Regional 5-HT1A Research Articles

Nicotine and fluoxetine alter adolescent dopamine-mediated behaviors via 5-HT1A receptor activation.

Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse. Using a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats. Nicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT1A receptor antagonists, WAY-100,635 (100 µg/kg, i.v.) or S-15535 (300 µg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPAT-stimulated [35S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala. Given their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT1A receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT1A activity after nicotine or fluoxetine exposure may potentiate hyper-responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.

Effects of sleep deprivation on the gene expression of 5-serotonin 1A receptor and dopamine 2 receptor in different brain regions of rats

Objective To analyze the influence of sleep deprivation on expression of serotonin receptor 1A(5-HT1A) and dopamine-2 receptor (D2R) gene and to explore the differences between different neurotransmitter pathways involved in sleep regulation through measuring the gene expression of 5-HT1A and D2R in regions of hippocampus, hypothalamus and striatum with different sleep deprivation models. Methods Sleep deprivation was performed to male SD rats of 10-week-old for 24 hours, 48 hours and 72 hours respectively as the experimental group and a control group was taken for comparison. The expressions of 5-HT1A and D2R gene in regions of hippocampus, hypothalamus and striatum were detected through RT-PCR technique to analyze the influence of sleep deprivation on gene expression in different regions. Results Sleep deprivation had a significant effect on the gene expression of 5-HT1A in regions of hippocampus and striatum(F=56.203, P<0.01; F=77.288, P<0.01). The three experimental groups were all superior to the control group and the difference was of statistic significance(P<0.05). In the hippocampus region, the expression quantity of the 72 hours group(0.618±0.054) was superior to that of the 24 hours group and of the 48 hours group(24 hours: 0.404±0.023, P<0.01; 48 hours: 0.455±0.042. P<0.05). In the striatum region, the differences between the 24 hours group(0.413±0.033), the 48 hours group(0.464±0.034) and the 72 hours group(0.610±0.040)were all of statistic significance(all P<0.05). Sleep deprivation had a significant effect on the expression of D2R gene in regions of hippocampus and striatum(F=74.708, P<0.01; F=80.687, P<0.01). The expression quantity of the three experimental groups in regions of hippocampus (24 hours: 0.386±0.027, 48 hours: 0.318±0.014, 72 hours: 0.250±0.010) and striatum(24 hours: 0.396±0.013, 48 hours: 0.349±0.017, 72 hours: 0.260±0.013) were all inferior to the control group. The differences were of statistic significance(all P<0.05). There was a negative correlation between the gene expressions of 5-HT1A and D2R of rats of the three experience groups(all P<0.05). Conclusion For the sleep deprivation rats, the gene expression of 5-HT1A rises while that of D2R falls in regions of hippocampus, hypothalamus, and there is a negative correlation between the expressions of the two genes. Key words: Sleep deprivation; Rat; Serotonin receptor 1A; Dopamine-2 receptor; Gene expression

PW01-155 - Seasonal alterations of serotonin-1A receptor binding in the healthy human brain

ObjectivesSerotonergic neurotransmission plays a key role in seasonal changes of mood and behaviour. Higher serotonin transporter availability in healthy human subjects in times of lesser light has been reported in recent studies. Furthermore, seasonal alterations of postsynaptic serotonin-1A receptors have been suggested by a recent animal study. Following that, this study aimed at identifying seasonal alterations of serotonin-1A receptor binding in the living human brain.MethodsThirty-six healthy, drug-naïve subjects were investigated using PET and the specific tracer [carbonyl-11C]WAY-100635. Regional serotonin-1A receptor binding (5-HT1A BPND) was related to the individual exposure to global radiation. Furthermore, the subjects were divided into two groups depending on individual exposure to global radiation, and the group differences in regional 5-HT1A BPND were determined.ResultsCorrelation analysis controlled for age and gender revealed highly significant positive correlations between regional postsynaptic 5-HT1A BPND and global radiation accumulated for 5 days (r=.32 to .48, p=.030 to .002). Highly significant differences in 5-HT1A BPND binding between subjects with low compared to high exposure to global radiation were revealed (T=-2.63 to -3.77, p .013 to .001). 20% to 30% lower 5-HT1A BPND was found in the subject group exposed to lower amount of global radiation.ConclusionSeasonal factors such as exposure to global radiation influence postsynaptic serotonin-1A receptor binding in various brain regions in healthy human subjects. In combination with seasonal alterations in serotonin turnover and 5-HTT availability revealed in recent studies, our results provide an essential contribution of molecular mechanisms in seasonal changes of human serotonergic neurotransmission.

Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans

The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

Brain Serotonin 1A Receptor Binding in Major Depression Is Related to Psychic and Somatic Anxiety

The anxious phenotype of the 5-HT1A receptor knockout mouse and the anxiolytic properties of 5-HT1A agonists suggest that the 5-HT1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT1A binding. Positron emission tomography with [carbonyl-11C]WAY-100635 was used to estimate regional 5-HT1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT1A BP. Higher psychic (beta >or= .63) and lower somatic (beta <or= -.70) anxiety predicted over 50% of the variance in 5-HT1A BP in multiple cortical regions, but not in amygdala, hippocampus, or autoreceptors of the raphe nuclei. The psychic and somatic anxiety components were not related to depression severity. Comorbid panic disorder was associated with lower cortical and subcortical 5-HT1A BP. The 5-HT1A receptor in the same brain regions has different relationships to psychic anxiety versus somatic anxiety. Lower 5-HT1A BP in panic disorder may be accounted for by higher somatic and lower psychic anxiety. Further study of the pathobiology of these anxiety components may identify distinct therapeutic targets or mechanisms.

Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography.

The augmentation effect of (-)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-11C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.) occupies 5-HT1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The 5-HT1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration. Two hours after pindolol administration, the regional 5-HT1A receptor occupancy was within the range 7-21% in the three subjects. The study confirms that the 5-HT1A-receptor may be a clinically significant target for pindolol.