Co-administration of modafinil, atomoxetine, and citalopram increases exploratory behavior, produces withdrawal signs, and enhances self-administration of this drug mixture

The monoaminergic systems are necessary for the motor and reinforcing effects of addictive psychostimulants such as cocaine and amphetamines. The participation of the dopaminergic system (DA) in relation to these properties has been studied extensively, but the role of the noradrenergic (NA) and serotoninergic (5-HT) systems has not been clarified. Clinical psychostimulants like modafinil have not shown clear evidence of addictive effects, perhaps due to differential activity in the latter two systems. The aim of this study was to determine the effect of monotherapies with modafinil (MOD, a drug with main activity in the inhibition of dopamine reuptake), atomoxetine (ATX, a selective norepinephrine reuptake inhibitor), and citalopram (CIT, a selective serotonin reuptake inhibitor), and coadministration (MOD+ATX+CIT), on locomotor activity, signs of anhedonia after drug withdrawal and self-administration of MOD and the mixture of these substances. Male Wistar rats were treated chronically (16 days) via the endogastric route with ATX at 2 mg/kg, CIT at 3 mg/kg, MOD at 60 mg/kg, or a combination (2ATX+3CIT+60MOD). The co-administered rats (COAD) increased exploratory behavior and showed signs of anhedonia post-withdrawal. The MOD and COAD groups showed higher MOD intake after being water-deprived for 12 h, while a sensitization of exploratory behavior was observed in the COAD group after consuming the ATX+CIT+MOD mixture. Higher seeking self-administration of the mixture was noted only in the COAD group. Results suggest that early simultaneous activation of the DA, NA, and 5-HT systems produces plastic changes that favor the posterior self-administration and rewarding effects of drugs that activate these three neurotransmission systems.