Background (±)-Modafinil has piqued interest as a treatment for ADHD and stimulant dependence. The R-enantiomer of modafinil may have unique pharmacological properties that should be further investigated. Methods (±)-Modafinil and its R-(−)- and S-(+)-enantiomers were synthesized and tested for inhibition of [3H]DA uptake and [3H]WIN 35,428 binding in hDAT WT and mutants with altered conformational equilibria. Data were compared to cocaine and the atypical dopamine uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse NAc shell and in a cocaine discrimination procedure. Results (±)-, R- and S-Modafinil bind to the DAT and inhibit dopamine uptake less potently than cocaine, with R-modafinil having ~3-fold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared to wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward facing conformation better than cocaine, which was further supported by MTSET reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the NAc shell less efficaciously than cocaine, and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. Conclusions R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.

Summary Human genetic studies have recently suggested that the postsynaptic Activity-regulated cytoskeleton-associated protein (Arc) complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescue Arc-dependent cognitive and psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia.

Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.

Background Two subtypes of sigma (σ) receptors, σ1 and σ2, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. σ-receptor antagonists block cocaine place conditioning and σ-receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration has been related to increased dopamine (DA) neurotransmission for different drug classes. Actions of σ-receptor agonists on mesolimbic DA have not been fully characterized. Methods Receptor-binding studies assessed affinities of different σ-receptor ligands for σ-receptor subtypes, and for the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in-vivo microdialysis. Results Cocaine (0.1–1.0 mg/kg i.v.), the non-selective σ1/2-receptor agonist DTG (1.0–5.6 mg/kg i.v.), and the selective σ1-receptor agonist PRE-084 (0.32–10 mg/kg i.v.) dose-dependently increased DA, with maxima of about 275, 150, and 160%, respectively. DTG-induced stimulation of DA was antagonized by the nonselective σ1/2-receptor antagonist, BD 1008 (10 mg/kg i.p.), and by the preferential σ2-receptor antagonist SN79 (1–3 mg/kg i.p.), but not by the preferential σ1-receptor antagonist, BD 1063 (10–30 mg/kg i.p.). Neither PRE-084 nor cocaine was antagonized by either BD1063 or BD1008. Conclusions Stimulation of DA by σ-receptor agonists in a brain area involved in the reinforcing effects of cocaine was demonstrated. The effects appear to be mediated by σ2-receptors rather than σ1-receptors. However σ-receptors are not likely involved in mediating the acute cocaine- and PRE-084-induced stimulation of DA transmission. Different mechanisms might underlie the dopaminergic and reinforcing effects of σ-receptor agonists suggesting a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders.

Rationale and Objectives Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated non-medical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population. Results and Conclusions MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for treatment of substance use disorders in certain patient populations.

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.

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The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia.