Cerebrospinal fluid kynurenic acid and depressive symptoms in HIV-infected individuals

Aims: While the mechanisms underlying the therapeutic efficacy of (±)-Modafinil (MOD) are not fully understood, actions at the dopamine (DA) transporter (DAT) appear to be involved.With some exceptions, DAT blockers administered in combination potentiate the behavioral and reinforcing effects of psychostimulants (PSY) like cocaine (COC). That potentiation is related to increased accumbens (ACC) DA levels. However, recent clinical studies suggested efficacy ofMOD in treating PSY abuse, suggesting a potential reduction of COC use in PSY abusers rather than a potentiation. Methods: Effects of MOD and COC, were tested alone and in combination, on microdialysate ACC DA levels in rats (n=48), and mice (n=60), self-administration (SA) (n=12) in rats, and subjective effects (n=12) in mice trained to discriminate COC. Results: MOD alone (0.03–10mg/kg i.v.) did not maintain SA above vehicle levels when substituted for COC, but at those doses increased DA levels dose-dependently. MOD pretreatments (10–32mg/kg i.p., 5min prior) also dose-dependently (pu003c0.05) potentiated COC SA, but microdialysis studies showed no significant enhancement of the effects of COC (0.03–3.0mg/kg i.v.) on stimulation of DA levels in ACC in excess of those produced by COC alone. In mice, MOD alone (10–100mg/kg) produced COClike subjective effects and potentiated the subjective effects of low COC doses (pu003c0.05). In mice, MOD elicited significant (pu003c0.05) increases in DA levels without significant differences between ACC shell and core, distinguishing MOD from PSYs abused by humans. Conclusions: MOD alone has a reduced PSY profile compared to COC. Our preclinical results suggest it might enhance reinforcing effects when taken in combination with sub-threshold doses of COC, independently from stimulation of DA levels. Based on clinical reports, these effects suggest a basis for use of MOD as a substitution agonist therapy for PSY abuse. Studies are in progress to better address the mechanisms underlying these effects. Financial support: NIDA/IRP.