Faculty Bibliography

The effect of supramaximal electric field stimulation on 3H released from rat spleen strips was studied after loading with either [3H]dopamine ([3H]DA) or [3H]norepinephrine ([3H]NE). In some experiments, [3H]DA and [3H]NE stored in the tissue or released in response to electrical stimulation were separated from their tritiated metabolites using HPLC followed by radiochemical detection. The stimulation-evoked release of 3H after loading with either derivative was subject to negative feedback modulation through alpha2-adrenergic, D2-dopamine and muscarinic acetylcholine receptors, and could be prevented by either calcium removal or tetrodotoxin blocking of Na+ influx, indicating its neuronal and vesicular origin. After the separation of radioactive metabolites by HPLC, both the tissue loaded with [3H]DA and the fractions collected during electrical stimulation contained a considerable amount of [3H]NE, providing evidence that the neurons it originated from were adrenergic in function. [3H]DA was also released during electrical stimulation. Since the spleen does not receive dopaminergic innervation, it was concluded that the noradrenergic axon terminals in the spleen were able to take up DA, convert it in part into NE, and release it as both DA and NE in response to neural activity. The ratio of [3H]DA and [3H]NE in the spleen loaded with [3H]DA was found to be dependent on both temperature and time of loading, and could be modulated by various drugs such as desmethylimipramine, a NE uptake blocker, and disulfiram or fusaric acid, dopamine beta-hydroxylase inhibitors. The phenomenon may reveal a new mechanism by which immunocytes in the spleen can be regulated by the neuroendocrine system

The pharmacological features of putative nicotinic acetylcholine receptor sites involved in the release of [3H]noradrenaline were assessed in rat hippocampus. The effect of nicotinic agonists to induce [3H]noradrenaline release was examined in superfused slices. The nicotinic agonists (-)-epibatidine, (+)-anatoxin-a, dimethylphenylpiperazinium, (-)-nicotine and (-)-lobeline released [3H]noradrenaline. The dose-response curves to nicotinic agonists were bell shaped, and indicated that their functional efficacies and potency vary across agonists. Maximal efficacy was seen with dimethyl-phenylpiperazinium and lobeline (Emax values two to three times higher than other agonists). The rank order of potency for the agonists to release [3H]noradrenaline was (-)-epibatidine > (+)- anatoxin-a > dimethylphenylpiperazinium > cytisine > nicotine > (-)-lobeline. The nicotinic acetylcholine receptor antagonists (n-bungarotoxin > mecamylamine > (+)-tubocurarine > hexamethonium > alpha-bungarotoxin = dihydro-beta-erythroidine) and tetrodotoxin antagonized the effect of dimethylphenylpiperazinium to release [3H]noradrenaline. The results, based on these pharmacological profiles, suggest the possible involvement of alpha 3 and beta 2 nicotinic acetylcholine receptor subunits in the control of [3H]noradrenaline release from hippocampal slices. The absence of effect of alpha-bungarotoxin and alpha-conotoxin-IMI excludes the possible involvement of nicotinic acetylcholine receptors containing the alpha 7 subunit. The release of [3H]noradrenaline by dimethylphenylpiperazinium was Ca2+ dependent. Nifedipine failed to prevent the dimethylphenylpiperazinium-induced release of [3H]noradrenaline, but Cd2+, omega-conotoxin and Ca(2+)-free conditions significantly reduced the dimethylphenylpiperazinium-induced release, suggesting that N-type voltage-sensitive Ca2+ channels are involved in the nicotinic acetylcholine receptor response. These voltage-sensitive Ca2+ channels are activated by the local depolarization produced by sodium influx through the nicotinic channels activated by dimethylphenylpiperazinium. Thus, the observed tetrodotoxin sensitivity of dimethylphenylpiperazinium-induced release of [3H]noradrenaline can be explained either by local depolarization and subsequent generation of action potentials at the preterminal area or that these nicotinic acetylcholine receptors are located on interneurons rather than directly on noradrenergic terminals

Ibogaine is an indole alkaloid that has been of interest in recent years due to its putative efficacy in the treatment of drug dependence. For the most part, animal data have shown attenuation of some of the effects of stimulant drugs, for example, motor stimulation and self-administration. The mechanism of this inhibition of drug-induced behavior seems to suggest the action of the dopamine, serotonin, NMDA, kappa, and/or sigma receptor sites, as indicated by the affinity of ibogaine to receptor selective ligands in binding competition studies. However, affinity for receptors does not in itself indicate their involvement. In vitro perfusion studies have proven a useful model to study the effect of ibogaine on neurotransmitter systems and the functional effects of such interactions. This review summarizes these data and the support of multiple effects of ibogaine, and the potential importance of its action on serotonergic modulation of dopamine release

Iminodipropionitrile (IDPN), a compound that causes dyskinetic symptoms in animals and has possible use as a model for human dyskinesia, was tested in mice and rats for its effect on cerebral amino acids. In mice, 2 h after IDPN administration, the level of total brain alanine was reduced; after 5 h the levels of aspartic acid and glutamic acid were also reduced, and the level of glutamine was increased. In rats, after chronic administration of IDPN, the level of glutamic acid in the total brain tissue was reduced. After acute administration of IDPN using microdialysis, extracellular GABA and extracellular glutamine levels in the striatum were elevated. This study shows that IDPN causes alterations in total and extracellular levels of neurotransmitter amino acids in the brain, which could have a role in IDPN-induced dyskinesia