QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.070466v1 311/2/700    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Braga, M. F. M. Articles by Albuquerque, E. X. Search for Related Content PubMed PubMed Citation Articles by Braga, M. F. M. Articles by Albuquerque, E. X.

TOXICOLOGY

Pb²⁺ via Protein Kinase C Inhibits Nicotinic Cholinergic Modulation of Synaptic Transmission in the Hippocampus

Department of Pharmacology and Experimental Therapeutics (M.F.M.B., E.F.R.P., A.M., E.X.A.), University of Maryland School of Medicine, Baltimore, Maryland; and Departamento de Farmacologia Básica e Clínica (E.X.A.), Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

The present study was designed to investigate the effects of Pb²⁺ on modulation of synaptic transmission by nicotinic receptors (nAChRs) in the rat hippocampus. To this end, inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were recorded by means of the whole-cell mode of the patch-clamp technique from rat hippocampal neurons in culture. Acetylcholine (ACh, 1 mM; 1-s pulses) triggered GABA release via activation of 42^* and 7^* nAChRs. It also triggered glutamate release via activation of 7^* nAChRs. Pb²⁺ (0.1 and 1 µM) blocked ACh-triggered transmitter release. Blockade by Pb²⁺ of ACh-triggered IPSCs was partially reversible upon washing of the neurons. In contrast, even after 30- to 60-min washing, there was no reversibility of Pb²⁺-induced blockade of ACh-triggered EPSCs. The effects of Pb²⁺ on GABA release triggered by activation of 7^* and 42^* nACRs were mimicked by the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (1 µM) and blocked by the indolocarbazole Gö 7874 (50 nM) and the bisindolylmaleimide Ro-31-8425 (150 nM), which are selective PKC inhibitors. After washing of fully functional neuronal networks that had been exposed for 5 min to Pb²⁺, the irreversible inhibition by Pb²⁺ of ACh-triggered glutamate release was partially overridden by a disinhibitory mechanism that is likely to involve 42^* nAChR activation in interneurons that synapse onto other interneurons synapsing onto pyramidal neurons. Long-lasting inhibition of 7^* nAChR modulation of synaptic transmission may contribute to the persistent cognitive impairment that results from childhood Pb²⁺ intoxication.

Address correspondence to: Dr. Edson X. Albuquerque, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore St., Baltimore, MD 21201. E-mail: ealbuque{at}umaryland.edu