Serotonergic and Noradrenergic Modulation of Emotion Processing by Single Dose Antidepressants

Serotonergic and noradrenergic pathways are the main targets of antidepressants. Their differential effects on emotion processing-related brain activation are, however, to be further characterized. We aimed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task, which was earlier shown to be associated with depressiveness. In a single-blind pseudo-randomized crossover study, 21 healthy subjects (16 subjects finally included in the analysis) participated to ingest a single dose at three time points of either 40 mg citalopram, a selective serotonin-reuptake inhibitor, 8 mg reboxetine, a selective noradrenaline-reuptake inhibitor, or placebo 2–3 h before functional magnetic resonance imaging (fMRI). During fMRI, subjects performed a task comprising the anticipation and perception of pictures of either ‘known'' (positive, negative, neutral) or ‘unknown'' valence (randomly 50% positive or negative). In direct comparison with citalopram and with placebo, reboxetine increased brain activity in the medial thalamus. Citalopram modulated certain prefrontal and insular areas more prominently. Other frontal and parieto-occipital areas were modulated by both drugs. In conclusion, the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas, and a prefrontal and insular focus of serotonergic modulation. These findings could have implications for future selection criteria concerning personalized antidepressant medication in depression.     

Effects of acute tryptophan depletion on neural processing of facial expressions of emotion in humans

Introduction

Acute tryptophan depletion (ATD) temporarily lowers brain serotonin (5-HT) synthesis, and behavioral studies have shown that this alters the processing of facial expressions of emotion.

Materials and methods

The neural basis for these alterations is not known. Therefore, we employed ATD and event-related functional magnetic resonance imaging (fMRI) to examine neural responses during incidental processing of fearful, happy, sad, and disgusted facial expressions. Fourteen healthy male controls (age, 28?±?10) were scanned under both placebo (SHAM) and depletion (ATD) conditions.

Results and discussion

We predicted that ATD would be associated with changes in neural activity within facial emotion-processing networks. We found that serotonergic modulation did not affect performance on the fMRI tasks, but was associated with widespread effects on neural response to components of face processing networks for fearful, disgusted, and happy but not sad expressions across differing intensities.

Conclusion

Hence, the 5-HT system affects brain function (in ‘limbic’ and ‘face processing’ regions) during incidental processing of emotional facial expressions; but this varies with emotion type and intensities.     

Greater risk sensitivity of dorsolateral prefrontal cortex in young smokers than in nonsmokers

Rationale

Despite a national reduction in the prevalence of cigarette smoking, ~19 % of the adult US population persists in this behavior, with the highest prevalence among 18–25-year-olds. Given that the choice to smoke imposes a known health risk, clarification of brain function related to decision-making, particularly involving risk-taking, in smokers may inform prevention and smoking cessation strategies.

Objectives

This study aimed to compare brain function related to decision-making in young smokers and nonsmokers.

Methods

The Balloon Analogue Risk Task (BART) is a computerized risky decision-making task in which participants pump virtual balloons, each pump associated with an incremental increase in potential payoff on a given trial but also with greater risk of balloon explosion and loss of payoff. We used this task to compare brain activation associated with risky decision-making in smokers (n?=?18) and nonsmokers (n?=?25), while they performed the BART during functional magnetic resonance imaging (fMRI). The participants were young men and women, 17–21 years of age.

Results

Risk level (number of pumps) modulated brain activation in the right dorsolateral and ventrolateral prefrontal cortices more in smokers than in nonsmokers, and smoking severity (Heaviness of Smoking Index) was positively related to this modulation in an adjacent frontal region.

Conclusions

Given evidence for involvement of the right dorsolateral and ventrolateral prefrontal cortices in inhibitory control, these findings suggest that young smokers have a different contribution of prefrontal cortical substrates to risky decision-making than nonsmokers. Future studies are warranted to determine whether the observed neurobiological differences precede or result from smoking.     

Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging

Rationale

The majority of psychoactive compounds, including antidepressants in clinical practice, were discovered largely by serendipity. The underlying neuropharmacological mechanisms of action of these compounds leading to resolution of depressive symptomatology are targets of the current research. Pharmacological magnetic resonance imaging (phMRI), a rapidly developing advancement of blood oxygenation level dependent (BOLD) contrast offers the potential to localize the regional sites of action in the CNS.

Objective

Acute and chronic effects of the clinically effective selective serotonin reuptake inhibitor (SSRI) citalopram were examined for changes in BOLD contrast using phMRI in rats. To pharmacologically characterize the specific involvement of the 5-HT_1A receptors, citalopram was co-administered with a highly selective 5-HT_1A receptor antagonist WAY100635.

Results

Acute citalopram treatment (10 and 20?mg/kg i.p.) produced a widespread and dose-dependent activation throughout the whole brain. Following 14?days of chronic daily administration of citalopram (20?mg/kg i.p.), localized effects were observed; regions integral in the therapeutic antidepressant effects included the hypothalamus, hippocampus, and cortical regions, suggesting desensitization of serotonergic receptors in the midbrain contributing to elevated levels of 5-HT. Co-administration with WAY100635 (0.3?mg/kg s.c.) increased BOLD activation in the frontal cortex and decreased BOLD contrast in the hypothalamus, hippocampus, and hindbrain structures.

Conclusion

The present findings highlight the adaptive nature of responses to citalopram which exhibits regional and pharmacological specificity. These findings translate well to the clinical findings and suggest that this approach may offer the opportunity to develop more efficacious antidepressants with a faster clinical response.     

Chronic therapy with citalopram decreases regional cerebral glucose utilization in OBX, and not sham-operated, rats: an autoradiographic study

Rationale

Chronic treatment with the selective serotonin reuptake inhibitor, citalopram, normalizes several behavioral and neurochemical abnormalities in the olfactory bulbectomized (OBX) rat model of depression.

Objective

To assess the changes in regional cerebral glucose utilization (rCGU) following chronic treatment with citalopram in OBX and sham-operated rats.

Methods

Male Sprague Dawley rats (160–190 g) were used. Two weeks following the surgeries, the rats were implanted with osmotic minipumps which delivered 10 mg/kg/day of citalopram (the sham-CTP and OBX-CTP groups) or saline (to the sham-SAL and OBX-SAL groups) for 2 weeks. Following the treatment, the rates of rCGU were determined in 43 brain regions using 2-[¹⁴C]deoxyglucose (2-[¹⁴C]DG) autoradiography.

Results

The general linear model statistical analysis revealed significantly lower rCGU in the OBX-SAL group compared to the sham-SAL group in the medial prefrontal cortex and the median forebrain bundle. The sham-CTP group had significantly lower rCGU relative to the sham-SAL group in the medial prefrontal cortex. The OBX-CTP group had significantly lower rCGU than the OBX-SAL group in the anterior olfactory nucleus, orbitofrontal cortex, frontal cortex, anterior cingulate cortex, visual cortex, and substantia nigra—pars reticulata. The rCGU in the OBX-CTP group was significantly lower than that in the sham-CTP group in the anterior olfactory nucleus, orbitofrontal cortex, visual cortex, and substantia nigra—pars reticulata.

Conclusion

The results imply that chronic citalopram treatment, shown previously to result in behavioral normalization in OBX rats, establishes a new pattern of rCGU, rather than normalizing it to the pattern of the sham-CTP rats.     

Adverse effects from antidepressant treatment: randomised controlled trial of 601 depressed individuals

Rationale

Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment.

Objectives

To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment.

Methods

Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation.

Results

Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p?=?0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p?=?0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants.

Conclusions

The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects.     

Involvement of serotonin 5-HT3 receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain

Rationale

Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression.

Objectives

This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect.

Methods

Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats.

