One of the less useful suggestions that depressed people can receive from "helpful" friends or relatives is to "just snap out of it."
But in a few years, doctors may be telling their patients the same thing, albeit fortified with the medicine to make it happen. In a paper that now is available online and will be published in print in the Nov. 29, 2005, issue of the Proceedings of the National Academy of Sciences, scientists from Paramus, N.J.-based Lundbeck Research USA Inc. and the Karolinska Institutet in Stockholm, Sweden, present preclinical data on the molecule SNAP 37889 and its more soluble analogue SNAP 398299 that suggest those compounds are promising antidepressants and anti-anxiety compounds.
Both SNAPs are specific antagonists of galanin-3 receptors. The neuropeptide galanin, among a variety of roles both central and peripheral, interacts with serotonin neurotransmission in the midbrain and is known to play a role in anxiety and depression.
The distribution of the galanin-3 receptor subtype suggested it was the most likely candidate for mediating such effects. Lead author Chad Swanson, scientist at Lundbeck, told BioWorld Today that targeting galanin possibly could open up a treatment option with fewer side effects, "or for patients who are not helped by or cannot tolerate serotonergic compounds." But to date, no specific antagonists of the three known galanin receptors were available, complicating the study of galanin's effects and complicating its investigation for clinical purposes.
The researchers tested SNAP 37889 and SNAP 398299, which were identified by classical screening methods, in a variety of behavioral tests that measure depression and anxiety, respectively.
Additional tests of binding affinity, electrophysiological recordings in whole animals and brain slices, and microdialysis experiments confirmed the specificity of both molecules and gave some insight into their molecular mechanisms of action.
The scientists used social interaction tests, they punished water intake and they separated the models from their mothers to measure SNAP's effects on anxiety, and forced swimming to test its effects on depression. Rats treated either acutely with a single dose of SNAP or chronically for two weeks increased their social interaction with other animals; in comparison, a benzodiazepine anxiolytic was effective only with short-term administration. SNAP and the benzodiazepine were equally effective in reducing a stress response generated by being handled by the experimenters.
In another behavioral test for anxiety, the scientists measured the effects of maternal separation on guinea pig pups. Much like in their human counterparts, separation from mom in the rodents produces anxiety, quickly followed by miserable wailing. When the guinea pig pups were given SNAP 37889 prior to being separated from their mothers, such vocalizations were reduced. Somewhat surprising was the result that a placebo also reduced vocalization in a control group; Swanson did not comment on that finding directly, but pointed out that overall, the studies still "support our hypothesis that Gal3 antagonists are antidepressants."
Microdialysis studies showed that administering galanin reduced serotonin levels in the hippocampus and that the reduction could be reversed partially by giving a SNAP and a serotonin receptor agonist in combination, though neither drug alone had a significant effect.
Swanson declined to say whether SNAP or other Gal3 antagonists were headed for the clinic, saying only that "we do not comment on our pipeline."
In other news, scientists at Rutgers University, Columbia University, Harvard University and the Albert Einstein College of Medicine reported in the Nov. 18, 2005, issue of Cell that they have created a fearless mouse by knocking out the gene for stathmin in the amygdala.
Stathmin knockouts showed less innate fear in response to open spaces (venturing where no mouse has dared to go), and less learned fear in response to unpleasant stimuli, though their general learning ability was as good as that of their normal peers. Their creators hope the mice will be useful both to study basic mechanisms of anxiety and to serve as animal models in the development of new anti-anxiety agents.
Finally, it may seem like benzodiazepines were invented shortly after the wheel - F. Hoffmann-La Roche's Valium, the most famous member of the class, was approved in 1963. But for all that, their exact molecular mechanism of action still is unclear, and the study of their receptor, the GABA receptor, continues to yield new information. In the Nov. 16, 2005, issue of Journal of Neuroscience, researchers from Merck Sharp and Dohme Research Laboratories in Harlow, UK, reported on genetic and electrophysiological evidence that alpha-3, rather than alpha-2, subunits of GABA-A receptors might be the ones that mediate anti-anxiety effects of benzodiazepines. Like their colleagues, they hope their findings ultimately will lead to the development of better anti-anxiety drugs.