Inbred Lewis and Fischer 344 rat strains differ not only in novelty- and amphetamine-induced behaviors, but also in dopamine transporter activity in vivo.

Inbred Lewis (LEW) and Fischer 344 (F344) rats are differentially sensitive to drugs of abuse, making them useful for studying addiction-related neural mechanisms. Here, we investigated whether strain differences in dopamine transporters (DATs) in dorsal striatum (dSTR) and/or nucleus accumbens (NAc) may help to explain their behavioral differences. The behavior of male LEW and F344 rats was assessed in an open-field arena during habituation to novelty and after an i.v. infusion of saline and/or 0.5 mg/kg d-amphetamine (AMPH). In vitro measures of DAT binding, protein and cell-surface expression, as well as in vitro and in vivo measures of function, were used to compare DATs in dSTR and NAc of these two strains. We found that LEW rats exhibited higher novelty- and AMPH-induced locomotion, but F344 rats exhibited greater AMPH-induced rearing and stereotypy. An initial habituation session with i.v. saline minimized the strain differences in AMPH-induced behaviors except that the more frequent AMPH-induced rearing in F344 rats persisted. Strain differences in DAT total protein and basal activity were also observed, with LEW rats having less protein and slower in vivo clearance of locally applied DA in dSTR and NAc. AMPH inhibited in vivo DA clearance in dSTR and NAc of both strains, but to a greater extent in F344 rats. Taken together, the lower basal DAT function in LEW rats is consistent with their greater novelty-induced locomotor activation, whereas the greater inhibition of DA clearance by AMPH in F344 rats is consistent with their marked AMPH-induced rearing behavior.

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague-Dawley rats.

Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.

Effects of the competitive N-methyl-D-aspartate receptor antagonist, LY235959 [(-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], on responding for cocaine under both fixed and progressive ratio schedules of reinforcement.

It is difficult to determine the precise role of the N-methyl-D-aspartate (NMDA) receptor system in the reinforcing effects of cocaine since uncompetitive NMDA receptor antagonists alter cocaine self-administration in different ways, depending on the antagonist examined and the behavior being measured. To increase understanding of the role of the NMDA system in cocaine's reinforcing effects, this study measured the effects of the competitive NMDA receptor antagonist, LY235959 [(-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], in rats that self-administered cocaine under both fixed ratio (FR) 1 and progressive ratio (PR) schedules of reinforcement. Rats were trained to self-administer cocaine (0.33 mg/infusion) under an FR1 schedule of reinforcement. Thereafter, the effects of pretreatment with LY235959, or the uncompetitive antagonists dextromethorphan and dizocilpine, were examined. The number of infusions earned during the first 10 min of responding under the FR1 schedule was analyzed separately. When rats responded for 0.33 mg/infusion cocaine under an FR1 schedule of reinforcement, 3 mg/kg LY235959 decreased cocaine self-administration only during the first 10 min of the responding. This effect was dose and time dependent and blocked by the competitive NMDA receptor agonist, NMDA. LY235959 (3 mg/kg) decreased total responding for cocaine only when the self-administered dose of cocaine was small (0.02-0.04 mg/infusion) or when responding was reinforced under the PR schedule. In contrast, dizocilpine decreased responding under the FR1 schedule but increased responding under the PR schedule. These data suggest that LY235959 decreased the reinforcing effectiveness of cocaine, a finding reported with systemically administered NMDA receptor antagonists other than dizocilpine.