Behavioural Brain Research 118 (2001) 195 – 200 Research report Nitric oxide modulates lithium-induced conditioned taste aversion Gregers Wegener a,b, *, Vallo Volke c , Zhale Bandpey a , Raben Rosenberg a a Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Skoagerej 2, DK-8240, Rissko, Denmark b Centre for Clinical Pharmacology, Uniersity of Aarhus, Aarhus, Denmark c Department of Physiology, Uniersity of Tartu, 19 Raila Street, 50411, Tartu, Estonia Received 21 March 2000; received in revised form 7 September 2000; accepted 7 September 2000 Abstract Nitric oxide (NO) has been shown to affect the behaviour in animal models of depression, anxiety and avoidance learning. Lithium has marked effect in avoidance learning, an effect that can be modulated via the 5-HT system. Experiments were carried out using the conditioned taste aversion (CTA) paradigm to investigate whether administration of NO-modifying drugs, serotonergic drugs and lithium, alone or in combination, induced or affected a CTA. The NO-precursor L-arginine (L-Arg), the non-specific inhibitor of NOS and guanylate cyclase, methylene blue (MB) and the specific NOS inhibitor 7-Nitroindazole (7-NI) all produced CTAs in a dose-dependent fashion. Furthermore, we found that L-Arg counteracted the CTAs induced by LiCl or MB but failed to modulate the CTA produced by 7-NI. The administration of the selective 5-HT 1A agonist, 8-OH-DPAT, counteracted the CTAs produced by MB and 7-NI. In contrast, depletion of 5-HT by p -Chlorophenylalanine did not affect the aversions produced by MB and 7-NI, but counteracted the CTA produced by L-Arg. Our results suggest that NO plays a role in the acquisition of the CTA induced by LiCl. Furthermore, the results suggest that the 5-HT 1A receptor plays an important role in the CTA induced by MB and 7-NI, thus indicating a possible interaction between the 5-HT and NO systems. © 2001 Elsevier Science B.V. All rights reserved. Keywords: L-Arginine, Conditioned taste aversion; Lithium; Methylene blue; Nitric oxide; Nitric oxide synthase; 7-Nitroindazole; 8-OH-DPAT www.elsevier.com/locate/bbr 1. Introduction Nitric Oxide (NO) modulating agents have over the last few years been the focus of an increasing number of studies. NO is thought to be an intracellular messenger or neurotransmitter in the central nervous system (CNS) [10]. It has also been proposed that NO, due to its free diffusibility, acts as a retrograde transmitter in the CNS, mediating long term potentiation [5,12,26,33]. In addition, inhibitors of Nitric oxide synthase (NOS) possess anti-depressant and anxiolytic properties [6,7,13,37] and have been shown to influence serotonin (5-HT) and dopamine (DA) in various areas of the brain [17,21,35,43]. The current study used the development of condi- tioned taste aversion (CTA) as an indicator of drug effect. A CTA can be produced following exposure to a variety of stimuli paired with a novel food item [9]. It has earlier been reported that a NO-donor was able to produce a CTA, which could be prevented by pre-treat- ment with a NOS inhibitor [30]. Additionally, hippocampal NO has been shown to play an important role at the time of training in avoidance learning [4]. It has been speculated that NO and other free radicals function as neurotoxins in mediating the neurodegener- ative changes associated with exposure to toxic treat- ments or aging processes [8,16,18]. Interestingly, one of the classic agents used in pro- ducing CTA — lithium chloride [24], has been pro- posed to increase the NOS activity in rat hippocampus [3]. Moreover, several studies indicate that lithium con- tributes to a net elevation of 5-HT neurotransmission [29,40]. * Corresponding author. Tel.: +45-7789-3524; fax: +45-7789- 3549. E-mail address: wegener@dadlnet.dk (G. Wegener). 0166-4328/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII:S0166-4328(00)00329-6