Denervation of the locus coeruleus projections by treatment with the selective neurotoxin DSP-4 [N(2-chloroethyl)-N-ethyl-2- bromobenzylamine] reduces dopamine release potential in the nucleus accumbens shell in conscious rats Riina Ha ¨ idkind a , Toomas Kivastik b , Marika Eller a , Ivo Kolts c , Lars Oreland d , Jaanus Harro a, * a Department of Psychology, Centre of Behavioural and Health Sciences, University of Tartu, EE-50410 Tartu, Estonia b Department of Pharmacology, University of Tartu, EE-50410 Tartu, Estonia c Department of Anatomy, University of Tartu, EE-50410 Tartu, Estonia d Department of Neuroscience, Pharmacology, University of Uppsala, Biomedical Centre, Uppsala, Sweden Received 14 June 2002; received in revised form 5 July 2002; accepted 18 July 2002 Abstract Pretreatment with DSP-4, a neurotoxin highly selective for the locus coeruleus (LC) noradrenergic projections, 2 weeks before in vivo microdialysis in conscious rats had no effect on baseline extracellular dopamine (DA) levels in the nucleus accumbens shell, but reduced dose-dependently the dopamine response to depolarisation induced by 50 mM KCl. DA metabolism in the frontal cortex, as measured ex vivo, was increased in animals treated with a low (10 mg/kg) but not with a high dose (50 mg/kg) of DSP-4, possibly indicating an increased sensitivity to stress in these animals and thus suggesting differential regulation of DA in the forebrain by the LC lesions. The reduced DA release potential in the nucleus accumbens after DSP-4 treatment suggests that weakening of the LC input to DA nerve cells contributes to motivational deficits. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Nucleus accumbens; Frontal cortex; Dopamine; DSP-4 [N(2-chloroethyl)-N-ethyl-2-bromobenzylamine]; Locus coeruleus; In vivo microdialysis Dopaminergic (DA-ergic) neurotransmission, particu- larly DA release in the nucleus accumbens, has been impli- cated in the mechanism of action of addictive drugs [1,4], and reduction in DA-ergic neurotransmission in the accum- bens may serve as the basis for anhedonia and loss of energy in depression [6]. It is well established that there is a nora- drenergic (NA-ergic) stimulatory input from the locus coer- uleus (LC) to the mesencephalic DA-ergic cell groups (see ref. [6] for references), which provide DA-ergic innervation to forebrain regions. There is some evidence that lesions of the LC projections can be a reason for a reduced DA release in the accumbens. Thus, in anaesthetised rats, a 28% reduc- tion in basal DA overflow was observed using in vivo microdialysis in the nucleus accumbens after pretreatment with DSP-4, a selective NA-ergic neurotoxin [13]. This study also observed a reduction in extracellular DA in the striatum after DSP-4 treatment. On the other hand, we have previously been unable to see any change in either basal or KCl-induced DA release in the frontal cortex after DSP-4 pretreatment [12]. In a recent study in conscious rats no decrease in the extracellular DA in the nucleus accumbens core was found after DSP-4 treatment [10]. The aim of the present investigation was to study whether partial or nearly complete denervation of the LC by DSP-4 treatment influ- ences DA overflow in the nucleus accumbens shell in conscious animals. Male Wistar rats (300–400 g, Kuopio, Finland) were housed individually under 12 h light/dark cycle (lights on at 07:00 h) with food and water available ad libitum. DSP-4 [N(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (Astra, Sweden) was administered as a single dose of 10 or 50 mg/kg (expressed as for hydrochloride) intraperitoneally (IP) at the start of individual housing. Each dose was weighed separately, dissolved in distilled water and imme- Neuroscience Letters 332 (2002) 79–82 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)00817-0 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 1372-7-375-911; fax: 1372-7-375- 900. E-mail address: jharro@psych.ut.ee (J. Harro).