concurrent with the decreased ethanol potentiation of BK channels and decreased BK current density in terminals (Knott et al, 2002).…”

“…First, studies of the chronology of tolerance, using the sucrose fade technique, are impeded by the period necessary for the establishment of consistent blood alcohol levels (Knott et al, 2000). Use of the HNS explant allows precise control over dosage and time of exposure to exogenous agents (Rossi, 2004;Somponpun and Sladek, 2004).…”

Integrated Channel Plasticity Contributes to Alcohol Tolerance in Neurohypophysial Terminals

“…The rat hypothalamic-neurohypophysial system provides an ideal model to study the short-term and long-term actions of ethanol. Short-term ethanol challenge blocks the release of arginine vasopressin and oxytocin (OT) from both the intact neurohypophysis and from isolated neurohypophysial terminals (Wang et al, 1991a,b;Knott et al, 2000). The diuretic effect of short-term alcohol exposure exhibits tolerance after prolonged ethanol exposure (Schrier et al, 1979;Crabbe et al, 1981;Pohorecky, 1985).…”