Results

Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E _max?=?141?±?13 %) and simultaneously decreased NA in the PFC (E_max?=??46?±?7 %). In the local presence into the LC of the α₂-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (E_max?=?157?±?25 %) and PFC (E_max?=?175?±?24 %). Local citalopram (0.1–100 μM) into the LC induced NA increase in the LC (E_max?=?210?±?25 %) and decrease in the PFC (E_max?=??38?±?9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT₃ receptor antagonist MDL72222 (1 μM) but not the 5-HT_1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (E_max?=?158?±?26 %). Local citalopram into the PFC enhanced NA (E_max?=?376?±?18 %) in the area, which was prevented by MDL72222.

Conclusions

The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT₃ receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT₃ receptors and somatodendritic α₂-adrenoceptors in the LC play an important role in the global effect of SSRIs.     

Alcohol attenuates amygdala–frontal connectivity during processing social signals in heavy social drinkers

Rationale

Convergent evidence shows that alcohol exerts its effects on social behavior via modulation of amygdala reactivity to affective stimuli. Given that affective processing involves dynamic interactions between the amygdala and the prefrontal cortex (PFC), alcohol’s effects are likely to extend beyond regional changes in brain activity to changes that manifest on a broader functional circuit level.

Objective

The current study examines alcohol’s effects on functional connectivity (i.e., "coupling") between the amygdala and the PFC during the processing of socio-emotional stimuli using functional magnetic resonance imaging (fMRI).

Methods

In a randomized, double blind, placebo-controlled, within-subjects cross-over design, 12 heavy, social drinkers performed an fMRI task designed to probe amygdala response to socio-emotional stimuli (angry, fearful, and happy faces) following acute ingestion of alcohol or placebo. Functional connectivity between the amygdala and PFC was examined and compared between alcohol and placebo sessions using a conventional generalized psychophysiological interaction (gPPI) analysis.

Results

Relative to placebo, alcohol reduced functional coupling between the amygdala and the right orbitofrontal cortex (OFC) during processing of both angry and fearful faces. Alcohol also reduced functional coupling between the amygdala and left OFC during processing of happy faces.

Conclusions

These preliminary findings suggest that alcohol’s effects on social behavior may be mediated by alternations in functional connectivity between the amygdala and OFC during processing of emotional faces.     

Evidence for modulation of facial emotional processing bias during emotional expression decoding by serotonergic and noradrenergic antidepressants: an event-related potential (ERP) study

RATIONALE: Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing such that perceptual bias is shifted away from negative and towards positive emotional material. However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown. OBJECTIVE: The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with 'structural encoding' (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli. MATERIALS AND METHODS: This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg). RESULTS: Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP). CONCLUSIONS: Citalopram and reboxetine have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli.     

Neural substrates of acupuncture in the modulation of cravings induced by smoking-related visual cues: an FMRI study

Rationale

Cue reactivity is a key factor in modulating motivational and goal-directed behaviors associated with compulsive drug intake and relapse. Smoking-associated cues produce smoking urges and cravings and are accompanied by the activation of brain regions involved in attention, motivation, and reward.

Objectives

We investigated whether acupuncture ameliorates cravings induced by smoking-related visual cues, and we explored the neural mechanisms underlying the effects of acupuncture on modulating smoking urges.

Methods

After 36 h of smoking abstinence, 25 right-handed male smokers underwent fMRI, during which smoking-related and neutral visual cues were presented. Twelve subjects were treated with real acupuncture (RA) at HT7 and 13 subjects received sham acupuncture (SA). During the scanning sessions, craving scores to smoking-related visual cues were assessed before and after RA or SA treatment. The differences in brain responses to smoking vs. neutral cues after treatment between the RA and SA groups were detected using three-way ANOVAs (Cue × Session × Group).

Results

After treatment, the craving scores were significantly decreased in the RA group, as compared to the SA group. When we explored the neural substrates of acupuncture on the modulation of cravings induced by smoking cues, significant differences were found in the medial prefrontal cortex, the premotor cortex, the amygdala, the hippocampus, and the thalamus.

Conclusions

These findings suggest that acupuncture alleviates cue-induced cravings through the regulation of activity in brain regions involved in attention, motivation, and reward relative to craving scores in the initial abstinence phase.     

Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission

Rationale

Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induced hyperlocomotion. The mechanism for the antipsychotic effect of mGlu2/3 receptor agonists was studied in a hypoglutamatergic model, but not a hyperdopaminergic model.

