Critical role of dopamine D3 receptor in structural plasticity generated by exposure to drugs of addiction in mesencephalic dopaminergic neurons

Dopamine plays a critical role in substance misuse and addiction. Recent view on the factors involved in the maintenance of drug taking indicates in structural plasticity of neuronal network controlling rewards and motivation one of the key cellular mechanisms. Addictive drugs generally increase the release of dopamine and it was suggested that dopamine itself could play a neurotrophic action on certain neurons, resulting in functionally relevant morphologic changes. Using an in vitro model of primary cultures of mesencephalic dopaminergic neurons prepared from the mouse embryo, we recently showed that cocaine, amphetamine, nicotine and ketamine increases dendritic arborisation and soma size, and that this effect depends upon the availability of functional dopamine D3 autoreceptor (D3R) and activation of ERK and Akt intracellular pathways. Interestingly, a strong activation of the mTORC1 pathway was also observed, indicating the engagement of a series of intracellular signalling involved in cell growth and survival. These effects were absent in mice carrying a null mutation for D3R and were pharmacologically blocked by D3R antagonists in a dose-dependent manner. Prenatal exposure to cocaine and nicotine in mice, resulted in increased soma size of dopaminergic neurons in the mesencephalon of the offspring, indicating that the structural changes observed in vitro are reflected in vivo. These data suggest a critical permissive role of D3R in drug-induced structural plasticity of mesencephalic dopaminergic neurons, suggesting that an increased dendritic harborization and capacity to receive synaptic inputs could play the role of common pathogenetic factor in the dysfunctional reward-related behaviour of drug addiction.