Conclusions

The emerging neurochemical understanding of the basic psychobehavioral processes of the mammalian brain is providing a remarkable number of novel brain targets for psychiatric drug development. If emotional principles of brain organization, derived mostly from animal studies, also apply to humans, then neurochemical modulation of neuropeptide systems should provide remarkable opportunities to promote and dampen the many distinct affective capacities of the human brain/mind. However, optimal development in this area may require more investigators to seriously consider the evolved emotional-affective nature of the brain and to better evaluate such central processes using behavioral procedures in sensitive animal models.

Compelling concepts have been emerging from basic animal research for some time. However, because of the success of the previous generation of agents (based largely on an understanding of biogenic amine systems), the development and implementation of neuropeptide related concepts in biological psychiatry has lagged far behind the preclinical evidence. As already discussed, neuropeptide concepts have also been notoriously difficult to translate into clinical practice. Partly this is because of species differences in pharmacokinetics and dynamics (Appendix A), but there are also a sufficient number of other relevant differences, including SNPs in the genetic coding regions for the relevant receptors to make simple translations from animal models to human uses problematic. Also, it is now clear that the social environmental variables impact gene expressions in the brain (e.g., Meaney, 2001; Bester-Meredith and Marler, 2001). Such neurochemical background effects may have important consequences on how other neurochemical factors operate.

Despite the rapid development of nonpeptide analogs, many prominent pharmacologists still do not believe that peptides are good targets for drug development. What they commonly overlook is the possibility that these agents may be used prophylac-tically, since many neuropeptides are only released in response to stress and other kinds of emotional arousal. The general principle here might be that such comparatively mild medicinals may need socioenvironmental supports for optimal efficacy. If so, such agents may also find wider usage for everyday emotional problems, as in the controversial concept of "cosmetic" psychopharmacology introduced by Kramer (1993). Indeed, neuropeptide modulators may have psychological effects that may help hone theoretical concepts in psychiatry to a finer edge.

With the clarification of the human genome, and the revelation of remarkable relations to those of other animals, we stand at the threshold of new drug discoveries that will emerge from the analysis of gene expression patterns in different environments (Panksepp et al., 2002b), some of which may be distinct for different individuals. As Florian Holsboer put it (2001a, p. 62): "We are awaiting a wealth of new information from functional genomics and proteomics, and it is most important that psychiatrists, psychologists, biologists and other professions involved in the process of... drug discovery find quickly a common platform suited to exploit this new research for the benefit of our... patients. While the prospect that... drug therapy will become personalized according to an individual's genotype may sound futuristic, I predict that a concerted interdisciplinary exploitation of biotechnology leads to knowledge so powerful that clinicians and patients will wonder how they ever got along without it."

Of course, if this comes to pass, we will be confronted by a host of ethical dilemmas. As Victor Hruby (2002, p. 856) remarked "It is often suggested that ethical considerations are not appropriate in a scientific discussion. In the case of drug design, this seems irresponsible at best____Certainly, the desire to relieve human pain and disease is noble, but increasingly, scientists and the institutions in which they work ignore their ethical responsibilities. Just a few brief examples highlight some problems: first, the responsibility to put new knowledge in the public domain and make it widely accessible; second, the honest and rapid revelation of side effects of drugs; third, modification of human behavior—who decides what behaviors to modify? Who will profit? Who will benefit? And fourth, "pollution" of the human and other genomes—who can predict the long-term consequences?" Surely these concerns should remain of foremost importance as we come to develop new agents that have the potential to alter the normal and abnormal emotional dynamics of the human mind.

0 0

Post a comment