Objectives

To study the mechanism for the antipsychotic effect of the agonist in the hyperdopaminergic model, this study examined the effects of the selective mGlu2/3 receptor agonist MGS0028 on methamphetamine-induced hyperlocomotion and the increases in extracellular levels of serotonin, dopamine, noradrenaline, and glutamate in the prefrontal cortex and nucleus accumbens of mice.

Results

Systemic administration of MGS0028 attenuated methamphetamine-induced hyperlocomotion in a dose-dependent manner. Microdialysis studies showed that MGS0028 significantly inhibited methamphetamine-induced increases in the extracellular serotonin, but not dopamine and noradrenaline, levels in the prefrontal cortex, and it did not affect methamphetamine-induced increases in the extracellular amine levels in the nucleus accumbens. Methamphetamine did not affect the glutamate release in the prefrontal cortex and nucleus accumbens. Local application of MGS0028 into the prefrontal cortex also attenuated methamphetamine-induced hyperlocomotion and increases in the extracellular serotonin levels in the prefrontal cortex. Moreover, MGS0028 did not affect methamphetamine-induced hyperlocomotion in the mice pretreated with p-chlorophenylalanine, a serotonin synthesis inhibitor.

Conclusions

Activation of prefrontal mGlu2/3 receptors inhibits the psychomotor stimulant effect of methamphetamine in mice, and the prefrontal serotonergic system may be involved in this effect. The finding provides evidence that prefrontal mGlu2/3 receptors are functionally coupled with the serotonergic system.     

A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?

Introduction

The prefrontal cortex (PFC) receives serotonergic input from the dorsal raphe nucleus of the brainstem, as well as noradrenergic input from another brainstem nucleus, the locus coeruleus. A large number of studies have shown that these two neurotransmitter systems, and drugs that affect them, modulate the functional properties of the PFC in both humans and animal models.

Results

Here I examine the hypothesis that serotonin (5-HT) plays a general role in activating the PFC, whereas norepinephrine (NE) plays a general role in deactivating this brain region. In this manner, the two neurotransmitter systems may have opposing effects on PFC-influenced behavior. To assess this hypothesis, three primary lines of evidence are examined comprising the effects of 5-HT and NE on impulsivity, cognitive flexibility, and working memory.

Discussion

While all of the existing data do not unequivocally support the activation/deactivation hypothesis, there is a large body of support for it.     

Differential responses to anticipation of reward after an acute dose of the designer drugs benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) alone and in combination using functional magnetic resonance imaging (fMRI)

Rationale

Functional magnetic resonance imaging (fMRI) studies have reported increased activation of the mesolimbic system in response to anticipation of rewarding stimuli. The anticipation of uncertain outcomes evokes activation in the amygdala, orbitofrontal cortex, inferior frontal gyrus and insula. Drugs known to effect dopaminergic and serotonergic neurons also alter regional activation.

Objectives

Benzylpiperazine (BZP) and/or trifluoromethylphenylpiperazine (TFMPP) have been recreationally used worldwide for more than a decade. BZP affects mainly dopaminergic neurons, while TFMPP has serotonergic effects.

Methods

We investigated the effects of an acute dose of BZP, TFMPP or a combination of BZP and TFMPP on the anticipation of reward in a double-blind, placebo-controlled, crossover study using fMRI. An event-related gambling paradigm was completed by healthy controls 90 min after taking an oral dose of either BZP (200 mg), TFMPP (either 50 or 60 mg), BZP + TFMPP (100?+?30 mg) or placebo.

Results

After giving BZP, the anticipation of a $4 reward decreased the activation of the inferior frontal gyrus, insula and occipital regions in comparison to placebo. TFMPP increased the activation of the putamen but decreased the activity in the insula relative to placebo. When BZP and TFMPP were given in combination, activation of the rolandic operculum occurred. The magnitude of reward also affected neural correlates.

