DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP-4 treatment on amphetamine-induced hyperlocomotion are contradictory. In this study, DSP-4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D2 receptors in the striatum as evidenced by [3H]-raclopride binding. In an open field test, DSP-4 reduced locomotor activity. D-Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP-4-pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP-4-pretreated animals. These data suggest that supersensitivity of D2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP-4-treated rats is masked by neophobia.

DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP-4 treatment on amphetamine-induced hyperlocomotion are contradictory. In this study, DSP-4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D 2 receptors in the striatum as evidenced by [ In an open field test, DSP-4 reduced locomotor activity. D-Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP-4-pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP-4-pretreated animals. These data suggest that supersensitivity of D 2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP-4-treated rats is masked by neophobia.After the first report on N(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (Ross 1976), this neurotoxin has been widely used for selective destruction of the nerve terminals originating from the locus coeruleus (Jonsson et al. 1981;Fritschy & Grzanna 1989). Peripheral administration of DSP-4 depletes noradrenaline (NA) in the brain regions which are innervated by the locus coeruleus and it has no direct effect on serotonin and dopamine (DA) terminals in the rat (Ö gren et al. 1980;Chrobak et al. 1985;Harro et al. 1992;Somboonthum et al. 1997;Al-Zahrani et al. 1998;Hughes & Stanford 1998), even though some investigators have found small but significant reductions in 5-HT levels (Jonsson et al. 1982;Ohno et al. 1996).Previous studies have shown that DSP-4-induced lesions cause no gross changes in spontaneous behaviour (Jonsson et al. 1982), nor does treatment with the drug interfere with simple attentional tasks (Ruotsalainen et al. 1997). However, in more complex learning tasks, the locus coeruleusdenervated rats are less successful and the animals fail to engage in active behaviour necessary to cope with environmental changes (Archer 1983;Archer et al. 1984), possibly due to an increase in neophobia and some reduction in their motivation to explore (Harro et al. 1995).Contradictory data exist about the effect of locus coeruleus denervation by DSP-4 treatment on locomotor activity Author for correspondence: Jaanus Harro, Department of Psychology, University of Tartu, Tiigi 78, EE-50410 Tartu, Estonia (fax π372 7 375900, e-mail jharro/ut.ee).and amphetamine-induced hyperlocomotion. In early studies using 6-hydroxydopamine lesions of the NA-containing pathways, it was found that large NA depletions in several forebrain regions did not modify the locomotor stimulant effect of amphetamine (Hollister et al. 1974;Roberts et al. 1975). However, since the study of Ö gren et al. (1983), it is generally believed that the hyperactivity induced by amphetamine is significantly reduced after selective locus coeruleus denervatio...