Summary

The future trends in the development of drugs for the treatment affective disorders have followed the high degree of anatomical overlap in the distribution and coexistence of monoamine and neuropeptide neurons in limbic regions of the human brain. The intimacy of the relationship between monoamines and neuropeptides suggests a common downstream effect on neural systems that mediate stress. The relationship between stress-related interactions among glutamate, CRF, galanin, NPY, SP, and vasopressin V1B and monoamines in the brain is well documented. However, the role of neuropeptides in depression is still in its infancy and it is premature to speculate on whether and how these systems might exert common downstream effects on brain pathways that mediate stress and emotion. Thus, although SP, CRF, vasopressin, NPY, MCH, and galanin demonstrate important functional interactions with monoamines implicated in the etiology and treatment of stress-related disorders, their effects almost certainly go beyond modulation of these neurotransmitters. Understanding these effects is a central goal of future research in this field. There are certain characteristics common to neuropeptides that might make them attractive targets for novel therapeutics.

Because neuropeptides possess a more discrete neuroanatomical localization than monoamines and GABA, neuropeptide receptor ligands might be expected to produce relatively little disruption of normal physiology. Thus, pharmacological alteration of neuropeptide function might normalize pathological activity in circuits mediating stress, such as the HPA axis, without producing unwanted side effects. Moreover, antagonists might be less likely than agonists to produce tolerance and dependence. Indeed, drugs that are antagonists at CRF, vasopressin, NPY, and galanin receptors might have a particularly low side-effect burden because such compounds would not be expected to disrupt normal physiology in the absence of neuropeptide release. Preliminary clinical data appear to be encouraging in this regard.

Several ligands that target neuropeptide receptors are currently undergoing clinical evaluation to determine whether they provide efficacious alternatives to existing drug treatments for depression and anxiety disorders. Establishing the safety, therapeutic efficacy, and an acceptable tolerability profile of drugs that target neuropeptides in depression and anxiety disorders would represent a major advance in the treatment of these diseases. The validation of future targets will be facilitated by the generation of mutant rodents to elucidate neuropeptide function, particularly where a paucity of selective, brain-penetrant ligands limits conventional psychopharmacological approaches. The effects of constitutive neuropeptide mutations can be skewed by developmental alterations that compensate for the mutated neuropeptide or cause changes in other systems that confound interpretation of stress-related phenotypes. Therefore, engineering neuropeptide mutations that are limited to specific developmental stages and brain regions, or improving other molecular manipulations (e.g., RNA interference, antisense, and viral vector delivery techniques), will be valuable. Once promising targets are identified, a further challenge is the generation of small-molecule neuropeptide receptor ligands that are soluble, bioavailable, brain penetrant, and have a low potential for tachyphylaxis. Although there are important obstacles to surmount, neuropeptide-based therapeutic strategies for depression and affective disorders represent a highly promising approach to treating these debilitating conditions.

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