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.

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.

The effect of denervation of the locus coeruleus projections with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on cocaine-induced locomotion and place preference in rats.

The potential contribution of locus coeruleus (LC)-derived noradrenaline (NA) in the motor activating and rewarding effects of cocaine (15 mg/kg) were assessed following administration of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). In Experiment 1, administration of 10 mg/kg of DSP-4 similarly to substantial denervation with 50 mg/kg of DSP-4 significantly attenuated the activating effects of cocaine during the first cocaine-paired training session (30 min) in the conditioned place preference (CPP) apparatus. Only administration of the higher dose (50 mg/kg) of DSP-4 attenuated line crossings during the last training, while both doses reduced rearings. Thus, both minor and substantial denervation of LC reduced but did not abolish locomotion activating effect of cocaine. Cocaine CPP as measured by increment of time spent in the previously cocaine-paired chamber during drug-free conditions before and after cocaine-paired trainings was clearly revealed only in animals with intact projections from the LC, and was entirely absent after a large lesion of LC projections by DSP-4 (50 mg/kg). Because recovery of noradrenaline levels by the end of experiment did not allow assessment of the efficacy of the neurotoxin, the effect of DSP-4 pre-treatment on the acute psychomotor effect of cocaine was re-examined in an independent experiment (Experiment 2). Near complete denervation of the LC projections again reduced the effect of cocaine, but the lower dose of DSP-4 had no effect, suggesting that small lesions of the LC do not have a robust impact. Overall, this study demonstrates that both unconditioned and conditioned effects of cocaine depend upon the integrity of LC projections.