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.

Research highlights▶ Locus coeruleus (LC) denervation attenuates cocaine-induced locomotion. ▶ LC denervation abolished cocaine conditioned place preference. ▶ Both unconditioned and conditioned effects of cocaine are partly dependent on intact LC system.