Allelic Variants of the Serotonin_2C Receptor and Neuroendocrinological Responses to the Serotonin_2C Receptor Agonist m-Chlorophenylpiperazine in Healthy Male Volunteers

The neurotransmitter serotonin (5-HT) possesses several receptors and their subtypes, some of which are polymorphic, such as the 5-HT_2C receptor. The latter has been implicated in the control of neuroendocrine function, and has been discussed in the pathophysiology and pharmacotherapy of psychiatric disorders such as obsessive-compulsive disorder, panic disorder and bipolar affective disorder.

To investigate whether the 5-HT_2C receptor polymorphism contributes to the variation of neuroendocrinological responses elicited by activation of the hypothalamic-pituitary axis, we performed an m-chlorophenylpiperazine (m-CPP) challenge and monitored m-CPP and ACTH, cortisol and prolactin plasma levels in 16 healthy male volunteers carrying the common 5-HT_2C-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT_2C-ser-23 receptor gene.

The 5-HT_2C polymorphism contributed little to the variation of the scores regarding hormonal responses of ACTH, cortisol and prolactin to the m-CPP challenge. The group carrying the rare 5-HT_2C-ser-23 receptor gene showed a faster and stronger but not statistically significant ACTH response to the challenge. However, it is noteworthy that there is a ‘medium’ effect size of the ACTH response according to the conventions of Cohen, and thus comparable to other studies. Both groups show similar major scores in the Temperament and Character Inventory (TCI).

