By David N. Leff

"A box of chocolates and a dozen roses on Valentine's Day are not likely to boost the romantic mood, if a protein called DARPP-32 is missing from the brain."

This sentiment was voiced by molecular and cellular biologist Shaila Mani, at Baylor College of Medicine in Houston. She recalled hearing it two years ago at a scientific meeting. "Around Valentine's Day of 1998," Mani recounted, "a group had shown that if you consume chocolate, it increases dopamine in your brain's limbic system. That was where the whole idea came up, asking: 'Well, if you give chocolate to a woman, you are getting her motivated, but then if her DARPP-32 is missing, will she be able to perform?'"

Another of Mani's colleagues commented: "What about female sex hormones? If the neurotransmitter dopamine is a chemical for motivation, for desire, might estrogen and progesterone also have something to do with it"?

Mani herself is lead author of a research report in today's issue of Science, dated Feb. 11, 2000. Its title: "Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice."

We have shown how different components in the brain come together," she told BioWorld Today, "and alter the neural circuitry for any behavioral response. In essence we are saying it's the integration of different signals, not just a steroid hormone but neurotransmitters, too, which are coming together to elicit one behavior - in this case, sex behavior."

The go-between protein, DARPP - 32 kiloDaltons in size - stands for "dopamine- and adenosine 3', 5'-monophosphate (cAMP)-regulated phosphoprotein." It's present in all the dopamine neurotransmitter systems in the brain.

"We showed a few years ago," Mani recalled, "that there was some kind of chemical crosstalk going on between dopamine and the female ovarian hormones, because both could elicit sex behavior. You might call it molecular pillow talk." In that crosstalk analogy, DARPP-32 plays the part of the pillow.

Dopamine: Brain's Desire, Pleasure Interlocutor

Mani pointed out, "Dopamine is known to be definitely released prior to, and even during, the time of mating responses. It's considered to be a chemical that induces desire - the motivation to do certain things." Anecdotal evidence of this phenomenon comes from Parkinson's disease (PD), for which dopaminergic drugs are the treatment of choice. "I have heard," Mani observed, "that dopamine does have this behavioral effect in at least some Parkinsonian patients. A neurologist once told me, 'Some of our PD patients seem to let me know they have increased libido - and we see them just chasing the nurses around."

On the hormonal side of PARPP-32's equation, Mani observed, "Progesterone is one of the ovarian hormones that facilitate sexual receptivity. During a particular time in the sexual cycle of a rodent or a woman, just prior to ovulation, they have increased levels of progesterone. This stimulates the brain's luteinizing hormone system, which sends out signals to the ovaries, saying: 'You are ready for ovulation. Go ahead. Ovulate!' Provided that copulation or fertilization by artificial insemination also occurs at that time," she added, "the result in one woman can be septuplets."

A female rodent signals her sexual receptivity to an interested male by arching her back in a characteristic pose called lordosis. "By thus exposing her rump to the male," Mani explained, "lordosis says, 'Look, I'm ready for you to copulate.'" She added, "It's like foreplay in humans, or the baboon's red derriere."

In vivo experiments to demonstrate DAPRR-32's role in the dichotomy of hormone and neurotransmitter, Mani and her co-authors began with rats. "First, we ovariectomized them, to clear all of their endogenous hormones. Then we treated them with estrogen and progesterone, and looked at their behavior."

She noted, "Progesterone's actions are not effective until the animals are primed with estrogen. So we gave estrogen, waited 48 hours, then gave progesterone. After maybe an hour, we put the female rats with the males, to see how the females were responding. Lacking sex hormone," she went on, "these animals lost all interest in sex, and even aggressively fought off approaching males. Injections of estrogen and progesterone did not reverse this attitude, because the hormones were ineffective without DARPP-32.

"In knockout mice lacking the gene encoding that protein," Mani continued, "we did similar experiments Luckily for us, we collaborated with Dr. Paul Greengard's group at The Rockefeller University, because they were already producing those KO rodents. We injected dopamine or progesterone into their brains, then looked for the sex behavior. What we saw was that those hormones could facilitate receptivity in their wild-mouse littermates, where the gene was not KO, whereas in KO mice we did not see any such behavior."

Knockout Mice KO'd Randy Impulses

Greengard, a co-author of Baylor's Science paper, told BioWorld Today: "Abnormalities of dopamine signaling are associated with several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, Alzheimer's disease, Huntington's chorea and drug abuse. In 1998 we showed that if we deleted - knocked out - the DARPP-32 gene, all of the effects of dopamine were greatly reduced or abolished, and the same thing for antipsychotic drugs, as well as drugs of abuse. Now, since dopamine and progesterone affect sexual receptivity in female rodents, our collaborative study with the people in Houston found that these KO mice given either dopamine or progesterone have greatly reduced lordosis, compared to controls."

Picturing a clinical scenario, Mani observed: "There are people being treated for, say, mental illnesses or depression. Clinicians tend to give them antidepressants and antipsychotic drugs that turn out to be dopamine antagonists. So they prevent the action of dopamine, which means they prevent the action of DARPP-32 in their brains.

"So these patients' sexual motivation - the drive, the libido or performance - is reduced. If that be the case," Mani suggested, "then the researchers designing new drugs should pay attention to the fact that not only can dopamine do something, but steroid hormones also can be cutting into the behavioral pathways. This is a conjecture," she concluded. "It could true or it could be an idea to solve."