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Psychopharmacology group

The psychopharmacology group is devoted to clinical and preclinical research into the fields of psychopharmacology and biological psychiatry. Below is provided a brief summary of current projects and previous achievements.

Group members: Britt-Marie Benbow, Gunilla Bourghardt, Johan Fredrik Emilsson, Elias Eriksson (group leader), Melker Hagsäter, Fredrik Hieronymus, Alexander Lisinski, Jakob Näslund, Robert Pettersson, Ann-Christin Reinhold, Erik Studer.

Previous PhD students: Maria Carlsson, Agneta Ekman, Charlotta Sundblad, Christer Nilsson, Marie Olsson, Hoi-Por Ho, Jonas Melke, Lars Westberg, Monika Hellstrand, Jessica Bah, Kristina Annerbrink, Susanne Henningsson.

Serotonin reuptake inhibitors (SRIs): indications and mechanism of action

Previous results:

We were the first to show that serotonergic antidepressant clomipramine is superior to the less serotonergic drug imipramine for the treatment of panic disorder (prevalence: 5%), hence challenging the conventional wisdom at the time that the beneficial effects of antidepressants in this condition is due to their influence on noradrenalin (rather than serotonin), and paving the way for the introduction in Europe of clomipramine for panic disorder (which was the first time ever an antidepressant was approved for this indication).

We were also the first to show that premenstrual dysphoric disorder (PMDD) (prevalence among women: 5%) may be treated with serotonin reuptake inhibitors (SRIs), that these are superior to non-serotonergic antidepressants for this condition, and that SRIs in PMDD display a surprisingly short onset of action, enabling intermittent administration. Today SRIs are generally regarded as first line treatment for PMDD worldwide.

Based e.g. on the impressive efficacy of SRIs for premenstrual irritability, the response rate being 90%, we have suggested that a major physiological role of serotonin may be to dampen sex steroid-driven behaviour. In this vein, we have published e.g. on the influence of SRIs on sexual behaviour in rodents and humans, on the influence of SRIs on oestrus cycle-related aggression in female rats, on sex differences and the influence of sex steroids on serotonergic neurotransmission in rodents. Our group was also the first to report that bulimia nervosa may be associated with enhanced androgen levels, and that an androgen antagonist reduces the symptoms of this disorder as effectively as does an SRI.

We have also published extensively on the influence of SRIs on respiration in rodents, and suggested that the beneficial effect of these drugs in panic disorder may partly be the consequence of their modulating effects on breathing.

Current studies:

In ongoing studies we are exploring the influence of an SRI or placebo on cerebrospinal fluid biomarkers, various neuropsychological tests reflecting emotionality (including the startle paradigm), markers of inflammation, respiration and heart rate variability in healthy subjects and in patients with depression, panic disorder or premenstrual dysphoric disorder.

In ongoing animal experiments, we are addressing the as yet unanswered question if serotonin should be regarded mainly as an anxiogenic or an anxiety-reducing transmitter, and the equally unanswered question if the influence of long-term administration of an SRI on serotonergic output is best explained as an increase or a reduction. A second aim of these studies, which are conducted using normal and transgenic rodents, respectively, and in which behavioural and biochemical assessments are combined, is to shed further light on the interplay between sex steroids and serotonergic neurotransmission, and to pinpoint the receptor subtypes mediating the inhibitory influence of serotonin on aggression and sexual activity.

Genetic association studies

Previous results:

We have to some extent contributed to the current knowledge on of how serotonin-related genes may influence inter-individual differences in behaviour. We were thus one of the first groups to replicate the finding by Lesch and co-workers that a polymorphism in the serotonin transporter gene may be associated with anxiety-related personality traits7. More importantly, we were the first to show an association between a polymorphism in the 5HT2C receptor and low body weight in women (most of which had anorexia nervosa): this finding has now been replicated in several independent studies. Our finding, based on two independent populations, that a rare polymorphism in the gene coding for the 5HT3 receptor is associated with anxiety has been replicated and also gained support from a recent study showing this polymorphism to influence brain activity following fearful stimuli. Moreover, in a recent study we have found very strong associations between premenstrual dysphoria and three serotonin-related genes, i.e. the gene encoding GATA 2 (=a transcription factor of importance for the early development of serotonergic neurons), the gene encoding tryptophan hydroxylase II and the the gene encoding 5HT3 receptor. We have also – in collaboration with Mats Fredriksson and Tomas Furmark at Uppsala University – obtained support for an influence of polymorphisms in serotonin-related genes on amygdala activity, and on proneness to respond to placebo, in patients with social phobia.