References

• 1 Arato M, Bagdy G. Gender difference in m-CPP challenge test in healthy volunteers.  Int J Neuropsychopharmacol. 1998;  1 121-124
• 2 Badgy G, Arato M. Gender-dependent dissociation between oxytocin but not ACTH, cortisol or TSH responses to m-chlorophenylpiperazine in healthy subjects.  Psychopharmacology. 1998;  136 342-348
• 3 Benkert O, Wetzel H, Szegedi A. Serotonin dysfunction syndromes: a functional common denominator for classification of depression, anxiety, and obsessive-compulsive disorder.  Int Clin Psychopharmacol. 1993;  8 (suppl 1) 3-14
• 4 Buchwalder A, Welch S K, Peroutka S J. Exclusion of 5-HT2A and 5-HT2C receptor genes as candidate genes for migraine.  Headache. 1996;  36 254-258
• 5 Burnet P W, Harrison P J, Goodwin G M, Battersby S, Ogilvie A D, Olesen J, Russel M B. Allelic variation in the serotonin 5-HT2C receptor gene and migraine.  Neuroreport. 1997;  8 2651-2653
• 6 Cavallini M C, Di Bella D, Pasquale L, Henin M, Bellodi L. 5HT2C CYS23/SER23 polymorphism is not associated with obsessive-compulsive disorder.  Psychiatry Res. 1998;  77 97-104
• 7 Cloninger C R, Svrakic D M, Przybeck T R. A psychobiological model of temperament and character.  Arch Gen Psychiatry. 1993;  50 975-990
• 8 Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd Edition Hillsdale, New Jersey; Lawrence Erlbaum Associates 1988
• 9 Ebstein R P, Segman R, Benjamin J, Osher Y, Nemanov L, Belmaker R H. 5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms.  Am J Med Genet. 1997;  74 65-72
• 10 Fehr C, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N. Sex differences in allelic frequencies of the 5-HT2C and Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study.  Psychiatr Genet. 2000;  10 59-65
• 11 Göthert M, Propping P, Bönisch H, Bruss M, Nöthen M M. Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role.  Ann N Y Acad Sci. 1998;  861 26-30
• 12 Green A R. The mechanism of action of antidepressant treatments: basic aspects.  Pharmacopsychiatry. 1988;  21 3-5
• 13 Gutierrez B, Fananas L, Arranz M J, Valles V, Guillamat R, Van Os J, Collier D. Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder.  Neurosci Lett. 1996;  212 65-67
• 14 Hoyer D, Clarke D E, Fozard J R, Hartig P R, Martin G R, Mylecharane E J, Saxena P R, Humphrey P P. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).  Pharmacol Rev. 1994;  46 157-203
• 15 Kahn R S, Wetzler S. m-Chlorophenylpiperazine as a probe of serotonin function.  Biol Psychiatry. 1991;  30 1139-1166
• 16 Khanna S, John J P, Lakshmi Reddy P. Neuroendocrine and behavioral responses to mCPP in obsessive-compulsive disorder.  Psychoneuroendocrinology. 2001;  26 209-23
• 17 Kühn K U, Meyer K, Nöthen M M, Gänsicke M, Papassotiropoulos A, Maier W. Allelic variants of dopamine receptor D4 (DRD4) and serotonin receptor 5HT2C (HTR2C) and temperament factors: replication tests.  Am J Med Genet. 1999;  88 168-172
• 18 Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu D H, Virkkunen M, Weight F, Linnoila M, Goldman D. Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2C receptor gene (HTR2C).  Genomics. 1995;  27 274-9
• 19 Lappalainen J, Long J C, Virkkunen M, Ozaki N, Goldman D, Linnoila M. HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnose.  Biol Psychiatry. 1999;  46 821-6
• 20 Lentes K U, Hinney A, Ziegler A, Rosenkranz K, Wurmser H, Barth N, Jacob K, Coners H, Mayer H, Grzeschik K H, Schafer H, Remschmidt H, Pirke K M, Hebebrand J. Evaluation of a Cys23Ser mutation within the human 5-HT2C receptor gene: no evidence for an association of the mutant allele with obesity or underweight in children, adolescents and young adults.  Life Sci. 1997;  61 PL9-16
• 21 Masellis M, Basile V, Meltzer H Y, Lieberman J A, Sevy S, Macciardi F M, Cola P, Howard A, Badri F, Nothen M M, Kalow W, Kennedy J L. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients.  Neuropsychopharmacology. 1998;  19 123-32
• 22 Murad I, Kremer I, Dobrusin M, Muhaheed M, Bannoura I, Muller D J, Schulze T G, Reshef A, Blanaru M, Gathas S, Tsenter V, Rietschel M, Belmaker R H, Maier W, Ebstein R P. A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia.  Am J Med Genet. 2001;  105 236-8
• 23 Murphy D L, Lesch K P, Auklah C S, Pigeott T A. Serotonin-selective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans.  Pharmacol Rev. 1991;  43 527-52
• 24 Murphy D L, Anndrews A M, Wichems C H, Li Q, Tohda M, Greenberg B. Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs.  J Clin Psychiatry. 1998;  59 (suppl 15) 4-12
• 25 Oruc L, Verheyen G R, Furac I, Jakovljevi I, Ivezi S, Raeymaekers P, Van Broeckhoven C. Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder.  Am J Med Genet. 1997;  74 504-506
• 26 Quested D J, Whale R, Sharpley A L, McGavin C L, Crossland N, Harrison P F, Cowen P F. Allelic variation in the 5-HT_2C receptor (HTR2C) and functional responses to the 5-HT_2C receptor agonist, m-chlorophenylpiperazine.  Psychopharmacology. 1999;  144 306-307
• 27 Rietschel M, Naber D, Fimmers R, Möller H J, Propping P, Nöthen M M. Efficacy an side-effects of clozapine not associated with variation in the 5-HT_2C receptor.  Neuroreport. 1997;  8 1999-2003
• 28 Samochowiec J, Smolka M, Winterer G, Rommelspacher H, Schmidt L G, Sander T. Association analysis between a Cys23ser substitution polymorphism of the human 5-HT2C receptor gene and neuronal hyperexcitability.  Am J Med Genet. 1999;  88 126-130
• 29 Sodhi M S, Arranz M J, Curtis D, Ball D M, Sham P, Roberts G W, Price J, Collier D A, Kerwin R. Association between clozapine response and allelic variation in the 5-HT2C receptor gene.  Neuroreport. 1995;  7 169-72
• 30 Su T P, Schmidt P J, Danaceau M, Murphy D L, Rubinow D R. Effect of menstrual cycle phase on neuroendocrine and behavioral responses to the serotonin agonist m-chlorophenylpiperazine in women with premenstrual syndrome and controls.  J Clin Endocrinol Metab. 1997;  82 1220-1228
• 31 Van de Kar L D. 5-HT receptors involved in the regulation of hormone secretion. In Baumgarten HG, Göthert M, editors Serotonergic Neurons and 5-HT Receptors in the CNS. Berlin; Springer 1997: pp. 537-562
• 32 Van Praag H M, Asnis G M, Kahn R S, Brown S L, Korn M, Friedman J M, Wetzler S. Monoamines and abnormal behaviour. A multi-aminergic perspective.  Br J Psychiatry. 1990;  157 723-34