Conclusion

We propose that the effects of BZP and TFMPP on dopaminergic and serotonergic circuitry, respectively, reflect regional changes. The dopaminergic effects of BZP appear to increase positive arousal and subsequently reduce the response to uncertainty, while TFMPP appears to alter the response to uncertainty by increasing emotional responses.     

Evaluation of the emotional phenotype and serotonergic neurotransmission of fatty acid amide hydrolase-deficient mice

Rationale

By enhancing brain anandamide tone, inhibitors of fatty acid amide hydrolase (FAAH) induce anxiolytic-like effects in rodents and enhance brain serotonergic transmission. Mice lacking the faah gene (FAAH^?/?) show higher anandamide levels. However, their emotional phenotype is still debated and their brain serotonergic tone remained unexplored.

Objectives and methods

In this study, we tested FAAH^?/? mice in the social interaction and the open field tests performed under different lighting conditions (dim and bright) since variations of the experimental context were proposed to explain opposite findings. Moreover, by microdialysis performed under dim light, we analyzed their serotonergic transmission in frontal cortex (FC) and ventral hippocampus (vHIPP).

Results

In both light conditions, FAAH^?/? mice showed reduced emotionality, compared to wt controls, as suggested by the increased rearing and reduced thigmotaxis displayed in the open field and by the longer time spent in social interaction. Basal serotonergic tone was higher in the FC of mutant mice as compared to control mice, while no difference was observed in the vHIPP. K⁺-induced depolarization produced similar increases of serotonin in both areas of both genotypes. An acute treatment with the CB1 antagonist rimonabant completely abolished the emotional phenotype of FAAH^?/? mice and prevented the K⁺-stimulated release of serotonin in their FC and vHIPP, without producing any effect in wt mice.

Conclusions

Our results support the role of FAAH in the regulation of emotional reactivity and suggest that anandamide-mediated hyperactivation of CB1 is responsible for the emotional phenotype of FAAH^?/? mice and for their enhanced serotonergic tone.     

Sibutramine promotes amygdala activity under fasting conditions in obese women

Rationale

Sibutramine, a centrally-acting selective monoamine reuptake inhibitor, has been used as an appetite suppressant drug in obesity.

Objectives

To gain insight into the central nervous actions of sibutramine, brain responses to pictures of food items after sibutramine vs placebo application were assessed by functional magnetic resonance imaging (fMRI) in obese women.

Methods

In a randomized double-blind crossover design, 10 healthy obese women (BMI 31.8–39.9?kg/m²) received 15?mg/d of sibutramine vs placebo for 14?d. Obese participants, and a group of 10 age-matched normal weight controls, viewed pictures of food items and control objects in hungry and satiated states while lying in the MR scanner. The paradigm followed a block design. In obese participants, fMRI measurements were conducted prior and after two weeks of daily sibutramine or placebo administration, whereas control participants were scanned only at one point in time.

Results

Upon food item presentation, obese participants showed increased brain activity in areas related to emotional and reward processing, perceptual processing, and cognitive control as compared to normal weight controls. Sibutramine exerted a divergent satiety-dependent effect on amygdala activity in obese participants, increasing activity in the hungry state while decreasing it under conditions of satiation.

Conclusions

Our results demonstrate a modulatory influence of sibutramine on amygdala activity in obese women which may underlie the appetite suppressant effects of the drug.     

Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors‘ Behavioral and Neurochemical Effects

Backgound:

The neurobiological changes underlying depression resistant to treatments remain poorly understood, and failure to respond to selective serotonin reuptake inhibitors may result from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine.

Methods:

Using behavioral (tail suspension test) and neurochemical (in vivo microdialysis, Western-blot analysis) approaches, here we report that antidepressant responses to selective serotonin reuptake inhibitors (citalopram or paroxetine) are abolished in mice unable to synthesize histamine due to either targeted disruption of histidine decarboxylase gene (HDC^-/-) or injection of alpha-fluoromethylhistidine, a suicide inhibitor of this enzyme.

