Clinical studies suggest that the most favorable outcomes from clinical trials with MOD administered as a psychostimulant use disorder treatment were seen in selected subpopulations of patients (e.g. cocaine addicts who did not show comorbidity with abuse of alcohol). We have provided recent evidence that the DAT is MODs main pharmacologic target. Thus, like cocaine and other abused psychostimulants, MOD reduces synaptic clearance of DA by inhibiting dopamine reuptake. However, the resulting stimulation of DA levels and the efficacy of MOD as a behavioral reinforcer are among the lowest in its class. Moreover, our results confirm that MOD does not work as a behavioral reinforcer in rats under different schedules of self-administration behavior in which abused psychostimulants demonstrate high levels of reinforcing efficacy. Recently, we have further explored the neurochemical and behavioral actions of MOD to better characterize its psychostimulant profile. Swiss-Webster mice were implanted with microdialysis probes in the NAS or NAC to evaluate changes in DA levels related to acute reinforcing actions of drugs of abuse. Additionally, subjective effects were studied in mice trained to discriminate 10 mg/kg cocaine (i.p.) from saline. MOD (17-300 mg/kg, i.p.) significantly increased NAS and NAC DA levels that at the highest doses reached 300% at 1 hour, and lasted >6 hours in duration. These elevated DA levels did not show statistically significant regional differences between the NAS and NAC. MOD produced cocaine-like subjective effects at 56-100 mg/kg when administered at 5 and 60 minutes before the start of the session, and enhanced cocaine effects when the two were administered in combination. Despite sharing subjective effects with cocaine, MODs psychostimulant profile was unique compared to that of cocaine. MOD had a lower potency and efficacy than cocaine in stimulating NAS DA. Additionally, the cocaine-like subjective effects of MOD were obtained at lower doses and earlier onset times than expected based on its dopaminergic effects. Our tests with MOD suggest that although inhibition of DA reuptake may be a primary mechanism underlying MODs therapeutic actions, non DA-dependent actions may be playing a role in its pharmacological profile. We are now investigating the potential of GAP-junctions to facilitate the effects of MOD on cocaines reinforcing actions. Thus even if MOD might provide useful as a treatment for specific addicted populations, effective medications for psychostimulant use disorders are still an unmet medical need. Recently, the (+)-enantiomers of naloxone and naltrexone, identified as TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments we extended the previous assessments to include a wider range of doses and procedures. We have tested the effects of administration of (+)-naloxone and (+)-naltrexone on the acute dopaminergic actions of cocaine and heroin determined by in vivo microdialysis; we have also tested these drugs on the reinforcing effects of cocaine and the opioid agonist, remifentanil, under intra-venous self-administration procedures, as well as on the subjective effects of cocaine determined by discriminative-stimulus effects in rats. We found that pretreatment with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the NAS. Further, while an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone or (+)-naltrexone with the subjective effects of cocaine. Thus our studies do not confirm the suggested involvement of TLR4 antagonists as potential medications for cocaine or opioid use disorders. In particular, under a wide range of doses and experimental conditions, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists. Another topic of interest has been suggested by reports that the neuropeptide oxytocin, which plays a role in reward, stress, social affiliation, learning, and memory processes, might also be a potential treatment for substance use disorders. The endogenous brain oxytocin system is altered after exposure to drugs of abuse. Preclinical studies have investigated whether oxytocin can reverse the neuroadaptations occurring with repeated drug and alcohol use. In addition, a few small clinical studies have been conducted in cocaine, cannabis, and alcohol dependent subjects. In our preclinical laboratories the dopaminergic effects of oxytocin pretreatments, given intranasal or intraperitoneal to rats, have been tested after intravenous injection with increasing doses of methylphenidate. While oxytocin given alone does not produce any significant change to DA levels in the NAS, it can elicit a greater methylphenidate-induced stimulation of dopamine as compared to methylphenidate alone. This effect might indicate a potentiation of methylphenidate effects. However, preliminary behavioral data show that oxytocin blunts the reinforcing effects of methylphenidate, a dose-dependent effect that shifts the entire dose response downward in self-administration procedures. These results suggest that oxytocin might be tested in humans as a potential pharmacologic treatment for psychostimulant dependence. In a recent publication about preclinical tests with newly synthesized analogs of R-Modafinil, we found that in rats, systemic administration of R-MOD alone (10-30mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016 (10-30mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.
