Investigator of Neurotransmitters' Role in Male Sexual Functioning Receives $1.5 Million NIMH Grant

BUFFALO, N.Y. -- New understanding of the mechanisms of sex differentiation could result from research in the neuropharmacology of sexual behavior being conducted at the University at Buffalo.

Elaine M. Hull, Ph.D., UB professor of psychology and an expert in the field, has received a new five-year, $1.5 million grant from the National Institute of Mental Health (NIMH) to further clarify the role of neurotransmitters in determining sex differentiation and in regulating male sexual behavior.

Hull's research, which has been funded by the NIH for 20 years, ultimately could lead to new treatments for sexual dysfunction and may help to explain some of the variations in sexual orientation. Her work resulted in her receiving a prestigious NIMH Independent Investigator Award in 2000.

Hull was the first to show that the neurotransmitter dopamine, in addition to testosterone, contributes to early developmental sex differentiation and identified a major brain region where dopamine exerts its control of male sexual response. She carried out the work in UB's animal biobehavioral research laboratory using the rat as an animal model.

"Our findings showed that increases or decreases in brain dopamine function resulted in impairment of sexual differentiation," said Hull.

"To my knowledge this was the first report of demasculinization by drugs that don't affect steroid hormones either directly or indirectly."

Hull went on to identify the small, ancient site located behind the eyes at the base of the brain, called the medial preoptic area, or MPOA, as a major region where testosterone increases dopamine release, and thereby activates male sexual behavior in adulthood.

"This was novel," Hull said. "Nobody had even thought to look in the MPOA for a dopamine effect. We were able to show that dopamine activity in the MPOA specifically focuses attention on sexual behavior and also enhances erectile function."

As a check, the group carried out similar experiments in the mesolimbic tract, which increases motivation for many different goals. They found that shutting down neural activity in the mesolimbic tract slowed the male rat's general motor activity, but did not affect the percentage of trials on which he chose to be with the female.

"These two brain area, we learned, are like two essential parts of a car," said Hull. "The mesolimbic system is the motor that gets the male going, but the MPOA is the 'steering wheel' that directs his attention to the receptive female and focuses it on copulation when he gets to her.

"It controls three critical aspects of behavior: focusing attention on the act, increasing the efficiency of copulation by inducing faster and more frequent insertions, and promoting erections and ejaculation."

Using microdialysis to sample brain neurotransmitters and capillary chromatography to detect them, Hull and colleagues then were able to define a complex cascade of hormones and neurotransmitters that is necessary for normal male sexual functioning. They showed that testosterone increases production of the enzyme nitric oxide synthase in the MPOA, which produces more nitric oxide, a potent soluble gas, which, in turn, promotes the release of dopamine, both under normal conditions and in sexual situations. Increased release of dopamine in sexual situations then promotes sexual motivation, genital reflexes and copulation.

In yet another finding, the researchers showed that serotonin, another neurotransmitter and the primary target of the antidepressant Prozac, is released in another area of the brain at ejaculation and dampens sexual interest.

Prozac helps relieve depression by increasing the amount of serotonin in the brain's extracellular fluid, but in men it also is known to decrease libido and cause difficulty in ejaculation. Hull's findings eventually could point the way to development of a drug that would restore sexual functioning, hopefully without interfering with Prozac's antidepressive activity.

She recently completed the definitive chapter on male sexual behavior for a three-volume work titled "Hormones, Brain and Behavior," to be published by Academic Press.