Espen Walderhaug

Interactive Effects of Sex and 5-HTTLPR on Mood and Impulsivity During Tryptophan Depletion in Healthy People

BACKGROUND Serotonin (5-HT) plays a central role in mood regulation and impulsivity. We studied whether healthy men and women react differently on mood and impulsivity measures during acute tryptophan depletion (ATD). We also studied the relative contribution of a functional length triallelic polymorphism in the promoter region of the serotonin transporter, designated 5-HTTLPR, to the behavioral responses to ATD. METHODS Thirty-nine men and 44 women participated in a randomized, double-blind, parallel group ATD study. Behavioral measures of impulsivity and mood were obtained. RESULTS During ATD, women reported mood reduction and showed a cautious response style, which is commonly associated with depression. Men showed an impulsive response style and did not report mood reduction. The 5-HTTLPR influenced the mood response to ATD in women. CONCLUSIONS Healthy men became more impulsive, whereas healthy women showed mood reduction in response to ATD. This suggests that 5-HT could be one mechanism contributing to the sex differences in the prevalence of mood and impulsivity disorders. The influence of 5-HTTLPR on mood responses in women further substantiates the relevance of this variant in the pathophysiology of at least a subgroup of patients with major depressive disorder.

Serotonin 1B receptor imaging in pathological gambling

Abstract Objectives. Although serotonergic mechanisms have been implicated in pathological gambling (PG), no ligand-based imaging studies have assessed serotonin receptors in individuals with PG. Given its role in substance addictions and its abundance in brain regions implicated in PG, we evaluated serotonin 1B receptors (5-HT1BRs) in PG. Methods. Ten medication-free subjects with PG (mean ± SD age = 36.3 ± 9.4 years, nine men) and ten control comparison (CC) subjects (mean ± SD age = 35.8 ± 9.9 years, nine men) underwent [11C]P943 positron emission scanning on a high resolution research tomograph. Results. 5-HT1BR BPND values were similar in PG and CC subjects (P > 0.1). Among PG subjects, scores on the South Oaks Gambling Screen (SOGS) correlated positively with 5-HT1BR BPND values in the ventral striatum (r = 0.66; P = 0.04), putamen (r = 0.67; P = 0.03) and anterior cingulate cortex (r = 0.73; P = 0.02). Conclusions. These findings provide the first evidence that PG severity in humans is linked to increased levels of 5-HT1BRs in regions previously implicated in functional neuroimaging studies of PG. These findings indicate a potential role for serotonergic function in the ventral striatum and anterior cingulate cortex contributing to problem gambling severity and warrant further studies to investigate whether numbers of available 5-HT1BRs might represent a vulnerability factor for PG or develop in relationship to problem gambling.

A synergic effect between lowered serotonin and novel situations on impulsivity measured by CPT.

Rapid tryptophan depletion studies investigate serotonin using amino acid precursor depletion, which transiently reduces the brain level of serotonin. This study compares the effects of serotonin reduction given on the first test day (when the situation is novel) with the effects of serotonin reduction given on the second test day (when the environment and test battery are familiar). A total of 24 healthy young males were given either active tryptophan depletion or placebo in this randomized cross-over design, while impulsivity was measured by a continuous performance test. The participants showed more impulsive responses and reduced attention during tryptophan depletion, but only when this was given on the first test day when the task was novel. This could be caused by a synergic effect between novel situations and reduced neurotransmission of serotonin.

Age Effects on Serotonin Receptor 1B as Assessed by PET

Previous imaging studies have suggested that there is an age-related decline in brain serotonin (5-hydroxytryptamine) measures in healthy subjects. This paper addresses whether the availability of 5-hydroxytryptamine receptor 1B (5-HT1B) is seen to decrease with aging via PET imaging. Methods: Forty-eight healthy control subjects (mean age ± SD, 30 ± 10 y; age range, 18–61 y; 33 men, 15 women) underwent 11C-P943 scanning on a high-resolution PET tomograph. Regions were examined with and without gray matter masking, the latter in an attempt to control for age-related gray matter atrophy on nondisplaceable binding potential (BPND) as determined by a validated multilinear reference tissue model. Results: 5-HT1B BPND decreased in the cortex at an average rate of 8% per decade without and 9% with gray matter masking. A negative association with age was also observed in all individual cortical regions. Differences in the putamen and pallidum (positive association) were significant after adjustment for multiple comparisons. No sex- or race-related effects on 5-HT1B BPND were found in any regions. Conclusion: These findings indicate that age is a relevant factor for 5-HT1B in the cortex of healthy adults.

