Selective Changes in GABAergic Transmission in Substantia Nigra and Superior Colliculus Caused by Ethanol and Ethanol Withdrawal

Abstract

One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal from chronic ethanol exposure increases convulsant activity. An increase in neuronal transmission in the GABAergic pathways from striatum to the substantia nigra (SN) and a decrease in GABAergic transmission from SN to superior colliculus (SC) both appear to play a major role in inhibiting seizure propagation. If this is the case, then the changes in seizure sensitivity caused by ethanol may be expected to affect GABAergic transmission in opposite ways in SN and SC. We measured the effects of in vitro ethanol on pre- and postsynaptic indices of GABA transmission using SN and SC tissue from both ethanol-naive rats and rats given ethanol in their drinking water for 24 days and then withdrawn for 24 hr, a treatment that decreases seizure latency. While ethanol inhibited 3H-GABA release from slices of SC at low concentrations (20-100 nM), much higher concentrations were required to inhibit release from SN (100-500 mM). In fact, release from SN was increased by low concentrations of ethanol. Ethanol in vitro (20-1000 mM) also inhibited specific binding of 35S-TBPS to the GABAA receptor but this effect was similar in both potency and efficacy in SC and SN. Next, the in vitro effects of ethanol were measured in rats that had consumed an average of 9.8 g ethanol/kg body weight/day and were then withdrawn for 24 hr. Ethanol inhibition of 3H-GABA release from SC was significantly less in ethanol-treated rats compared to controls whereas the inhibitory effect of ethanol was increased in SN from ethanol-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype

“…Thus, even low concentrations of EtOH significantly disrupt SDR cerebellar processing (Hanchar et al, 2005). In contrast, other than the central nucleus of the amygdala (Roberto et al, 2003), the GABA A R system in most other brain nuclei (e.g., hippocampus, nucleus accumbens, thalamus, ventral tegmental area, and substantia nigra; Peris et al, 1992; Nie et al, 2000; Liang et al, 2006; Jia et al, 2008; Theile et al, 2008, 2009), is not affected by concentrations of EtOH below ~50 mM EtOH. Given that even the most avid rodent consumers of EtOH (e.g., high drinking in the dark selected mice, C57BL/6 mice and alcohol preferring rats) only voluntarily consume enough EtOH to reach BECs of ~20–25 mM, it is likely that in rodents, the GC GABA A R system is a primary mediator of symptoms of acute intoxication.…”

“…In electrophysiological studies of SDR cerebellar brain slices, acute application of EtOH increases the frequency of spontaneous GABAergic IPSCs, and increases the magnitude of the tonic GABA A -mediated current (Carta et al, 2004; Hanchar et al, 2005; Kaplan et al, 2013). Importantly, in contrast to many brain regions (e.g., hippocampus, nucleus accumbens, thalamus, ventral tegmental area, substantia nigra) (Peris et al, 1992; Nie et al, 2000; Liang et al, 2006; Jia et al, 2008; Theile et al, 2008, 2009), where EtOH only affects GABA A R transmission at concentrations far above those typically achieved during voluntary consumption by rodents or humans (≥50 mM), enhancement of GC GABA A R transmission occurs at low, readily achieved concentrations of alcohol (5–30 mM). Furthermore, although the changes in tonic GABA A R currents that are induced by such low concentrations of EtOH are small (1–5 pA), because of their constant nature, tonic GABA A R currents make up 75% of the total inhibitory current in GCs (Rossi and Hamann, 1998; Hamann et al, 2002a), which combined with the electrically compact nature of GCs (Rossi and Slater, 1993), enables such small tonic currents to profoundly influence transmission through the cerebellar cortex (Hamann et al, 2002a; Duguid et al, 2012).…”

Tolerance to ethanol sedation and withdrawal hyper-excitability is mediated via neuropeptide Y Y1 and Y5 receptors

“…Moreover, alpha-melanocyte stimulating hormone (α-MSH) and serotonin system in the hypothalamus, raphe nucleus, hippocampus and amygdala are reported to process the action of ethanol in depression-related behaviors (Zafar et al 2000;Yamane et al 2003;Kokare et al 2008;Uzbay 2008). Glutamatergic system in hippocampus and amygdala, and GABAergic transmission in substantia nigra and superior colliculus are involved in the ethanol withdrawal seizures (Peris et al 1992;Brailowsky and García 1999;Feng et al 2007;Stepanyan et al 2008). …”

Chronic Ethanol Exposure Increases 3H‐GABA Release in Rat Hippocampus by Presynaptic Muscarinic Receptor Modulation

“…'H-GABA release and release were measured using an adap- Ferraro et al7 1997;Leranth and Frotscher, 1987). tation of a method described previously (Peris et al, 1992(Peris et al, , 1997. The GABAergic neurons in CAl, CA3, and dentate gyrus of hippocampus was dissected from both sides of a single rat brain, and hippocampus express muscarinic cholinergic receptors (Van der zee and Luiten, 1993); and, more specifically, GABAergic interneurons in hippocampus express M, muscarinic acetylcholine (Ach) receptors (Hajos et al, 1998).…”