Lesioning of Locus coeruleus Projections by DSP‐4 Neurotoxin Treatment: Effect on Amphetamine‐Induced Hyperlocomotion and Dopamine D₂ Receptor Binding in Rats

Abstract

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...

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

“…However, using homogenate of rat striatum, we could only detect the effect of D 1 receptors on AC activity. All the agonists of D 1 receptors tested resulted in a concentration-dependent activation of cAMP accumulation with EC 50 values being in agreement with the potencies reported earlier for striatal membranes (23,24 (7) has been used to observe changes in signal transduction of D 2 receptors caused by dopaminergic denervation with 6-OHDA (25) or partial noradrenergic denervation with DSP-4 (26,27), as well as by manipulation of animals (12).…”

The locus coeruleus directs sensory-motor reflex amplitude across environmental contexts

“…Disruption of noradrenergic signalling had minor effects on locomotor activity. In agreement with previous studies we observed a reduced open field path length after injection of DSP-4 (Harro et al 2000). Additionally, in a task that required increased locomotor effort we did observe that mice with disrupted noradrenergic signalling had altered stepping (shorter and faster steps) when compared to control animals.…”

The Effects of Amphetamine and Methamphetamine on the Release of Norepinephrine, Dopamine and Acetylcholine From the Brainstem Reticular Formation

“…In addition, a reduction of TH within LC neurons ( via RNA interference) potentiates D1 receptor-dependent AMPHs-induced sensitization in the ventral striatum, to an extent, which is not replicated by DAT inhibition (Smith and Greene, 2012). In line with this, Harro et al (2000) found that a loss of NE axons increases AMPHs-induced locomotor activity while up-regulating striatal D2 receptors. Again, a damage to LC neurons enhances nigrostriatal METH toxicity in both mice and rats (Fornai et al, 1995, 1996a,b), an effect, which is related to increased DA sensitivity to METH rather than to METH pharmacokinetics (Fornai et al, 1997, 1998, 1999).…”