Brain Research 947 (2002) 150–156 www.bres-interactive.com Interactive report Iontophoresis of lithium antagonizes noradrenergic action on prefrontal neurons of the rat * ´ ´ ´ ´ Peter Kovacs, Istvan Hernadi ´ ´´ ´ Department of General Zoology and Neurobiology, Faculty of Natural Sciences, University of Pecs,6 Ifjusag Str., H-7624 Pecs, Hungary Accepted 20 June 2002 Abstract 1 Various lithium (Li ) compounds have been proven to be effective in the therapy of bipolar affective disorder, but their mechanism of pharmacological action is not clearly defined. In our present in vivo electrophysiological study we tested the action of microiontophoreti- 1 cally applied Li and NE on the maintained firing activity of prefrontal cortical neurons of the rat. Target cells were located in the prelimbic cortical projection region (PrL) of the ascending norepinephrinergic pathway. Our data, collected from single unit activity of 59 PrL neurons, demonstrate that lithium can (1) suppress maintained discharge activity, or (2) antagonize both the inhibitory and excitatory 1 modulation of firing activity elicited by NE. These effects of Li were not replicable with GABA-initiated inhibition or glutamate 1 analogue-initiated excitation of discharge activity. Our findings suggest that the action of Li mainly targets the NE-coupled receptor mechanisms and, therefore, it may play an important role in stabilizing the modulation of discharge activity in the PFC caused by different extracellular levels of NE.  2002 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Catecholamines Keywords: Lithium; Norepinephrine; Iontophoresis; Prefrontal cortex; Manic psychosis 1. Introduction changes have also been demonstrated in neural elements 1 after the long-term action of Li treatment [26]. Lithium salts are commonly used as the mainstay in the Research carried out by means of microiontophoretical pharmacotherapy of manic-depressive illness [13,14]. techniques has shown that increasing doses of NE can Lithium has also been proven to be highly effective in elicit two distinct profiles of action on the evoked dis- reducing the usual fluctuation of norepinephrine (NE) charge activity of cortical neurons in vitro [6]. It has also 1 levels in specific brain regions, such as the prefrontal been demonstrated that Li can antagonize NE produced cortex (PFC) and the hippocampus. Unbalanced transmit- inhibition of single unit activity of cerebellar Purkinje cells ter levels may act as the most important factor in the [24] and hippocampal neurons in vivo [23]. Other pharma- 1 development of manic psychoses (bipolar disorder) cological observations of short-term Li administration on 1 [20,22]. Much pharmaceutical research has widely demon- NE metabolism suggest that Li has regionally variable strated several positive and negative aspects of the ad- effects on the turnover of NE in the rat brain, exerting its 1 ministration of lithium ion (Li ) in manic psychoses action mainly in limbic forebrain areas rather than the 1 [10,11]. It has been suggested that Li also acts as a hemispheres [3]. 1 neuroprotective agent in cortical slices [4], while structural The action of Li on norepinephrinergic terminals was also demonstrated by pharmacological stimulation of alpha-1 receptors in the PFC of freely moving and *Corresponding author. Present address: Department of Anatomy, behaving rats. High levels of norepinephrinergic receptor University of Cambridge, Downing Street, Cambridge CB2 3DY, UK. activation were shown to impair cognitive function, and Tel.: 144-1223-333-779; fax: 144-1223-333-786. 1 ´ E-mail addresses: hernadi@ttk.pte.hu, ih226@cam.ac.uk (I. Hernadi). impairments were successfully blocked with Li pretreat- 0006-8993 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0006-8993(02)03150-5