Low cocaine responding rats have a greater basal number of hippocampal norepinephrine transporters than high cocaine responding rats

Abstract

Cocaine inhibits dopamine (DA) and norepinephrine (NE) uptake by blocking DA and NE transporters (DATs and NETs, respectively). We have classified outbred male Sprague‐Dawley rats given an acute low dose of cocaine (10 mg/kg, i.p.) as either low or high cocaine responders (LCRs or HCRs, respectively) based on the median split of the first 30 min of cocaine‐induced locomotor activity. This model of differential individual responsiveness to cocaine has revealed that LCRs, which exhibit greater cocaine‐induced locomotor sensitization, reward and reinforcement, have more striatal DATs at baseline than HCRs. To examine if basal NET numbers also differ, here we quantitated indirect saturation binding with a NET inhibitor ([3H]nisoxetine, 4 nM) in hippocampal membranes 35 min after acute cocaine. As expected, HCRs (n = 9) exhibited ~4 fold greater cocaine‐induced locomotor activity than LCRs (n = 7). Affinities of hippocampal NETs (Kd = 5 nM) did not differ significantly between LCRs and HCRs. In contrast, LCRs had 41% more hippocampal NET binding sites than HCRs (Bmax = 137 vs. 97 fmol/mg protein, respectively; p < 0.05, t‐test). Whether these differences in NET number result in corresponding functional differences still must be determined. Nonetheless, the greater basal number of NETs in LCRs is consistent with LCRs being less sensitive to the initial effects of low dose cocaine than HCRs. Supported by DA004216 & DA015050.