Additional evidence for the pathogenesis of the serotonergic system in OCD was provided by challenge studies. Obsessive-compulsive (OC) symptoms can be induced specifically by either behavioral or pharmacological challenge . Behavioral challenge is individually tailored according to a known stressful stimulus for the patient, while pharmacological challenge is directed towards a specific receptor subsystem in the brain. Inducing symptoms via challenge can reveal state-dependent features of pathological brain mechanisms . The typical design for a challenge test consists of within-subject and across-states repeated measures of several dependent variables, such as behavioral, physiological or brain measures. Exacerbation of OC symptoms has been described in challenge studies applying methyl-chlorophenylpiperazine (mCPP)—a serotonergic agonist of 5HT1D, 5HT2/ 5HT1C and 5HT1A .

This exacerbation was blocked by pre-treatment with metergoline, a non-specific 5HT antagonist , and down-regulated by chronic treatment with clomipramine. Others, however, have failed to show that mCPP challenge induces exacerbation of OC symptoms (Charney et al., 1988). In a detailed review of the literature it has been demonstrated that about 50% of OCD patients challenged by mCPP had some OC symptom exacerbation. However, no OC symptom exacerbation has been demonstrated, following challenge with either ipsapirone or MK-212 (specific agonists of 5HT1A and 5HT2/5HT1C, respectively). Based on such observation, OC symptom provocation following mCPP challenge was related specifically to the 5HT1D receptor subtype . We have examined this assumption by using sumatriptan, a 5HT1D agonist, as a pharmacological challenge in comparison to placebo in OCD patients . OC symptom exacerbation was demonstrated in about 50% of the patients with sumatriptan and none with placebo.

Challenges with L-Tryptophan , mCPP , sumatriptan (5-HT1D agonist-(6)), ipsapirone (a 5HT1A receptor ligand-(28)) and MK-212 (affecting 5HT1A and 5HT2C-(29)) among others were used to evaluate whether they worsen obsessive-compulsive symptoms or whether they have other differentiating physiologic responses (thermal or neuroendocrine) in OCD patients, as compared with controls. Only two compounds (mCPP and sumatriptan) have shown behavioral hypersensitivity and neuroendocrine hyposensitivity to be characteristic of the OCD challenge response. These studies have the potential to pinpoint the receptor subtype involved in OCD, raising the possibility that 5HT2C and 5HT1D receptors, but not 5HT1A, may be involved in OCD .

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