The present findings clearly demonstrated that the administration of drugs which directly activate or inhibit GABA receptors can cause a predictable modulation of the motor impairing action of moderate doses of ethanol in the rat. For example, direct activation of GABA receptors with GABA, muscimol or THIP potentiated ethanol-induced impairment. Furthermore, drugs such as GAG, AOAA, EOS or DABA that are thought to enhance the activity of GABA receptors indirectly by blocking the catabolism of endogenous GABA (Schechter et al., 1977
; Wallach, 1961
; Fowler and John, 1972
) or by inhibiting GABA uptake from the synaptic cleft (Sutton and Simmonds, 1974
), all enhanced the depression of aerial righting after ethanol. This action was observed with doses which alone had no significant effect on the ability of rats to right themselves.
Also important was the finding that bicuculline, a specific GABA receptor antagonist, significantly reduced this action of ethanol. This finding extends that of Leitch et al. (1977)
who found that picrotoxin, a drug which probably antagonizes the combined functioning of the GABA receptor-chloride iontophore complex (Ticku et al., 1978
), also reduced the impairment of aerial righting in ethanol-intoxicated rats. In addition, our findings parallel the results of Häkkinen and Kulonen (1976)
, who found that AOAA pretreatment increased, whereas bicuculline treatment decreased the impairment caused by ethanol in rats performing a tilting plane test.
A previous report showed that the effects of ethanol were antagonized by naloxone (Vogel et al., 1981
). However, this action required doses of naloxone (30–60 mg/kg) far in excess of those necessary for the antagonism of opiate or endorphin receptor activity. Naloxone has previously been reported to exert a GABA-antagonistic action (Billingsley and Kubena, 1978
; Dingledine et al., 1978
). The present work with bicuculline is consistent with the hypothesis that large doses of naloxone reduced ethanol-induced impairment via
a GABAergic antagonistic mechanism (Vogel et al., 1981
Certain “GABA-like” agents including AOAA have been shown to inhibit the locomotor stimulant action of ethanol in mice (Cott et al., 1976
). It was suggested that these drugs might unmask the depressant action of ethanol as a result of selectively eliminating ethanol-induced stimulation (Cott et al., 1976
). The present investigation further suggests that activation of GABA receptors modulates the depressant effects of ethanol on motor function. Thus, it is possible that a synergistic potentiation of the depressant actions of ethanol might occur after the activation of GABA receptors and this could mask the stimulant effects of ethanol.
Data in failed to establish a clear relationship between the concentration of GABA in three brain areas that play important roles in motor function and the magnitude of aerial righting impairment after ethanol or GAG treatments. For example, doses of ethanol (2.25 g/kg) or GAG (200 mg/kg) which alone caused minor impairment of the height of aerial righting had markedly different effects on GABA concentrations in the cerebellum, cortex and brainstem (). Ethanol exerted no effect on GABA concentrations, whereas GAG increased them several-fold over control levels. These findings are in sharp contrast to those of Grimm et al. (1975)
who have suggested that a direct relationship exists between the effects of AOAA and di-n
-propyl-acetate to increase cerebral cortical and cerebellar GABA concentrations and the ability of these drugs to impair motor performance. The results of a multitude of studies on seizure mechanisms now suggest that a rough correlation exists between the concentration of GABA in brain tissue and susceptibility to seizures. Reduction of brain GABA concentrations frequently has been observed to occur coincident with increased susceptibility to seizures (Tapia, 1975
), whereas increased GABA concentrations often accompany anticonvulsant drug action (Wood and Peesker, 1975
). However, many exceptions to these data indicate that there exists no simple relationship between the concentration of GABA in brain tissue and seizure susceptibility (Wood, 1975
). Recently, Wood et al. (1979)
have shown that the concentration of GABA in nerve endings, in contrast to that in unfractionated brain tissue, may more consistently be correlated with the onset of seizure susceptibility. In addition, two reports suggest that ethanol causes dose-dependent changes in the rate of GABA accumulation after GABA transaminase inhibition (Wixon and Hunt, 1980
; Supavilai and Karobath, 1980
). Similar analysis dealing more specifically with changes in neuronal GABA may lead to a clearer understanding of the relationship between motor impairment due to ethanol and changes in brain GABA homeostasis.
Although the present results clearly indicate that activation or inhibition of GABA receptors can modulate ethanol-induced impairment of motor coordination, conclusive evidence for the hypothesis that GABA mediates this action of ethanol was not obtained. However, when these results are considered along with neurophysiological results suggesting that ethanol potentiates GABAergic hyperpolarization of cortical neurons (Nestoros, 1980
), binding data suggesting an in vivo
ethanol-induced change in GABA receptor kinetics (Ticku, 1980
; Ticku and Burch, 1980
; Reggiani et al., 1980
) and observed changes in measures of GABA turnover (Wixon and Hunt, 1980
; Supavilai and Karobath, 1980
), a direct involvement of GABA in the actions of ethanol, seems likely. Future work should attempt to resolve the molecular basis of this potential interaction.