Aripiprazole relieves motivational anhedonia in rats

Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms

“…The present results show that repeated lamotrigine treatment was able to reinstate the PKA-dopamine D 1 receptor-DARPP-32 signaling response elicited by a natural reinforcer in the NAcS of non-food-deprived rats. Confirming our working hypothesis, the effect on dopaminergic transmission was accompanied by the reinstated behavioral response to a positive stimulus, in agreement with our previous studies [ 35 , 37 , 38 , 39 ]. The role of the dopamine D 1 receptor pathway in the NAc in hedonic/anhedonic behaviors has also been demonstrated in a rat model of bipolar disorder [48] .…”

“…In our experimental conditions, lamotrigine effects differ from those observed after administration of aripiprazole, a second generation antipsychotic also used as add-on therapy in the treatment of bipolar disorder and treatment-resistant depression. Aripiprazole differently modulates the responses to aversive and rewarding stimuli, since it restores the motivation to operate for, and the dopaminergic response to, positive stimuli (sucrose), without affecting stress-induced decreased reactivity to aversive stimuli, confirming that motivations to operate for a reward or to avoid negative stimuli could be dissociated [39] . Thus, experimental models of depressive symptoms suggest that different drugs used for the treatment of mood disorders preferentially affect some of these domains and show that the pro-motivational effects of lithium and lamotrigine develop faster than those of classical antidepressants [ 35 , 37 , 39 ].…”

“…In the model used, the escape deficit is completely reverted by a long-term treatment (∼3 weeks) with antidepressant drugs, such as imipramine, fluoxetine, reboxetine, mirtazapine [ 34 , 37 , 52 , 53 ], while motivational anhedonia is only partially reverted by imipramine and unaffected by fluoxetine treatment [37] . On the other hand, the deficit in appetitive motivation is completely counteracted by lithium, clozapine, aripiprazole, and fenofibrate long-term administration [ 35 , 37 , 38 , 39 ]. It is interesting to note that lamotrigine, lithium, and aripiprazole that in our experimental model restored the responses to a natural reward are among the drugs that have been approved by FDA for maintenance treatment of bipolar disorder.…”

“…The dopaminergic responses are assessed by analyzing the levels of extraneuronal dopamine and measuring the dopamine D 1 receptor-dependent signaling, in terms of cAMP-dependent protein kinase (PKA)-dependent phosphorylation of the threonine (Thr)34 residue of dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) [36] . Pharmacological treatments that reinstate motivation to operate for a natural reinforcer in self-administration protocols (lithium, imipramine, clozapine, aripiprazole, and fenofibrate), also restore the dopaminergic response to sucrose consumption in the NAcS of stress-exposed rats, regardless of the acute molecular mechanism [ 35 , 37 , 38 , 39 ]. Thus, considering the reported effects of lamotrigine on the VTA dopaminergic neurons projecting to the NAc [27] , we investigated whether repeated lamotrigine treatment could reverse the stress-induced disruption of the dopaminergic transmission in response to sucrose consumption, evaluated in terms of Thr34 DARPP-32 phosphorylation levels in the NAcS.…”

“…Thus, considering the reported effects of lamotrigine on the VTA dopaminergic neurons projecting to the NAc [27] , we investigated whether repeated lamotrigine treatment could reverse the stress-induced disruption of the dopaminergic transmission in response to sucrose consumption, evaluated in terms of Thr34 DARPP-32 phosphorylation levels in the NAcS. Moreover, the study aimed to further validate the hypothesis that the re-established dopaminergic response to sucrose is accompanied by a restored motivation to operate for the reward disrupted by stress exposure, using a sucrose self administration protocol [ 35 , 37 , 38 , 39 ]. The results of this study may have a translational value as they could suggest possible clinical uses of lamotrigine to address specific symptoms in unipolar or bipolar depression, in particular the symptom domain of motivational anhedonia.…”