title: Effects of lobeline and dimethylphenylpiperazinium iodide (DMPP) on N-methyl-D-aspartate (NMDA)-evoked acetylcholine release in vitro: evidence for a lack of involvement of classical neuronal nicotinic acetylcholine receptors.
abstract: Biochemical, behavioral and electrophysiological evidence suggests interactions between pathways containing neuronal nicotinic acetylcholine receptors (NAChRs) and excitatory amino acid receptors. Recently, protective effects of nicotine against N-methyl-D-aspartate (NMDA)-induced toxicity in primary cortical cultures were reported. To address possible interactions between NAChR and NMDA receptor containing pathways, several NAChR agonists were evaluated for their effects on NMDA-evoked [3H]acetylcholine ([3H]ACh) release from slices of rat striatum. Nicotine, cytisine and epibatidine had no effect on NMDA-evoked release or basal release of [3H]ACh over a wide range of concentrations. Lobeline and dimethylphenylpiperazinium iodide (DMPP), however, decreased basal [3H]ACh release and attenuated NMDA-evoked [3H]ACh release with EC50 values of 35 and 155 microM, respectively. The NAChR antagonists, dihydro-beta-erythroidine (DH beta E) and d-tubocurarine had no effect on NMDA-evoked [3H]ACh release, whereas mecamylamine attenuated the NMDA-evoked [3H]ACh evoked release with an EC50 value of 144 microM. Methyllycaconitine (MLA), a highly selective and potent antagonist of the alpha-bungarotoxin-sensitive alpha 7 NAChR subtype, also had no effect on NMDA-evoked [3H]ACh release at concentrations upto 10 microM. The inhibitory effects of DMPP and lobeline on NMDA-evoked [3H[ACh release were relatively insensitive to mecamylamine, d-tubocurarine, MLA and DH beta E. In addition, DMPP or lobeline-induced attenuation of basal [3H]ACh release was insensitive to blockade by sulpiride, a dopamine (D2) receptor antagonist. In contrast to their effects on NMDA-evoked striatal [3H]ACh release, both DMPP and lobeline increased basal release of striatal [3H]DA and hippocampal [3H]norepinephrine ([3H]NE) and did not attenuate NMDA-evoked release of these two transmitters. Instead, DMPP and lobeline appeared to have an additive effect on both NMDA-evoked hippocampal [3H]NE release and striatal [3H]DA release. These pharmacological results suggest that the inhibitory effects on lobeline and DMPP on striatal [3H]ACh release are independent of their interactions with classical NAChRs or the NMDA receptor complex itself.
authors.affiliation: Neuropharmacology Laboratory, SIBIA Neurosciences Inc., La Jolla, CA 92037-4641, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Rao
authors.forename: L D
authors.initials: LD
authors.lastname: Correa
authors.forename: G K
authors.initials: GK
authors.lastname: Lloyd
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008120:Lobeline / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide; D016202:N-Methylaspartate; D008120:Lobeline; D000109:Acetylcholine