The dopamine (DA) transporter (DAT) is the main pharmacologic target of modafinil (MOD). Just like cocaine and other abused psychostimulants, MOD reduces synaptic clearance of DA by inhibiting DA 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 potentially related to reinforcing actions. Additionally, subjective effects were studied in mice trained to discriminate 10 mg/kg cocaine (i.p.) from saline. Our results suggest that MOD had a lower potency and efficacy than cocaine in stimulating NAS and NAC DA levels, but, at variance with other abused psychostimulants, those stimulations did not show statistically significant regional differences between NAS and NAC. Additionally, the cocaine-like subjective effects of MOD were obtained at lower doses and earlier onset times than expected based on its DA effects. Taken together those results 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 unique pharmacological profile. We are now investigating the potential of GAP-junctions to facilitate the effects of MOD on cocaines reinforcing actions. Clinical trials on modafinil (MOD) as a treatment for psychostimulant use disorder have shown the most favorable outcomes in selected subpopulations of patients (e.g. heavy crack-cocaine users, or cocaine addicts who did not show comorbidity with abuse of alcohol). Thus, even if MOD might prove useful as a treatment for specific addicted populations, broader effective medications for psychostimulant use disorders are still an unmet medical need. To this end, newly synthesized analogs of Modafinil (MOD) have been tested in our preclinical models of drug abuse and addiction. In rats, R-MOD alone dose-dependently increased locomotor activity and electrical brain-stimulation reward. At variance, the MOD analog JJC8-016 did not produce these effects, did not modify extracellular DA in the NAS, did not maintain self-administration behavior and failed to induce reinstatement of cocaine-seeking behavior. Moreover, 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 highest dose tested. These findings suggest that JJC8-016 has no cocaine-like abuse potential, and that as a pretreatment it inhibits cocaine reinforced behaviors, 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. Additional MOD analogs have also been tested as potential medications for methamphetamine (METH) use disorder. We tested the effects of systemic injections of R-MOD and four novel, chemically unique MOD analogs, JJC8-016, JJC8-088, JJC8-089 and JJC8-091, on intravenous (i.v.) METH self-administration in rats allowed short access (1 h; ShA) or long access (6 h; LgA) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA rats. JJC8-016, JJC8-089 and JJC8-091 decreased METH self-administration in both LgA and ShA rats. JJC8-088 did not have an effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorder. Among new targets that have been suggested as potential medications to treat substance use disorders, recent reports have shown that the (+)-enantiomers of naloxone and naltrexone, identified as TLR4 antagonists, may attenuate preclinical indicators of both opioid and stimulant abuse and dependence. To further examine the potential of these compounds as drug-abuse treatments we extended the previously reported assessments to include a wider range of doses and procedures. We have tested the effects of administration of (+)-naloxone and (+)-naltrexone on the acute DAergic 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 DA 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 DAergic 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 DA 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 use disorders.
