Paroxetine combined with a 5-HT1A receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats

Rationale: "Diminished interest or pleasure" in rewarding stimuli is an affective symptom of amphetamine withdrawal and a core symptom of depression. An operational measure of this symptom is elevation of brain stimulation reward thresholds during drug withdrawal. Data indicated that increasing serotonin neuro-transmission by co-administration of the selective serotonin reuptake inhibitor ( SSRI) fluoxetine and the serotonin-1A receptor antagonist p-MPPI reversed reward deficits observed during drug withdrawal (Harrison et al. 2001). Objectives: We tested the hypothesis that increased serotonergic and noradrenergic neurotransmission, using the SSRI paroxetine which also inhibits noradrenaline reuptake, would alleviate affective aspects of amphetamine withdrawal. Methods: A discrete-trial, current threshold, self-stimulation procedure was used to assess brain reward function. The effects of paroxetine and pMPPI alone and in combination were assessed in non-drug-withdrawing animals. We assessed also the effects of paroxetine and p-MPPI alone and in combination on reward deficits associated with amphetamine withdrawal. Results: Paroxetine or p-MPPI alone had no effect on thresholds, while the co-administration of p- MPPI ( 3 mg/ kg) and paroxetine ( 1.25 mg/ kg) elevated thresholds in non-withdrawing rats. Amphetamine withdrawal resulted in threshold elevations. The co- administration of p-MPPI and paroxetine reduced the duration of amphetamine-withdrawal-induced reward deficits. Conclusions: Increased serotonergic and noradrenergic neurotransmission decreased reward function in non-withdrawing rats, while the same treatment reversed reward deficits associated with amphetamine withdrawal. Considering that paroxetine acts on both the serotonin and noradrenaline transporter, these results indicate that the affective symptoms of amphetamine withdrawal, similar to non-drug-induced depressions, may be, in part, mediated through reduced serotonergic and noradrenergic neurotransmission.