Between the two of them, lithium and amphetamine have been approved by the FDA - for the treatment of bipolar disorder and attention deficit hyperactivity disorder, respectively - for more than 80 years.

And still no one really knows exactly how they work.

Two recent papers, one in the May 10, 2006, issue of Journal of Neuroscience and one in the June 2006 issue of Journal of Clinical Investigation try to shed some light on the cellular mechanisms of those stalwarts.

The JCI paper reported on research from Yale University in New Haven, Conn.; the Marine Biological Laboratory in Woods Hole, Mass; the University of Texas at Austin; the University of Magdeburg and the Charité hospital in Berlin, both in Germany; and the Center for Cellular and Molecular Biology in Hyderabad, India. The scientists set out to study neuronal calcium sensor (NCS), a calcium-binding protein that is up-regulated in bipolar patients, and whether its interaction with a specific type of receptor that opens and closes calcium channels is affected by lithium.

Using brain slice preparations, the scientists first confirmed that NCS and the receptor interacted in the presence of calcium. In artificial membranes, as well as intact cells, NCS increased the rate at which calcium channels opened and released calcium, which would result in enhanced calcium signals in the brain.

They then found that therapeutic levels of lithium blocked the effect of NCS on receptor function, suggesting that the interaction of NCS with the receptor is part of the mechanism of bipolar disorder.

Mechanistic experiments suggested that lithium binds to NCS in a way that prevents subsequent binding to calcium, which in turn makes NCS unable to enhance receptor function. The authors concluded that neuronal calcium sensor "is a promising target for the treatment of neuropsychiatric disorders."

The Journal of Neuroscience paper presented research from the Universities of Osaka and Tokyo, both in Japan, on how amphetamine works to combat attention deficit hyperactivity disorder (ADHD).

Perhaps somewhat astonishingly for a society that won't let its youth drink alcohol until the age of 21, amphetamine salts are an approved drug for the treatment of ADHD from the age of 3. Even more astonishingly, despite the fact that amphetamine salts were first approved for the treatment of ADHD in 1960, amphetamine's mechanism of action in ADHD still is unknown.

The Japanese researchers developed a knockout mouse that might shed some light on that mechanism. Pharmacological treatments for ADHD are thought to work by acting on dopamine and/or serotonin, the mice described in the JNS lack the gene for a different signaling molecule: a neuromodulator, adenylate cyclase activating polypeptide, which is produced in the hypothalamus. Rather than being quiet as a mouse, the knockouts are hyperlocomotive, that is, they run around more than their wild-type cousins. They also have deficits in prepulse inhibition, or PPI, a cellular mechanism of attention.

In the knockouts, amphetamine normalized prepulse inhibition and reduced motor activity. A serotonin receptor antagonist blocked the antihyperkinetic effect of amphetamine.

The authors wrote that the knockouts are "a long way from the clinical disorders of hyperkinesia and cognitive impairment." But they added that "we hope to provide models with some typical features of psychostimulant responses in these disorders."

Senior author Akemichi Baba, professor at the University of Osaka, elaborated on that for BioWorld Today. He said that particularly for the symptom of hyperlocomotion, the knockout showed behaviors that are similar to ADHD, and that there appear to be at least some underlying similarities in the brain mechanisms mediating those behaviors.

Furthermore, the finding that blocking serotonin receptors can reduce hyperactivity provided "new insights into the mechanisms underlying the psychostimulant's effects in treating ADHD."

Where the model falls short, Baba said, is in the areas of impulsivity and inattention. "One of the striking results of our paper is that paired-pulse inhibition was impaired and improved by amphetamine in [the knockout] mice." But Baba said that "we cannot relate these results to human ADHD," because in ADHD patients, paired-pulse inhibition is seen only in patients that also have obsessive-compulsive disorder.