Autism is a disorder that is particularly debilitating because it affects what is most important to people, social behavior. Sociability deficits, such as social anxiety and withdrawal, lack of social motivation, inattentiveness, and an inability to maintain close relationships are characteristic of autism spectrum disorders (ASDs), and also occur in schizophrenia and some mood disorders. Much effort has been devoted to identifying drug treatments for autism, and this effort has resulted in Food and Drug Administration (FDA) approval of Risperdal (risperidone) and Abilify (aripiprazole). Both are atypical antipsychotics that are most effective in reducing aggression, anger, and self-injury, yet their efficacy to treat other symptoms is limited. In particular, they do not improve impaired social behavior, the core symptom of autism. Thus, there is an urgent need to discover novel drugs to treat the social behavior problems characteristic of autism. Clinical and basic research indicates that dysfunction of the serotonin (5-HT) neurotransmitter system in the brain may well be a root cause of autism. This dysfunction may underlie social interaction deficiencies because 5-HT neurotransmission (signaling by serotonin neurons) in the brain appears to be suppressed in autistic individuals. Selective serotonin reuptake inhibitors (SSRIs) such as Prozac (fluoxetine) are most effective in reducing restricted, repetitive, and stereotyped behaviors, but improve sociability impairments only to a limited extent. SSRIs work by blocking the serotonin transporter (SERT) from taking up 5-HT from extracellular fluid into nerve cells, thereby increasing the levels of 5-HT in the extracellular fluid. However, genetic variants of SERT exist that reduce its expression and/or function. These variants have been linked to susceptibility for autism. It is especially problematic that individuals with these genetic SERT variants are even less effectively treated with SSRIs and atypical antipsychotics. Together, these findings underline the clear need to identify better drug treatments for autistic patients, particularly to treat the debilitating social interaction impairments. It is most likely that improvements and possible breakthroughs in the treatment of autism and other psychiatric disorders can result only from the discovery of new targets for therapeutic intervention. There is a need to find other means to promote 5-HT neurotransmission. Recently, we found another transporter capable of taking up 5-HT from extracellular fluid. This transporter, called the organic cation transporter 3 (OCT3), is one among a handful of other newly discovered alternative 5-HT transporters that may compensate for diminished SERT expression or functionality. If OCT3 is overexpressed or functions at a higher capacity, it could take up enough 5-HT to prevent SSRI-induced increases in extracellular 5-HT and thereby suppress neurotransmission. If this is indeed the case, OCT3 blockade could be an effective new approach to enhance 5-HT transmission and improve social behavior. The present proposal tests this idea. In response to the 2010 Congressionally Directed Medical Research Programs Autism Idea Initiative, we submitted a very similar proposal to study OCT3 blockade to improve social behavior. This application was rated "outstanding" (score of 1.5) by the panel of reviewers because of its novelty, impact, and approach. A consumer reviewer questioned whether there were already Food and Drug Administration (FDA)-approved drugs that we could use to study the role of OCT3 in modulating social behavior. Unfortunately, there are none; however, the reason for this highlights the novelty and potentially high impact of our approach. Our studies are key to the future development of new, FDA-approved drugs, with improved therapeutic efficacy to treat ASD and related disorders. Taken together, pursuit of OCT3 as a therapeutic target for treatment of ps...
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
