The lack of selective agonists and antagonists for serotonin 5-HT1B/1D receptors has made it difficult to determine the neurochemical, behavioral, and clinical effects controlled by 5-HT1B/1D receptors. However, by combining data from various compounds with different receptor affinity profiles, it is possible to tentatively determine those effects that result from interactions at the 5-HT1B/1D receptors.

This discussion contains a review of the in vitro and in vivo neuropharmacology of the 5-HT1B/1D group of receptor subtypes, and attempts to identify their possible functions and potential implications in central nervous system disorders.

Of all known neurotransmitters, 5-HT is the one most frequently mentioned in the pathophysiology of migraine. This review focuses on the relationship between the efficacy of sumatriptan and other migraine agents and their effects on specific 5-HT receptors in rodent models. These agents are seen to have effects on vascular constriction and the release of vasoactive and inflammatory peptides from trigeminovascular sensory neurons. Specific subtypes of the 5-HT1 receptors appear to mediate these effects.

Pharmacological challenge tests provide a method of assessing the functional responsiveness of serotonin (5-HT) receptor subtypes in the human brain. A number of selective agonist ligands for the 5-HT1B/1D receptor are available for human use; however, these compounds do not distinguish between 5-HT1B and 5-HT1D receptors, which is somewhat of a disadvantage. Acute administration of sumatriptan, rizatriptan, and zolmitriptan all increase plasma growth hormone in healthy subjects, possibly via activation of postsynaptic 5-HT1D receptors. This response is blunted in major depression. Sumatriptan lowers plasma prolactin, perhaps via activation of presynaptic 5-HT1B receptors. This response is not altered during repeated treatment with selective serotonin reuptake inhibitors (SSRIs), suggesting that 5-HT1B receptors retain the ability to restrain 5-HT outflow during short-term SSRI treatment.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder in which the patient suffers from recurrent intrusive ideas, impulses, thoughts (obsessions), and/or patterns of behavior (compulsions) that are ego-alien and produce anxiety if resisted. The ego-dystonic nature of OCD is one of the hallmarks of this disorder. OCD can be a disabling condition because the obsessions and compulsions are time-consuming and interfere with patients' everyday activities and their relationships with friends and family. In severe cases, OCD conflicts even with the simplest tasks of daily living.

Research interest in OCD has been growing steadily in the past decade. A search on MEDLINE reveals an over 300% increase in citations on OCD from 1986 to 1998. These range across the spectrum of research fields, from genetic studies, brain imaging, and neurobiological research examining the underlying pathogenesis of OCD to epidemiological studies evaluating the course of clinical symptoms, comorbidities, and outcomes. Each area represents an important piece in the complex jigsaw puzzle of OCD.

The endogenous peptide 5-HT–moduline has been characterized as a novel neuropeptide that binds to 5-HT1B receptors in the brain areas in which it is released. By inducing structural changes in these receptors, this peptide prevents 5-HT binding, thereby desensitizing the receptors and inhibiting serotonergic function. This novel mechanism may help to explain differential effects of the serotonergic system in varying areas of the brain that are innervated by the same or few neurons. In addition, dysfunction or disruption of the 5-HT–moduline system may contribute to psychiatric disorders such as depression and anxiety, and may have important implications for the development of new therapeutic agents for these disorders.