Prozac (fluoxetine), a commonly prescribed drug for anxiety and depression, is used during pregnancy by some women. But several studies are showing that prenatal exposure to the drug may increase the risk of having a child with autism.

Prozac, Zoloft (sertraline) and Paxil (paroxetine) are selective serotonin reuptake inhibitors (SSRI) – a class of antidepressants. SSRIs can cross the placenta, and it’s possible that exposure to the drugs affects fetal brain development, the researchers say. But until now, no one has been able to prove that this class of antidepressants is harmful to the fetus.

“Exposure to SSRIs could be changing the neurobiology of the child,” says Rebecca Larke, a doctoral candidate in Dr. Karen Bales’ lab at the University of California, Davis, who presented results of her unpublished research at the Society for Neuroscience meeting in Chicago, October 17–21, 2015.

Larke began her research on the effects of serotonin agonists in titi monkeys (Callicebus cupreus), a small monogamous primate species, at the California National Primate Research Center. In 2012, she received a pre-doctoral fellowship to conduct her research from the Autism Science Foundation: The Role of Serotonin in Social Bonding in Animal Models. She noted that the relationship between serotonin and oxytocin had been little studied with regard to its effects on social behavior and that some commonly used antidepressants such as Prozac have been increasingly used during pregnancy over the past decades.

Studies have indicated that Prozac and other SSRIs have been identified as a significant risk factor for autism. Larke’s studies investigated the role of serotonin-oxytocin interactions in social behavior in two monogamous animal species, the titi monkey and the prairie vole (Microtus ochrogaster). Establishing her initial research on how these drugs affect titi monkeys, she then began conducting her research on the effects of Prozac during pregnancy in the faster maturing prairie voles, who reach sexual maturity in a little over one month.

In her study, Larke and her colleagues explored the effects of prenatal and early-life fluoxetine exposure in prairie voles. These animals are highly social and form strong attachments to other voles, a trait that has been attributed to the presence of high levels of the oxytocin receptor.

The researchers injected pregnant prairie voles with either fluoxetine or saline daily throughout their pregnancies (gestation is 3 weeks) until their pups were born and weaned. They then administered a series of behavioral tests to some of the pups when they were adolescents and to the others when they were adults.

By studying these processes Larke and her team have shown that prairie vole pups exposed to the antidepressant fluoxetine in the womb show autism-like social deficits.

The researchers then looked at the density of brain receptors for oxytocin and vasopressin, both of which interact with serotonin, in certain regions of the brain. Both hormones influence social behavior and have been linked to autism. “Changes to the oxytocin system could underlie changes in social behavior,” says Larke.

Adult voles exposed to fluoxetine have fewer oxytocin receptors in the central portion of the amygdala — the almond-shaped emotion hub — than controls do, and fewer vasopressin receptors in the more medial portion. This finding is in line with the heightened anxiety and social impairment seen in the voles.

Larke, with colleague Sara Freeman, PhD, a postdoctoral researcher with Karen Bales, PhD (CNPRC Brain, Mind and Behavior Unit Leader), also looked at an area of the brain called the nucleus accumbens, which mediates social reward, where oxytocin receptors typically sit. The adolescent fluoxetine-exposed voles show less receptor density in the center of this region than do controls.

Exactly how these findings track with autism risk is difficult to parse. For example, exposure to fluoxetine could by itself trigger the behavioral changes in the voles, Larke says. But it’s probably more likely that changes are driven by a complex interchange between serotonin and the two hormone systems, she says.

Dr. Freeman will be expanding our understanding of these hormone systems by investigating oxytocin and vasopressin receptor densities in the postmortem brains of people with autism and controls. She and Dr. Bales are continuing this work with a National Institutes of Mental Health grant entitled: “Characterization of oxytocin receptors in autism spectrum disorder”. Dr. Freeman will have assistance from Michelle Palumbo, who as an undergraduate conducted the vasopressin receptor component in Larke’s study at the CNPRC.

Larke’s research was supported by an Autism Science Foundation Predoctoral Fellowship, National Institute of Child Health and Human Development grant HD053555 and HD071998, and the CNPRC Base Grant National Institutes of Health, Office of the Director, OD011107.