Serotonin transporter gene (SLC6A4) variation and sensory processing sensitivity-Comparison with other anxiety-related temperamental dimensions.

BACKGROUND: The short (s) allele of the 5-HTTLPR polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene SLC6A4 has previously been associated with anxiety-related personality dimensions. However, this relationship has not been confirmed in all studies and may be modified by environmental circumstances and/or psychiatric illness. This study examined whether the temperamental trait sensory processing sensitivity (SPS), characterized by increased responsivity to environmental stimuli, is related to 5-HTTLPR/rs25531 genotype. METHODS: 5-HTTLPR and rs25531 genotypes, level of SPS, self-reported Revised NEO Personality Inventory (NEO-PI-R) and Temperament and Character Inventory (TCI) personality profiles, and symptoms of psychological distress (SCL-90R Global Severity Index) were determined for 405 healthy volunteers. RESULTS: Sensory processing sensitivity was highly correlated with the anxiety-related dimensions of the NEO-PI-R and the TCI models of personality, Neuroticism, and Harm Avoidance, respectively. However, the level of SPS was not associated with the combined 5-HTTLPR and rs25531 s'/s' genotype. Neuroticism and Harm Avoidance were also not associated with 5-HTTLPR/rs25531 s'/s' genotype. Correcting for symptoms of psychological distress had no effect on the relationships between personality and genotype. CONCLUSION: The level of SPS was not associated with serotonin transporter gene variation. Further, combined 5-HTTLPR and rs25531 genotype was not associated with other anxiety-related dimensions.

Simultaneous polysubstance use among Danish 3,4-methylenedioxymethamphetamine and hallucinogen users: combination patterns and proposed biological bases.

OBJECTIVE: To describe patterns of simultaneous polysubstance use (SPU) among Danish 3,4-methylenedioxymethamphetamine (MDMA) ("Ecstasy") and hallucinogen users. METHODS: A cross-sectional survey of 98 active MDMA and/or hallucinogen users recruited through homepage advertisements, flyers, and word of mouth in Denmark. Lifetime and recent substance use and SPU at last recalled use was described by structured interviews. Hair samples from a subset of participants were analyzed for MDMA. RESULTS: The participants had used an average of 12.6 (95% confidence interval: 11.7-13.4) psychoactive substances during their lifetime. SPU was prevalent among MDMA, d-lysergic acid diethylamide (LSD), and psilocybin users, in particular with alcohol and cannabis. Among MDMA users, 69% had combined MDMA with amphetamines, 56% with hallucinogens, and 47% with cocaine. At last recalled use, MDMA was taken with 2.1 ± 1.2 substances in 32 different combinations. The participants preferred specific drug combinations and named several, which in their experience enhanced or counteracted each other. Alcohol and cannabis were typically used before, during, and after MDMA, LSD, and psilocybin, whereas amphetamines were predominantly taken before these substances. When LSD was combined with MDMA, the majority took MDMA after LSD. CONCLUSIONS: Simultaneous polysubstance use was common among Danish MDMA and hallucinogen users, and patterns of preferred substance combinations were evident.

A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans.

Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/- 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U-shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand.

Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice.

The 5-HT(4) receptor is a new potential target for antidepressant treatment and may be implicated in the pathogenesis of depression. This study investigated differences in 5-HT(4) receptor and 5-HT transporter (5-HTT) binding by quantitative autoradiography of [(3)H]SB207145 and (S)-[N-methyl-(3)H]citalopram in two murine models of depression-related states, olfactory bulbectomy and glucocorticoid receptor heterozygous (GR(+/-)) mice. The olfactory bulbectomy model is characterized by 5-HT system changes, while the GR(+/-) mice have a deficit in hypothalamic-pituitary-adrenal (HPA) system control. The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen. Among post hoc analyzed regions, there was a 14% decrease in 5-HT(4) receptor binding in the olfactory tubercles. The 5-HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus. In comparison, GR(+/-) mice had increased 5-HT(4) receptor (11%) binding in the caudal caudate putamen and decreased 5-HTT binding in the frontal caudate putamen but no changes in dorsal and ventral hippocampus. Post hoc analysis showed increased 5-HT(4) receptor binding in the olfactory tubercles of GR(+/-) mice. In conclusion, we have found brain regional changes in 5-HT(4) receptor and 5-HTT transporter binding in two murine models of depression-related states, characterized by 5-HT and HPA system changes.

The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration.

The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.