Nicotinic Receptors

Neuronal nicotinic receptor subtypes in the CNS and peripheral nervous system exhibit diverse pharmacological and biophysical properties (78). This heterogeneity is probably based on the isoforms of the a and p subunits (a2-a9, P2-4) which can combine to form hetero-oligomeric and homo-oligomeric (a7-9) nicotinic receptors (78). Although distributed throughout the CNS, the role of nicotinic receptors is not well understood, because there are few clear examples of synaptic transmission mediated by nicotinic receptors. However, clear effects of exogenously applied nicotinic agonists on neurotransmitter release (e.g., increases in the frequency of spontaneous postsynaptic currents mediated by GABA and glutamate) have been reported (78-80). Furthermore, neuronal nicotinic receptors are implicated in memory acquisition, anxiety, analgesia, synaptic plasticity, and excitotoxicity. Recently, certain isoforms of nicotinic receptor have been shown to be exceptionally sensitive to certain general anesthetics (81). Early studies with alphaxalone demonstrated both muscle nicotinic receptors and "neuronaltype" nicotinic receptor of bovine chromaffin cells to be inhibited by high micromolar concentrations of the anesthetic (10,82). Similarly, we have found alphaxalone to inhibit recombinant neuronal nicotinic receptors (a4p2 and a7) at such concentrations (Table 2). The water-soluble anesthetic minaxolone is similarly effective at these receptors (Table 2). To place these observations in context, the aqueous concentration of alphaxalone achieved during surgical anaesthesia is approximately 3.6 ^M (72). Hence, it is conceivable that an action at neuronal nicotinic receptors may contribute to the behavioral action of alphaxalone. However, for the nicotinic receptors of bovine chromaffin cells (10), and for a4p2 and a7 recombinant receptors expressed in oocytes, we found the behaviorally inert 3p-ol diastereomer of alphaxalone, betaxalone, to be equipotent in blocking the current evoked by nicotine or acetylcholine. Hence, it is unlikely that neuronal nicotinic receptors constitute an important locus of action for this steroid.

Progesterone (PROG) and testosterone (T), at high micromolar concentrations, also produce a rapid concentration-dependent inhibition of neuronal a4p2 nicotinic receptors expressed in oocytes (83). Interestingly PROG coupled to bovine serum albumin (BSA; a water soluble compound that does not partition into the plasma membrane) was equieffective with the parent steroid, suggesting the PROG site to be located extracellu-larly. In the same study, cholesterol and 3a,5p-THPROG were found to be inert (83).

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