Results:

In the tail suspension test, all classes of antidepressants tested reduced the immobility time of controls. Systemic reboxetine or imipramine reduced the immobility time of histamine-deprived mice as well, whereas selective serotonin reuptake inhibitors did not even though their serotonergic system is functional. In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT₁/5-HT₂ receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin. CREB phosphorylation, which is implicated in the molecular mechanisms of antidepressant treatment, was abolished in histamine-deficient mice treated with citalopram. The CREB pathway is not impaired in HDC^-/- mice, as administration of 8-bromoadenosine 3’, 5’-cyclic monophosphate increased CREB phosphorylation, and in the tail suspension test it significantly reduced the time spent immobile by mice of both genotypes.

Conclusions:

Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses.     

Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control

Rationale

Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic α₂ adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established.

Objectives

This study tested the effect of the postsynaptic α₂ adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex.

Methods

Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, cross-over design.

Results

Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response-related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions.

Conclusions

These results provide evidence that guanfacine stimulation of postsynaptic α₂ adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the α₂ adrenoceptor agonist treatment of attention-deficit hyperactivity disorder.     

Rasgrf2 controls noradrenergic involvement in the acute and subchronic effects of alcohol in the brain

Rationale

Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2^?/? mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT).

Objective

In order to further investigate how Rasgrf2 modifies the acute and subchronic effects of alcohol in the brain, we investigated its effects on the noradrenergic and serotonergic systems.

Methods

We measured noradrenaline and serotonin activity in the brain by in vivo microdialysis and RNA expression by chip analysis and RT-PCR after acute and sub-chronic alcohol exposure in Rasgrf2^?/? and WT mice.

Results

In vivo microdialysis showed a significantly reduced noradrenergic response and an absent serotonergic response in the nucleus accumbens (NAcc) and caudate putamen (CPu) after an alcohol challenge in Rasgrf2^?/? mice. A co-expression analysis showed that there is a high correlation between Rasgrf2 and α2 adrenoceptor RNA expression in the ventral striatum in naïve animals. Accordingly, we further assessed the role of Rasgrf2 in the response of the noradrenergic system to subchronic alcohol exposure. A decrease in β1 adrenoceptor gene expression was seen in Rasgrf2^+/+, but not Rasgrf2^?/? mice following alcohol exposure. Conversely, alcohol resulted in a decrease in both β2 and α2 adrenoceptor gene expression in knockout but not WT Rasgrf2 mice.

Conclusions

These findings suggest that adaptations in the noradrenergic system contribute to the Rasgrf2 enhanced risk of alcoholism.     

Serotoninergic effects on judgments and social learning of trustworthiness

Rationale

Certain disorders, such as depression and anxiety, to which serotonin dysfunction is historically associated, are also associated with lower assessments of other people's trustworthiness. Serotonergic changes are known to alter cognitive responses to threatening stimuli. This effect may manifest socially as reduced apparent trustworthiness of others. Trustworthiness judgments can emerge from either direct observation or references provided by third parties.

Objective

We assessed whether explicit judgments of trustworthiness and social influences on those judgments are altered by changes within serotonergic systems.

Methods

We implemented a double-blind between-subject design where 20 healthy female volunteers received a single dose of the selective serotonin reuptake inhibitor (SSRI) citalopram (2?×?20 mg), while 20 control subjects (matched on age, intelligence, and years of education) received a placebo. Subjects performed a face-rating task assessing how trustworthy they found 153 unfamiliar others (targets). After each rating, the subjects were told how other subjects, on average, rated the same target. The subjects then performed 30 min of distractor tasks before, unexpectedly, being asked to rate all 153 faces again, in a random order.

Results

Compared to subjects receiving a placebo, subjects receiving citalopram rated targets as less trustworthy. They also conformed more to opinions of others, when others rated targets to be even less trustworthy than subjects had initially indicated. The two effects were independent of negative effects of citalopram on subjective state.

Conclusions

This is evidence that serotonin systems can mediate explicit assessment and social learning of the trustworthiness of others.     

Effects of oxycodone on brain responses to emotional images

Rationale

Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans.

Objective

We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis.

Methods

In a three-session study, healthy adults (N?=?17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks.

Results

Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces.

Conclusions

Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates.