Heightened reward response is associated with HCN2 overexpression in the ventral tegmental area in morphine-sensitized rats

Morphine sensitization is associated with increased locomotion and stereotypies in rats. This persistent condition has been proposed as a model of manic-like symptoms. Modifications in reward threshold are considered a central feature of mania and have been related to changes in mesocorticolimbic dopaminergic transmission. Thus, to further characterize this model, we investigated reward responses in morphine-sensitized male rats and the mechanisms underlying the behavioral phenotype. In particular, we examined the possible involvement of hyperpolarization-activated cyclic nucleotide-gated channels as they play a critical role in regulating the excitability of dopaminergic neurons. Rats were trained to self-administer sucrose to study whether morphine sensitization affected motivated behavior. Next, the dopaminergic response to sucrose was examined in the nucleus accumbens shell by in vivo microdialysis. To investigate the possible mechanisms underlying the increased dopaminergic transmission in morphine-sensitized rats, HCN2 channel expression levels in mesocorticolimbic regions were analyzed by immunoblotting. Sensitized rats showed an enhanced motivation to work for sucrose that was accompanied by an increased dopaminergic response to sucrose consumption in the nucleus accumbens shell. Moreover, HCN2 expression levels were increased in the ventral tegmental area, suggesting that their increased expression may underpin the enhanced motivation for sucrose reward and nucleus accumbens shell dopaminergic response in sensitized rats. The modified behavioral and dopaminergic reward response observed in sensitized rats supports the suggestion that the condition of morphine sensitization can be regarded as a model of manic symptoms.