Changes in magnesium ion (Mg²⁺) concentration may be implicated in
alcohol-related behaviors through modulation of neuronal excitability by
actions on ligand-gated ion channels. To study whether putative
Mg²⁺-binding sites differ between two rat lines, alcohol-insensitive
(AT) and alcohol-sensitive (ANT) rats, selectively outbred for
differential sensitivity to the motor-impairing effect of ethanol, we
compared the effect of Mg²⁺ on [³⁵S]tert-butylbicyclophosphorothionate
([³⁵S]TBPS) binding to GABA_A receptors with the use of ligand
autoradiographic analyses of brain sections from these rats. There were
some slight differences between the rat lines in modulation of the
binding in the forebrain. A low concentration of Mg²⁺ (0.1 mM)
inhibited basal [³⁵S]TBPS binding more efficiently in the central gray
matter and hippocampus in the ANT rats than in the AT rats. In the
presence of gamma-aminobutyric acid, the effect of a low concentration
of Mg²⁺ was higher in the caudate-putamen and inner layer of the
cerebral cortex in the AT rats than in the ANT rats. No difference
between the rat lines was found at a higher (3 mM) Mg²⁺ concentration.
Furosemide, a GABA_A antagonist selective for cerebellar granule
cell-specific alpha6beta2/3 subunit-containing receptors, was less
efficient in antagonizing the Mg²⁺-induced inhibition of [³⁵S]TBPS
binding in the ANT rats than in the AT rats. Another divalent cation,
zinc ion, was less efficient in displacing [³⁵S]TBPS binding from the
cerebellar granule cell layer in the ANT rats than in the AT rats,
whereas a trivalent cation,
lanthanum ion, produced identical modulation of the binding in the two
rat lines. The results indicate that the alcohol-sensitive ANT rats have
altered cerebellar granule cell--specific alpha6 subunit--containing
GABA_A receptors and seem to indicate that these receptors might be
implicated in the sensitivity difference of the rat lines to ethanol and
sedative drugs.