Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

Abstract

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D1 and D2 receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.

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

“…Thus, one explanation for the reduced DA clearance that we observed in LEW rats is that, relative to F344 rats, LEW rats have fewer functional DATs in dSTR and/or NAc. The literature is equivocal on this issue, however, with one study indicating LEW rats have less DAT binding (Flores et al 1998), but another reporting no strain difference (George et al 1991). Here, using western-blot analysis of DAT immunoreactivity, we found statistically less (∼20%) DAT protein in both dSTR and NAc of LEW, as compared to F344, rats.…”

“…The influence of environmental novelty on strain differences in several of the AMPH responses is not surprising given results from outbred rat strains suggesting that familiarity with the open-field environment significantly influences cocaineinduced behavior (Kiyatikin 1992;Carey et al, 2005). The lack of consistency among previous studies reporting differential locomotor effects of acute psychostimulants in LEW and F344 rats (George et al 1991;Camp et al 1994;Kosten et al 1994;Brodkin et al 1998;Stöhr et al 1998;Haile et al 2001;Fernandez et al 2003;Miserendino et al 2003) may be attributable, at least in part, to this procedural factor. However, in at least one study, differences in AMPHinduced locomotion between LEW and F344 rats were not associated with differences in corticosterone levels or fecal boli responses (Miserendino et al 2003).…”

“…For example, compared to LEW rats, F344 rats are reported to have greater AMPH-induced locomotion at doses between 1 and 2 mg/kg (George et al, 1991;Miserendino et al, 2003; but see Camp et al, 1994, for methamphetamine). LEW rats, in contrast, tend to exhibit greater behavioral sensitization after repeated cocaine or methamphetamine treatment (Camp et al 1994;Kosten et al 1994;Haile et al 2001) and enhanced conditioned place preference for cocaine, nicotine and morphine (Guitart et al 1992;Kosten et al 1994;Horan et al 1997).…”

“…Differences in a wide variety of neurochemical systems have been suggested to be important for divergent behaviors in LEW and F344 rats (see Kosten and Ambrosio 2002 for review), but relatively little attention has been given to the role of strain differences in DATs. Indeed, the existing literature is somewhat inconsistent, with one report showing lower DAT binding in dSTR and NAc of LEW rats, compared to F344 rats (Flores et al 1998) and another finding no strain differences (George et al 1991). Recently, however, Haile and colleagues (2005) showed that the selective DAT inhibitor RTI336 alters cocaine-induced behaviors in a strain-dependent manner and suggested that these behavioral effects might reflect differences in NAc DAT levels (Haile et al 2005).…”

C57BL/6J mice show greater amphetamine-induced locomotor activation and dopamine efflux in the striatum than 129S2/SvHsd mice

“…Although there are strong similarities between cocaine-and AMPH-mediated behaviors, the stimulated behavioral patterns (e.g., Antoniou et al, 1998) and molecular components (Briegleb et al, 2004;George et al, 1991;He and Shippenberg, 2003) involved in behavioral stimulation are not exactly the same. Furthermore, dopamine efflux induced by psychostimulants has not been extensively examined in different strains of mice.…”