We have recently been the first to reveal an association between polymorphisms in the BDNF gene and serotonin transmission in the human brain as assessed using PET (together with professor Lars Farde). This finding is in excellent agreement with studies in rat showing BDNF to exert a profound influence on serotonergic transmission (and vice versa).

In a recent association study (published in PNAS), that has received vast attention both in scientific magazines and in the lay press, we have shown an intriguing association between a polymorphism in the vasopressin receptor gene and gender-dependent pair-bonding behaviour in humans (which is in line with what has previously been reported for voles). We have also reported on associations between polymorphisms in sex steroid-related genes and various aspects of behaviour. In a recent, unpublished study, we have detected a hitherto unknown association between a polymorphism in the orexin gene and panic disorder that is of particular interest given independent as yet unpublished observations from a US group suggesting orexin to mediate the anxiogenic effects of sodium lactate, hence playing a key role for panic disorder. Moreover, we have previously reported on an association between panic disorder and an angiotensin-related gene, which has been replicated, and which is also in line with animal experiments suggesting angiotensin to be involved in this disorder.

Ongoing studies:

We are pursuing our studies regarding the influence of polymorphisms in genes regulating serotonergic transmission, BDNF activity and sex steroid signalling, respectively, on various behavioural traits as well as on different biomarkers and endophenotypes.

Receptor studies

Previous results:

We were the first to show that haloperidol may act not merely as a neutral antagonist, but as an inverse agonist, vs dopaminergic D2 receptors. This was in fact also the first study ever showing that G-protein-coupled receptors could be the subject of inverse agonism.

We have also published extensively on the relationship between dopamine D2 receptor responsiveness and the intrinsic efficacy displayed by full and partial agonists. To this end, we were the first to show prolactin-regulating D2 receptors to be activated rather than antagonized by partial D2 agonists.

Ongoing studies:

In ongoing studies, we are exploring to what extent electroconvulsive therapy influences glutamatergic NMDA receptors and dopaminergic D2 receptors, respectively.

Selected publications

Sundblad C, Hedberg MA, Eriksson E: Clomipramine administered during the late luteal phase reduces the symptoms of premenstrual syndrome: a placebo-controlled trial. Neuropsychopharmacology, 9: 133-145 (1993).

Eriksson E, Alling C, Andersch B, Andersson K, Berggren U: Cerebrospinal fluid levels of monoamine metabolites: A preliminary study of their relation to menstrual cycle phase, sex steroids and pituitary hormones in healthy women and in women with premenstrual syndrome. Neuropsychopharmacology, 11: 201-213 (1994).

Eriksson E, Hedberg A, Andersch B, Sundblad C: The serotonin reuptake inhibitor paroxetine is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome. Neuropsychopharmacology, 12: 167-176 (1995).

Wikander I, Roos T, Stakkestad A, Eriksson E: Sodium lactate elicits a rapid increase in blood pressure in wistar rats and spontaneously Hypertensive rats: Effect of pretreatment with the antipanic drugs clomipramine and alprazolam. Neuropsychopharmacology, 12: 245-250 (1995).

Nilsson C, Ekman A, Hellstrand M, Eriksson E: Inverse agonism at dopamine D2 receptors: Haloperidol induced prolactin release from GH4C1 cells transfected with the human D2 receptor is antagonized by R (-)-n-propylnorapomorphine, raclopride, and phenoxybenzamine. Neuropsychopharmacology, 15: 53-61 (1996).

Vega Matuszczyk J, Larsson K, Eriksson E: Subchronic administration of fluoxetine impairs estrous behavior in intact female rats. Neuropsychopharmacology, 19: 492-498 (1998).

Eriksson E, Engberg G, Bing O, Nissbrandt H: Effects of mCPP on the extracellular concentrations of serotonin and dopamine in rat brain. Neuropsychopharmacology, 20: 287-296 (1999).

