Godar 2014

Role of neuroactive androgens in pathological gambling

Sean C. Godar1, Romina Pes1,2, Andrew T. Fox1, Laura J. Mosher1, Francesco Marrosu3, Steven C. Fowler1, Marco Bortolato1

1Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence (KS), USA, 2”Guy Everett” Laboratory, Department of Biomedical Sciences, 3Movement Disorders Center, Institute of Neurology, University of Cagliari, Italy

Pathological gambling (PG) is an impulse control disorder (ICD) characterized by persistent, recurrent and maladaptive gambling behavior. Convergent studies have documented that alterations in the neurotransmitter dopamine is involved in the pathophysiology of PG and other ICDs. In particular, recent reports indicate that the dopamine D2/D3 receptor agonist pramipexole, a therapeutic agent used for the early treatment of Parkinson’s disease (PD), can lead to PG in vulnerable individuals. Dopamine receptor antagonists, however, are not suitable therapeutic options due to their severe motor and cognitive side effects. These premises highlight the urgent need for novel therapeutic targets for the treatment of PG.

PG is more common in males, suggesting that neuroactive androgens (i.e, androgen steroids synthesized in the brain) may play a key role in the pathogenesis of PG. We previously showed that inhibition of 5-alpha reductase (5AR), a key enzyme catalyzing the conversion of testosterone into the more androgenic dihydrotestosterone, possesses anti-dopaminergic properties. These findings have prompted our group to hypothesize that PG may be underpinned by imbalances in the cross-regulation of androgens and dopamine in the brain and that 5AR inhibitors, such as finasteride (FIN) may serve as therapeutic tools for PG. To verify this possibility, we investigated the changes in PG severity following prolonged FIN treatment in three PD patients treated with pramipexole and/or dopamine-replacement therapies. Consistent with our hypothesis, FIN significantly reduced pathological gambling in all patients, without exacerbating motor symptoms. Interestingly, discontinuation of FIN in one patient led to a rapid relapse of PG. In order to study the neurobiological bases of PG, we developed a novel animal model based on the probability discounting task, a paradigm aimed at assessing preference for larger risky rewards over smaller safe rewards. We found that the combination of reserpine, a drug that depletes dopamine levels similar to PD, and pramipexole significantly increased risky choice preference in our model at several different levels of reward probability. Moreover, these effects were countered by treatment with finasteride, supporting the validity of our model. Collectively, our findings provide critical insights into the neurobiological mechanisms that underpin PG.