Rapid adaptation to neuronal membrane effects of ethanol and low temperature: some speculations on mechanism.
There is increasing evidence that ethanol exerts its primary effect at neuronal membranes by influencing specific lipid--protein or lipid--lipid interactions that control the state of organization of a specific membrane component; for example, a specific lipid--protein complex that controls a particular physiological property. This implies that tolerance to ethanol is the result of a change in the composition and/or state of organization of this critical membrane component. This altered state confers ethanol resistance. It may or may not have an effect on function in the absence of ethanol. One basis for these speculations comes from experiments using a sensitive and specific neurophysiological assay -- the rate of decay of posttetanic potentiation (PTP) at an identified synapse in an isolated, perfused Aplysia ganglion. We review evidence that PTP decay rate is strikingly accelerated by ethanol (a membrane-fluidizing agent) and strikingly decelerated below a transition temperature, presumably reflecting a transition in the structure of a membrane component. The ethanol and low-temperature effects are antagonistic. The system develops adaptation (tolerance) to either ethanol or low temperature within hours of its exposure. Tolerance persists for at least 12 hours, the longest interval tested thus far. In the absence of ethanol and at normal temperature the system behaves normally, that is it shows no "physical dependence". The system also has the remarkable property that when it becomes tolerant to either of these treatments, it shows tolerance to the other treatment that normally has the opposite effect. Therefore, the adaptation to either treatment cannot be a simple change in membrane composition governing overall membrane fluidity. A hypothesis which could explain the bidirectional cross-tolerance is considered in which adaptation to both treatments involves a shift from a homogeneous to a more heterogeneous composition of the critical membrane component, for example increasing heterogeneity in boundary lipid surrounding a critical membrane protein. It is becoming increasingly clear that ethanol exerts its primary effect by altering cell membrane structure -- by "fluidizing" or expanding neuronal and other membranes [1 - 6]. This effect results when ethanol, a somewhat hydrophobic molecule, intercalates between some fatty acid chains of membranes, reducing the degree of order of their alignment and increasing the lateral mobility of some membrane components. Decrease in the order of the fatty acid chains results in a measurable expansion of the membrane; and the change in fluidity is reflected in the change in mobility of appropriate probes that can be dissolved in the membrane [6, 7]. It is presumed that the physiological effects of ethanol are consequences of its fluidization of some critical membrane components; and that tolerance to ethanol is based on some form of resistance to this fluidization...
D000818:Animals; D001048:Aplysia; D003080:Cold Temperature; D004361:Drug Tolerance; D000431:Ethanol / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D005724:Ganglia / Q000187:drug effects; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D013570:Synaptic Membranes / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D008563:Membrane Lipids; D000431:Ethanol