Joanna Peris, Kevin J. Anderson, Thomas W. Vickroy , Michael. A. King, Bruce E. Hunter and Don W. Walker

6. CET-INDUCED CHANGES IN CHOLINERGIC TRANSMISSION IN HIPPOCAMPUS

Cholinergic innervation of hippocampus is also important for mediation of events leading to LTP. The balance between cholinergic and GABAergic systems may determine hippocampal theta activity (101) which has been shown to modulate LTP in vivo (75). The dentate gyrus is innervated by GABAergic and cholinergic fibers from the medial septum and the nucleus of the diagonal band (see 102) which can influence dentate gyrus excitability. There is a strong cholinergic influence on GABAergic and other neurons in hippocampus (103, 104). A vast majority of the GABA neurons in CA1, CA3 and dentate gyrus of hippocampus express muscarinic acetylcholine receptors (101). These muscarinic receptors may presynaptically influence GABA release in hippocampus and affect LTP.

Cholinergic influences also appear to be involved in the effects of CET on LTP in hippocampus. There are numerous reports that suggest that CET may induce a permanent loss in cholinergic function in hippocampus. CET decreases high affinity choline uptake in hippocampus (105) as well as ACh levels, choline acetyl transferase and acetylcholinesterase activity (19, 106, 107). Lesions of the septohippocampal nucleus block the effects of acute ethanol on LTP (108). Whether this effect is due to a loss of altered cholinergic influences on GABA neurons remains to be answered. CET decreases the effects of ACh on population spike amplitude but has no effects on carbachol-inhibition of EPSPs (109). Additionally, both cholinergic disinhibition and recurrent inhibition are decreased by CET. Similar results were found in response to application of carbachol (110). These data suggest that ACh response properties in CA1 exhibit differential sensitivity to CET and may reflect a distinct susceptibility of muscarinic receptor subtypes to the neurotoxic effects of ethanol. However, the reductions in cholinergic function produced by CET do not appear to be due to receptor loss since muscarinic receptor subtype densities were not found to be altered as determined by either immunoprecipitation of m_1-5 subtypes (111) or by maximal [³H]QNB binding and carbachol displacement of specific binding (112). Thus it is possible that the effects of CET on cholinergic transmission involve changes in muscarinic second messenger systems (e.g., PI metabolism) or very select populations of muscarinic receptors. The effect of carbachol on the EPSP is thought to be due to the presence of presynaptic muscarinic cholinergic receptors on the terminals of the stratum radiatum afferents. When these receptors are activated by carbachol, neurotransmitter release is reduced. Thus, the effects of CET to decrease the activation of muscarinic cholinergic receptors seem to be selective for postsynaptic rather than presynaptic cholinergic receptors.

In terms of presynaptic receptors, it appears that separate populations of presynaptic muscarinic cholinergic receptors may also be regulated differently by CET. The cholinergic agonist carbachol increases [³H]GABA release from superfused hippocampal slices and this effect is blocked by atropine (113). In CET rats, there is an increase in carbachol enhancement of [³H]GABA release compared to that measured in sucrose-treated rats (113). In contrast, the effect of atropine, a muscarinic antagonist, is significantly decreased (113). Thus, in addition to a CET-induced down-regulation of GABA_B autoreceptor function, presynaptic regulation of GABA release by ACh receptors in hippocampus is affected in a manner so as to increase GABA release. However, muscarinic receptors have been previously reported to decrease, not increase, GABA release in hippocampus or other brain regions. In contrast to these data, there is no effect of CET on the cholinergic control of presynaptic release of ACh. CET does not produce any reliable change in basal or stimulus-dependent [³H]ACh release in hippocampal slices (113). In addition, exposure of synaptosomes to the muscarinic cholinergic agonist oxotremorine causes an equivalent attenuation of potassium-evoked [³H]ACh release in both control and CET rats (113). The effects of the specific muscarinic cholinergic antagonist atropine are also similar (113). Therefore, in view of these findings, it appears that CET may be extremely selective in its effects on hippocampal cholinergic transmission.