Difficulty suppressing or inhibiting pre-potent behaviors (one dimension of 'impulsivity'or impulsive behaviors) has been associated with elevated risk for drug and alcohol use disorders in humans and with heightened drug self-administration phenotypes in animal models. Recent work indicates that impulsive behaviors are linked to changes in dopamine D2 receptor- sensitive corticostriatal networks and that both are under the influence of as-of-yet unknown genetic mechanisms. We have used a genome-wide linkage approach in inbred mice to identify novel gene modulators of impulsivity, and we identified syn3, which encodes synapsin III, as a very high priority candidate gene. Subsequent to our published study, it was shown that syn3 controls the amplitude of dopamine release events, presumably through its localization and functions in dopaminergic nerve terminals. Based upon all this information, we now test the novel and high-risk hypothesis that syn3 expression within dopaminergic neurons influences: 1) dopamine release, 2) expression of post-synaptic D2-like receptors, 3) inhibitory control and 4) drug self-administration. Using a newly available conditional model that allows for brain-wide or dopamine neuron-specific deletion of syn3, we seek to experimentally test the role for this gene in these varied phenotypes, in turn establishing its key role in regulating a series of biological and behavioral endophenotypes for addiction. These high-risk studies offer an opportunity to establish the significance of a novel candidate risk gene for addictions, supporting more systematic multi-level studies in humans and animal models regarding synapsin III and its link to drug abuse susceptibility. These studies will also set the stage for in depth, mechanistic studies aimed at understanding how altered dopaminergic transmission causally influences impulse control and drug self-administration.
Behavior addictions, including the abuse of or dependence on drugs of abuse, cause substantial personal and social costs, but prevention and cessation treatments are few and of limited efficacy. With that in mind, understanding the genetic architecture of risk for addictions raises new avenues, not just for quantifying liability, but for developing biomarkers that can be the target of prevention trials. Moreover, identification of the molecular genetic meditators of addictions raises new potential treatment targets.
|Linden, Jérôme; James, Alexander S; McDaniel, Colin et al. (2018) Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice. eNeuro 5:|
|Jentsch, J David; Ashenhurst, James R; Cervantes, M Catalina et al. (2014) Dissecting impulsivity and its relationships to drug addictions. Ann N Y Acad Sci 1327:1-26|