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Altered prolactin response to serotonergic rechallenge in healthy volunteers
104A
BIOL PSYCHIATRY" 1992;31:61A-252A
Stu6ies Related to the Serotonin System
STUDIES RELATED TO THE SEROTONIN SYSTEM T h u r s d a y , April 30, 4 : 3 0 - 6 : 0 0 PM
99
Ballroom
ALTERED PROLACTIN RESPONSE TO SEROTONERGIC RECHALLENGE IN HEALTHY VOLUNTEERS John H. Gilmore, Robert G. Ruegg, R. David Ekstrom, Bettina Knight, Robert N. Golden University of North Carolina, Chapel Hill, NC 27599. The effect of an initial challenge with the serotonin (5-HT) uptake inhibitor clomipramine (CMI) on rechallenge was studied in healthy male volunteers. Carefully screened volunteers were assigned to one of three conditions: (I) CMI challenge followed 2 weeks later by CMI rechallenge; (2) placebo challenged followed 2 weeks later by CMI challenge; and (3) CMI challenge followed 4 weeks later by CMI rechallenge. We found significant blunting af the prolactin response to CMI rechallenge 2 weeks (Signed Rank = - 13, p < 0.05), but not 4 weeks after an initial challenge. Placebo challenge did not effect CMI challenge 2 weeks later. These findings suggest that a single exposure to IV CMI may cause 5-HT receptor changes that are present 2, but not 4 weeks later. The ramifications of this finding with regard to the use of 5-HT challenge paradigms in a test-retest design should be considered. Supported by NIMH grants MH-41245, MH-33127, and MH-191 i i and by NIH grant RR00046.
100 IPSAPIRONE AS A PROBE FOR 5-HTla RECEPTORS:
A DOSE-RESPONSE STUDY IN HEALTHY SUBJECTS Ren6 S. Kahn, Robert Trestman, Brian Lawlor, Jason Gold, Larry Siever, Michael Davidson Bronx Veterans Administration Hospital, Mount Sinai School of Medicine, New York, NY 10468, Examina:ion of 5-14T recepto,' sensitivity has been hampered by the lack of agents selective for any of the 5-HT receptor subtypes. Ipsapirone (IPS) appears to be a sdective 5-HTI,, partial agonist. This ongoing study examines the effect of IPS (5, 10, 20 mg PO) in a double-blind placebo-controlled design in healthy male subjects. One hour alter an IV is inserted, IPS or placebo are administered at 10:00 AM. ACTH, body temperature, blood pressure, and heart rate are assessed every 30 rain from 9:00 AM until I:00 eM. Nine subjects have participated so far in (part) of the study. Preliminary results indicate that IPS decreases body temperature in a dose-dependent fashion as compared with placebo. In contrast, IPS increases ACTH levels only at the 20-mg dose. The 10- and 20..mg doses lowered diastolic (but not systolic) blood pressure. Because generally the presynaptic receptol is thought to be more sensitive than the postsynaptic receptor, the finding that ipsapirone affected temperature at considerably lower doses (i.e., 5 rag) than those needed to elicit ACTH release (i.e., 20 mg) suggests that its effect on temperature is mediated by presynaptic 5HT~ receptors, whereas its effect on ACTH is mediated by postsynaptic 5-HTt,, receptors. IPS-induced decrements in temperature may therefore be a reliable parameter for testing sensitivity of presynaptic 514f~ receptors, whereas IPS-induced ACTH release may be u~ed to assess postsynaptic 5-HTla receptor sensitivity. Finally, results suggest that stimulation of 5"HTta receptors may decrease blood pressure.
BIOL PSYCHIATRY" 1992;31:61A-252A
Stu6ies Related to the Serotonin System
STUDIES RELATED TO THE SEROTONIN SYSTEM T h u r s d a y , April 30, 4 : 3 0 - 6 : 0 0 PM
99
Ballroom
ALTERED PROLACTIN RESPONSE TO SEROTONERGIC RECHALLENGE IN HEALTHY VOLUNTEERS John H. Gilmore, Robert G. Ruegg, R. David Ekstrom, Bettina Knight, Robert N. Golden University of North Carolina, Chapel Hill, NC 27599. The effect of an initial challenge with the serotonin (5-HT) uptake inhibitor clomipramine (CMI) on rechallenge was studied in healthy male volunteers. Carefully screened volunteers were assigned to one of three conditions: (I) CMI challenge followed 2 weeks later by CMI rechallenge; (2) placebo challenged followed 2 weeks later by CMI challenge; and (3) CMI challenge followed 4 weeks later by CMI rechallenge. We found significant blunting af the prolactin response to CMI rechallenge 2 weeks (Signed Rank = - 13, p < 0.05), but not 4 weeks after an initial challenge. Placebo challenge did not effect CMI challenge 2 weeks later. These findings suggest that a single exposure to IV CMI may cause 5-HT receptor changes that are present 2, but not 4 weeks later. The ramifications of this finding with regard to the use of 5-HT challenge paradigms in a test-retest design should be considered. Supported by NIMH grants MH-41245, MH-33127, and MH-191 i i and by NIH grant RR00046.
100 IPSAPIRONE AS A PROBE FOR 5-HTla RECEPTORS:
A DOSE-RESPONSE STUDY IN HEALTHY SUBJECTS Ren6 S. Kahn, Robert Trestman, Brian Lawlor, Jason Gold, Larry Siever, Michael Davidson Bronx Veterans Administration Hospital, Mount Sinai School of Medicine, New York, NY 10468, Examina:ion of 5-14T recepto,' sensitivity has been hampered by the lack of agents selective for any of the 5-HT receptor subtypes. Ipsapirone (IPS) appears to be a sdective 5-HTI,, partial agonist. This ongoing study examines the effect of IPS (5, 10, 20 mg PO) in a double-blind placebo-controlled design in healthy male subjects. One hour alter an IV is inserted, IPS or placebo are administered at 10:00 AM. ACTH, body temperature, blood pressure, and heart rate are assessed every 30 rain from 9:00 AM until I:00 eM. Nine subjects have participated so far in (part) of the study. Preliminary results indicate that IPS decreases body temperature in a dose-dependent fashion as compared with placebo. In contrast, IPS increases ACTH levels only at the 20-mg dose. The 10- and 20..mg doses lowered diastolic (but not systolic) blood pressure. Because generally the presynaptic receptol is thought to be more sensitive than the postsynaptic receptor, the finding that ipsapirone affected temperature at considerably lower doses (i.e., 5 rag) than those needed to elicit ACTH release (i.e., 20 mg) suggests that its effect on temperature is mediated by presynaptic 5HT~ receptors, whereas its effect on ACTH is mediated by postsynaptic 5-HTt,, receptors. IPS-induced decrements in temperature may therefore be a reliable parameter for testing sensitivity of presynaptic 514f~ receptors, whereas IPS-induced ACTH release may be u~ed to assess postsynaptic 5-HTla receptor sensitivity. Finally, results suggest that stimulation of 5"HTta receptors may decrease blood pressure.