The triple reuptake inhibitor DOV 216,303 induces long-lasting enhancement of brain reward activity as measured by intracranial self-stimulation in rats

Abstract

Triple reuptake inhibitors (TRIs) are potential new antidepressants, which not only enhance brain serotonin and norepinephrine concentrations but also increase dopamine levels. Therefore TRIs are believed to have faster therapeutic onset than SSRIs, and may be particularly useful for the treatment of anhedonia (i.e. inability to experience pleasure), one of the core symptoms of major depression. The current study aimed at getting better insight into the rewarding properties of DOV 216,303, which is a TRI, regarding its possible use to treat anhedonia. It is known that psychostimulant drugs lower intracranial self-stimulation (ICSS) reward thresholds, reflecting enhanced brain reward activity, whereas withdrawal from those compounds mostly results in increased ICSS thresholds. Therefore we assessed the effects of DOV 216,303 on ICSS thresholds in rats. Animals were trained in the discrete-trial current-threshold procedure and after stable ICSS reward thresholds were established, animals received one injection per day of DOV 216,303 (20mg/kg) or amphetamine (5mg/kg) for four consecutive days. ICSS thresholds were assessed 3, 6, and 23h after each injection. DOV 216,303 decreased ICSS thresholds up to 6h after drug treatment. To our knowledge this is the first time that a triple reuptake inhibitor, DOV 216,303, induces relatively long-lasting enhancement of brain reward activity. Elevated ICSS thresholds were found after amphetamine administration, which is consistent with previously reported reward deficits induced after amphetamine-withdrawal.