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. 1990 Aug;254(2):528-38.

Site-specific enhancement of gamma-aminobutyric acid-mediated inhibition of neural activity by ethanol in the rat medial septal area

B S Givens  1 , G R Breese
Affiliations

Site-specific enhancement of gamma-aminobutyric acid-mediated inhibition of neural activity by ethanol in the rat medial septal area

B S Givens et al. J Pharmacol Exp Ther. 1990 Aug.

Abstract

Because of uncertainty concerning the interaction of ethanol with gamma-aminobutyric acid (GABA) receptor-mediated events, the present work was designed to investigate the effect of ethanol on GABA transmission in the rat septal area using behavioral and electrophysiological techniques. Microinjection of the GABAA agonist muscimol into the medial septal area (MSA) enhanced, and bicuculline administration antagonized, ethanol-induced impairment of the aerial righting reflex. Microinjection of these drugs into the lateral septum (LSi) did not influence this measure of ethanol-induced sedation. Furthermore, intraseptal injections of muscimol or bicuculline in saline-treated rats had no effect on the aerial righting reflex. These data suggest that the MSA plays a critical modulatory role in the sedative actions of ethanol. To assess the effect of ethanol on muscimol responses in the MSA and LSi at the cellular level, GABA was applied by iontophoresis to rhythmically bursting neurons of the MSA and to cells in the LSi. The magnitude of the resultant inhibition by GABA on these cells was assessed before and after systemic administration of ethanol. Ethanol enhanced GABA-mediated inhibition of MSA neural activity, but did not alter GABA-mediated inhibition of cellular activity in the LSi. In contrast, the inhibition of cellular activity in the MSA, caused by a maximally effective concentration of the benzodiazepine flurazepam, was not altered by ethanol. Other work in the MSA demonstrated that electrical stimulation of the fimbria caused an inhibition of ongoing single unit activity that was reduced by concurrent application of bicuculline. The duration of this electrically elicited inhibition in the MSA was enhanced after ethanol injection and then recovered to base-line levels. In addition, ethanol (1.5 mg/kg) caused an enhancement of the inhibition induced by nipecotic acid, a GABA uptake inhibitor. These findings demonstrate that GABA-mediated neural inhibition is enhanced by ethanol in the MSA but not the LSi, indicating that the actions of ethanol on GABA-induced inhibition can be site specific. It is proposed that the cellular action of ethanol may depend upon a specific molecular composition of the GABA receptor complex which may vary at selected sites in the brain.

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Figures

Fig. 1
Fig. 1
Effect of direct microinjection of muscimol (30 ng) and bicuculline (150 ng) into the MSA on the height of aerial righting in ethanol (1.5 g/ kg)-treated rats. There are six rats in each treatment group.*P < .01 when compared to the saline treatment.
Fig. 2
Fig. 2
Effect of direct microinjection of muscimol (30 ng) and bicuculline (150 ng) into the LSi on the height of aerial righting in rats after 1.5 g/kg of ethanol. There are six rats in each condition. There are no significant differences across the group (P > .1).
Fig. 3
Fig. 3
Histological location of the tips of electrodes that recorded rhythmically bursting MSA neurons (●) and irregularly firing LSi neurons (▼). Abbreviations are: cc, corpus callosum; cp, caudate-putamen; Is, lateral septum; ac, anterior commissure; ms, medial septum; db, diagonal band (vertical limb).
Fig. 4
Fig. 4
Current-response relationship between MSA cells and iontophoretic GABA pulses before and 60mm after the administration of 1.5 g/kg of ethanol in urethane-anesthetized rats. There are at least six determinations for each value recorded. *P <.05; **P<.01when compared to baseline.
Fig. 5
Fig. 5
Rate histogram demonstrating the effect of systemically administered ethanol (1.5 g/kg) on responses of MSA neurons to iontophoretically applied GABA in urethane-anesthetized rats. The acute firing rate decreases in the histogram occurred immediately upon the application of GABA to the neuron.
Fig. 6
Fig. 6
Oscilloscope traces of the response of a single rhythmically bursting MSA neuron to fimbria stimulation. The upper trace illustrates the long-lasting inhibition of unit activity after a single 0.2-msec electrical stimulation. The effect of bicuculline on the stimulus-evoked inhibition can be seen in the lower trace.
Fig. 7
Fig. 7
Response of MSA neurons to currents of increasing strengths through an electrode placed in the fimbria before and 30 min after i.p. administration of 1.5 g/kg of ethanol. Values are based on 11 determinations. For the analysis of variance analysis, F = 6.31 (1,174). *P < .05 when compare to base-line.
Fig. 8
Fig. 8
Inhibition of MSA neural activity after fimbria stimulation in the free-moving rat before (base-line) and 30 min (ethanol) or 90 min (recovery) after systemically administered ethanol at one of three doses. There are six determinations for each ethanol dose. *P < .05 when compared to base-line.
Fig. 9
Fig. 9
Current-response relationship of MSA neurons and iontophoretically applied flurazepam. Note that the maximal response is an approximate 30% suppression of activity. The bars above the histogram indicate when the designated current was applied to the flurazapam-containing pipette.
Fig. 10
Fig. 10
The response of MSA neurons to iontophoretically applied flurazepam 60 min after ethanol. A, rate histogram illustrating the inhibition in firing of an MSA neuron by flurazepam before and after systemic administration of ethanol (1.5 g/kg). Inhibition of firing rate in the histogram is due to the application of flurazepam to the neuron. B, summary of the effect of two different doses of ethanol on the flurazepam-elicited inhibition. No significant differences between ethanol and saline were observed.
Fig. 11
Fig. 11
The response of LSi neurons to iontophoretically applied GABA. A, rate histogram illustrating the inhibition in firing of a LSi neuron by GABA before and after systemic administration of ethanol (1.5 g/kg). The acute interruptions in the histogram are the points at which GABA was applied iontophoretically to the neuron. The inhibition that occurred during the first few minutes after ethanol is in response to the ethanol administration. B, summary of the effect of 1.5 g/kg of ethanol on GABA-elicited inhibition in the LSI measured 30 min postinjection. Ethanol produced no significant change in the neural response to GABA (P > .1).
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