There are a number of pharmacological hypotheses about the mechanisms responsible for the differences in behavioral effects between standard and atypical DAT inhibitors and drugs considered to be atypical DAT inhibitors. As all drugs have multiple actions, the contribution of activity at off-target sites has to be considered. Other hypotheses that will be considered in more detail below are that kinetic differences between standard and atypical DAT inhibitors contribute to the differences in their effects, and that differences between the actions of standard and atypical DAT inhibitors mediated by the DA transporter contribute to differences in their effects. To further pursue the off-target action hypothesis, several BZT analogs were screened for effects at over 100 mammalian receptor sites (Katz et al., 2004;Li et al., 2011). The initial focus was on sites at which all compounds tested uniformly had activity that was less than 10 M, or within 100-fold of the compounds affinity at the DAT, with the 100-fold parameter chosen based not entirely arbitrarily on a typical displacement curve reaching saturation within a 100-fold range of concentrations. Among the sites identified were D2 dopaminergic receptors. The hypothesis that activity at D2 dopaminergic receptors could contribute to atypical DAT effects of compounds was examined by assessing the antagonism of cocaine-induced locomotor stimulation by JHW 007 in D2 DAR knockout and wild-type mice, rather than with novel compounds. Although the locomotor-stimulant effects of cocaine were diminished in DA D2R knockout mice compared to that in their WT littermate controls, pretreatment with JHW007 blocked the stimulant effects of cocaine equally in both knockout and wild-type mice (Desai et al., 2014). Therefore the data suggest that a D2 dopamine receptor is not necessary for the atypical DAT inhibitor effects of JHW 007. Previous studies suggested that the isoxazol phenyltropane derivative, RTI-371 3β-(4-methylphenyl)-2β-3-(4-chlorophenyl)isoxazol-5-yltropane has effects similar to other atypical DAT-inhibitors. For example, RTI-371 failed to stimulate locomotor activity in mice across a range of behaviorally active doses and did not substitute in rats trained to discriminate cocaine from saline injections (Carroll et al., 2004). Further, a preliminary report indicated that RTI-371 blocked cocaine-induced locomotor stimulation (Navarro et al., 2005). Finally, because both RTI-371 and JHW007 produced positive-allosteric modulation of CB1Rs, and CB1Rs have been implicated in the neurobiology of cocaine addiction (see Tanda, 2007, for review), Navarro et al. (2009) suggested that the atypical effects of both of these compounds were a result of a positive allosteric modulation of CB1Rs, as indicated by the increased the efficacy of the CB1 agonist, CP 55940 in a calcium mobilization assay. From those results Navarro et al. suggested that enhanced endocannabinoid neurotransmission may contribute to the cocaine-antagonist effects observed with these atypical DAT inhibitors. This notion was tested with CB1R wild-type and knockout mice. Cocaine stimulated locomotor activity in both wild type and knockout mice. Additionally, co-injection of JHW007 significantly blunted the locomotor stimulant effects of cocaine in both CB1R wild-type and knockout mice (Hiranita et al., 2014). Thus it appears that positive allosteric modulation of CB1Rs is not necessary for the atypical effects of either of these compounds. A number of previous studies indicated that σ-receptor antagonists can block several of the effects of cocaine, including locomotor stimulation, sensitization, and place conditioning (see reviews by Matsumoto 2009 and Katz et al., 2011), though not its self administration (Martin-Fardon et al., 2007;Hiranita et al., 2011). However, the carbazole derivative, rimcazole which is a sigma receptor antagonist, blocked cocaine self-administration (Hiranita et al., 2011), as did two of its analogs, SH 3-21 and SH 3-28. Rimcazole is unique as σR antagonist as it has affinity for the σR as well as the DAT (Izenwasser et al., 1993;Hanbauer et al. 1993). Therefore, it was noteworthy that BZT analogs also have affinity for σRs (Katz et al., 2004;Li et al., 2011). To assess whether these mechanisms could produce effects similar to those of atypical DAT inhibitors, combinations of several selective σR antagonists and DAT inhibitors were administered to rats trained to self-administer cocaine, and effects like those of rimcazole were obtained (Hiranita et al., 2011). That effects similar to those of rimcazole were obtained with several different combinations of σR antagonists and DAT inhibitors indicates that the decreases in self administration were not isolated idiosyncratic effects. Additionally, the decreases in cocaine self administration were obtained at dose combinations that did not decrease comparable responding maintained by food reinforcement, a selectivity reminiscent of that seen with the atypical DAT inhibitors. Combinations of σR antagonists and DAT inhibitors were also effective against methamphetamine self-administration (Hiranita et al., 2014). Although many of the BZT analogs, as well as the carbazole analogs of rimcazole tested to date, have sigma receptor antagonist effects, the isoxazol phenyltropanes, RTI-336 and RTI-371, had relatively low affinity at sigma receptors (Hiranita et al., 2014). As discussed above, several characterizations of the in vivo effects of RTI-371 have indicated atypical DAT inhibitor effects (e.g. Carroll et al., 2004;Navarro et al., 2005), RTI-336 is a structural isomer of RTI-371 and has been the more fully studied of the two. There are several reports that pretreatment with RTI-336 decreases the self administration of cocaine doses that maintained maximal or near maximal rates of responding (e.g. Haile et al., 2005;Howell et al., 2007). However, there are also reports that RTI-336, in contrast to RTI-371, fully substitutes in rats trained to discriminate cocaine from saline injections (e.g. Carroll et al., 2004), an effect obtained neither with RTI-371 nor most of the BZT analogs (Katz et al., 1999). In self-administration studies with rats (Hiranita et al., 2014), RTI-336 was self-administered at levels greater than vehicle, an effect similar to that obtained with standard DAT inhibitors. As had been reported previously (e.g., Howell et al., 2007), the rates of responding maintained were less than those maintained by cocaine, an effect likely attributable to its long duration of action relative to that of cocaine. In contrast to those effects, its structural isomer, RTI-371, was not self-administered at rates above those obtained with vehicle, an effect similar to that obtained with atypical DAT inhibitors. Most importantly, RTI-336 produced dose-related leftward shifts in the cocaine self administration dose effect curve, whereas RTI-371 produced dose-related decreases in the maximum self-administration of cocaine, and effect reminiscent of that produced by the BZT and rimcazole analogs. Confounding attempts to find a single mechanistic explanation for atypical DAT inhibitor activity, neither isoxazole phenyltropane had appreciable affinity for sigma receptors. Further, despite differences in their behavioral profiles the structural isomers were similar to each other in their high affinities for the DAT and lower affinities for sigma receptors (Hiranita et al., 2014).
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