Differential conditioned fear response predicts duloxetine treatment outcome in male veterans with PTSD: a pilot study.

This pilot study tested whether posttraumatic stress disorder (PTSD) patients with impaired conditioned fear acquisition were refractory to open-label duloxetine treatment. Patients with a differential conditioned fear response at pre-treatment subsequently demonstrated significant reductions in PTSD symptoms. These data provide initial evidence of a putative biomarker of selective treatment response in PTSD.

The Role of the Aminergic Systems in the Pathophysiology of Bipolar Disorder

Bipolar disorder (BPD) is a major medical and social burden, but little is known about the specific pathophysiology of BPD. The key biogenic amines in the aminergic system include serotonin (5-HT), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh). By analyzing these neurotransmitters, this chapter highlights three hypotheses in the pathophysiology of BPD: the biogenic amine hypothesis, the cholinergic-aminergic balance hypothesis, and the permissive hypothesis. Evidence from select studies of cerebrospinal fluid, postmortem subjects, neuroimaging, genetic factors, and pharmacological agents will be used to reconcile these hypotheses. Possible explanations for discrepancies in these hypotheses are given, and directions for future studies are suggested.

The Relationship Between Mood, Stress, and Tobacco Smoking

The primary addictive substance in tobacco is nicotine (Le Foll and Goldberg, Handb Exp Pharmacol 192:335–367, 2009), although other chemicals also contribute to the reinforcing properties of tobacco smoke (Rose et al, Pharmacol Biochem Behav 23L:289–293, 1985); (Rose and Behm, Pharmacol Biochem Behav 28:305–310, 1987); (Rose and Levin, Br J Addict 86:605–609, 1991); (Rose et al, Pharmacol Biochem Behav 44:891–900, 1993); (Butschky et al, Pharmacol Biochem Behav 50:91–96, 1995); (Gross et al, Pharmacol Biochem Behav 57:159–165, 1997); (Pickworth et al, Nicotine Tob Res 1:357–364, 1999); (Rose et al, Pharmacol Biochem Behav 62:165–172, 1999); (Shahan et al, Psychopharmacology (Berl) 147:210–216, 1999); (Dallery et al, Psychopharmacology (Berl) 165:172–180, 2003); (Rose et al, Pharmacol Biochem Behav 76:243–250, 2003). Nicotine shares the reinforcing and dopamine-stimulating properties with other psychostimulants (Picciotto, Drug Alcohol Depend 51(1–2):165–172, 1998). Nicotine exerts its effect in all humans; however, the abuse potential of tobacco smoking is probably exacerbated in individuals with depression, during high stress and in people exhibiting negative emotions (Picciotto et al, Neuroreport 13(9):1097–1106, 2002). It is therefore of great interest to understand the neurobiological and behavioral effects of nicotine in healthy people and individuals with mood and anxiety disorders, all of which occur to be associated with high rates of nicotine dependence. Molecular imaging using single-photon emission computed tomography and positron emission tomography is currently the most powerful tool to better understand the relationship between nicotine addiction, mood, stress, and cognition; however, we have to acknowledge that this research is still in its infancy.

A sequencing-based survey of functional APAF1 alleles in a large sample of individuals with affective illness and population controls.

Rare apoptosis‐promoting functional variants in the apoptosis protease activating factor 1 (APAF1) gene were recently reported to co‐segregate with major depression in male members of families from Utah. In order to estimate the impact of these variants on risk for major depressive disorder (MDD) in the general population, we surveyed the frequency of the APAF1 putative MDD risk alleles using re‐sequencing in a large sample of northern European and European‐American subjects, including a large number of males with MDD. The E777K and N782T APAF1 variants previously described by Harlan et al. [Harlan et al. (2006) Mol Psychiatry 11(1):76–85] were found at low frequencies in affected individuals and population controls. The C450W and Q465R variants were not detected in any of the 632 subjects sequenced. These results show that the APAF1 variants associated with risk for MDD in the Utah pedigrees are very rare in Northern European and European‐American populations. In addition, the E777K and N782T variants were found at low frequencies both in patients and population controls, suggesting that these variants have limited impact on risk for MDD.