Ho H-P, Olsson M, Westberg L, Melke J, Eriksson E: The serotonin reuptake inhibitor fluoxetine reduces sex steroid-related aggression in female rats: An animal model of premenstrual irritability? Neuropsychopharmacology, 24: 502-510 (2001).

Westberg L, Bah J, Råstam M, Gillberg C, Wentz E, Melke J, Hellstrand M, Eriksson E: Association between a polymorphism of the 5-HT2C receptor and weight loss in teenage girls. Neuropsychopharmacology, 26: 789-793 (2002).

Olsson M, Ho H-P, Thylefors J, Eriksson E: Intravenous infusion of sodium lactate induces hyperventilation in Wistar rats. Neuropsychopharmacology, 27: 85-91 (2002).

Westberg L, Melke J, Landén M, Nilsson S, Baghaei F, Rosmond R, Jansson M, Holm G, Björntorp P, Eriksson E: Association between a dinucleotide repeat of the estrogen receptor alpha gene and personality traits in women. Molecular Psychiatry, 8: 118-122 (2003).

Olsson M, Ho H-P, Annerbrink K, Hedner J, Eriksson E: Association between estrus cycle related changes in respiration and cycle related aggression in outbred female Wistar rats. Neuropsychopharmacology, 28: 704-710 (2003).

Melke J, Westberg L, Nilsson S, Landén M, Soderstrom H, Baghaei F, Rosmond R, Holm G, Björntorp P, Nilsson L-G, Adolfsson R, Eriksson E: A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women. Arch Gen Psych, 60: 1017-1023 (2003).

Landen M, Nissbrandt H, Allgulander C, Sorvik K, Ysander C, Eriksson E: Placebo-controlled trial comparing intermittent and continuous paroxetine in premenstrual dysphoric disorder. Neuropsychopharmacology, 32:153-163 (2007).

Walum H, Westberg L, Henningsson S, Neiderhiser SM, Reiss D, Igl W, Ganiban JM, Spotts EL, Pedersen NL, Eriksson E, Lichtenstein P: Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans. Proc Nat Acad Sci, 105: 14153-14156 (2008).

Furmark T, Appel L, Henningsson S, Åhs F, Faria V, Linnman C, Pissiota A, Frans Ö, Bani M, Bettica P, Pich EM, Jacobsson E, Wahlsted W, Oreland L, Långström B, Eriksson E, Fredrikson M: A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci, 28: 13066-13074 (2008).

Yonkers KA, O’Brien S, Eriksson E: Premenstrual dysphoric disorder. Lancet, 371: 1200-1210 (2008).

Landén M, Erlandsson H, Bengtsson F, Andersch B, Eriksson E: Short onset of action of a serotonin reuptake inhibitor when used to reduce premenstrual irritability. Neuropsychopharmacology, 34(3): 585-592 (2009).

Henningsson S, Borg J, Lundberg J, Bah J, Lindström M, Ryding E, Träskman-Bendz L, Farde L, Eriksson E. Genetic variation in BDNF is associated with serotonin transporter availability in humans. Biol Psychiatry 66: 477-85 (2009).

Kauppi K, Nilsson LG, Adolfsson R, Eriksson E, Nyberg L. KIBRA polymorphism is related to enhanced memory and elevated hippocampal processing. J Neurosci.31:14218-22 (2011).

Bergman O, Westberg L, Lichtenstein P, Eriksson E, Larsson H. Study on the possible association of brain-derived neurotrophic factor polymorphism with the developmental course of symptoms of attention deficit and hyperactivity. Int J Neuropsychopharmacol. 14:1367-76 (2011).

Bejerot S, Eriksson JM, Bonde S, Carlström K, Humble MB. Eriksson E: The extreme male brain revisited: gender coherence in adults with autism spectrum disease. Br J Psychiatry, in press (2012).

Epperson CN, Steiner M, Hartlage SA, Eriksson E, Schmidt PJ, Jones I, Yonkers KA: Premenstrual Dysphoric Disorder: Evidence for a New Category for DSM-5. Am J Psychiatry, Mar 169: 465-475 (2012).

 

Contact Information

Department of Pharmacology

POB 431, SE-405 30 Gothenburg

Visiting Address:
Medicinaregatan 13

Phone:
+46 31 786 0000 (switchboard)

Fax:
+46 31 786 3164

Page Manager: Lennart Svensson|Last update: 5/16/2016
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