Convergent effects of acute stress and glucocorticoid exposure upon MAO-A in humans.

Monoamine oxidase-A (MAO-A), a key brain enzyme which metabolizes monoamines, is implicated in the pathophysiology of stress-related illnesses, including major depressive disorder, addiction, and violent behavior. Chronic stressors and glucocorticoid-administration typically associate with elevated MAO-A levels/activity. However, the relationship of shorter stress or glucocorticoid exposures and MAO-A levels/activity is not well established. Our objectives are to assess effects of acute stress upon MAO-A V(T,) an index of MAO-A density, in human brain and acute glucocorticoid exposure upon MAO-A levels in human neuronal and glial cell lines. Twelve healthy, non-smoking participants aged 18-50 underwent [(11)C]harmine positron emission tomography to measure brain MAO-A V(T) on two different days: One under acute psychosocial stress (via Trier Social Stress and Montreal Imaging Stress Tasks) and one under a non-stress condition. MAO-A density (by Western blot) and activity (by [(14)C]-5-HT metabolism and liquid scintillation spectroscopy) were measured in human neuronal and glial cell lines after 4 h exposure to dexamethasone. We observed a significant reduction in whole-brain MAO-A binding as reflected by reductions in 10 of 11 brain regions. Acute dexamethasone exposure in neuronal and glial cells significantly decreased MAO-A activity and protein levels. We observed a highly consistent relationship between acute stressors and glucocorticoid administration and decreased MAO-A binding, activity and protein levels. Since MAO-A metabolizes monoamines, this phenomenon may explain why acute stressors benefit healthy animals even though chronic stress is associated with illness.

Stress-induced dopamine release in humans at risk of psychosis: a [11C]raclopride PET study.

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [(11)C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [(11)C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.

Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial.

BACKGROUND: The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Δ9-tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex®) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment-seeking cannabis-dependent participants. METHODS: Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time. RESULTS: Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores. CONCLUSIONS: Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence.

Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series.

OBJECTIVES: Cannabis is the most commonly used illicit drug; a substantial minority of users develop dependence. The current lack of pharmacological treatments for cannabis dependence warrants the use of novel approaches and further investigation of promising pharmacotherapy. In this case series, we assessed the use of self-titrated dosages of Sativex (1:1, Δ-tetrahydrocannabinol [THC]/cannabidiol [CBD] combination) and motivational enhancement therapy and cognitive behavioral therapy (MET/CBT) for the treatment of cannabis dependence among 5 treatment-seeking community-recruited cannabis-dependent subjects. METHODS: Participants underwent a 3-month open-label self-titration phase with Sativex (up to 113.4 of THC/105 mg of CBD) and weekly MET/CBT, with a 3-month follow-up. RESULTS: Sativex was well-tolerated by all participants (average dosage 77.5 THC/71.7 mg CBD). The combination of Sativex and MET/CBT reduced the amount of cannabis use and progressively reduced craving and withdrawal scores. THC/CBD metabolite concentration indicated reduced cannabis use and compliance with medication. CONCLUSIONS: In summary, this pilot study found that with Sativex in combination with MET/CBT reduced cannabis use while preventing increases in craving and withdrawal in the 4 participants completing the study. Further systematic exploration of Sativex as a pharmacological treatment option for cannabis dependence should be performed.

mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors, some of which are localized in the spinal cord dorsal horn, and are involved with pain perception. The anti-nociceptive effects of intrathecal (i.t.) pretreatment with various mGlu receptor agonists and antagonists were assessed in Long Evans rats with mechanical and thermal hypersensitivity after sub-dermal injection of capsaicin in the hindpaw. Selective group II (aminopyrrolidine-2R,4R-dicarboxylate, APDC) and group III (l-2-amino-4-phosphonobutyrate, L-AP4) agonists, as well as selective mGlu(1) (1-aminoindan-1,5(R,S)-dicarboxylic acid, AIDA) and mGlu(5) (2-methyl-6-(phenylethynyl)-pyridine, MPEP) receptor subtype antagonists were compared with that of an NMDA receptor antagonist (dizocilipine maleate, MK-801). The rats were observed for signs of capsaicin-induced mechanical and thermal hypersensitivity 15 min after capsaicin injection, and 20 min following i.t. drug administration. Results indicate there was a dose-dependent reduction in capsaicin-induced mechanical hypersensitivity for all mGlu receptor agents; with maximal increases in mechanical thresholds that were 7-fold for AIDA and APDC, 7.5-fold for L-AP4 and 5.6-fold for MPEP. However, only a weak reduction (often non-significant) in thermal hypersensitivity was observed with each of the mGlu receptor drugs; thermal latencies were maximally increased by 125% (AIDA), 0% (MPEP), 8% APDC and 205% (L-AP4). By contrast, the highest dose of MK-801 was able to significantly reduce both mechanical (maximal 6.67-fold increase in threshold) and thermal (maximal 3-fold increase in latencies) hyperalgesia. We conclude that mGlu receptors contribute to the development of mechanical allodynia, but not thermal hyperalgesia, following capsaicin injury; while iGluRs may contribute to both thermal and mechanical hypersensitivity.

Mapping the depressed brain: a meta-analysis of structural and functional alterations in major depressive disorder.

BACKGROUND: Depression has a lifetime prevalence of up to 20%. Neuroimaging methods have revealed various structural and functional changes that occur in a human brain during a depressive episode. However, we still lack information concerning the extent to which structural and functional changes co-occur in a depressed brain. Furthermore, it is difficult to evaluate from a merely qualitative literature review what regional brain changes in volume and activation are robust across depressed patient samples and consistent across imaging centers. METHODOLOGY AND PRINCIPLE FINDINGS: This study is a meta-analysis from 10 selected studies published previously. We applied the statistical anatomical/activation likelihood estimate method (ALE) in a total of 176 depressed patients and 175 controls for the MRI modality and in a total of 102 depressed patients and 94 controls for the PET modality to quantitatively identify those brain regions that show concordant alteration in the midst of a depressive episode across imaging modalities and study sites. We find a convergent change in the limbic-cortical brain circuit in depression compared to controls of both Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) data. The specific changes include lower gray matter volumes in the amygdala, the dorsal frontomedian cortex, and the right paracingulate cortex, as well as increases in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices. CONCLUSIONS/SIGNIFICANCE: Our current findings represent an important first step towards a more focused approach to neuroimaging unipolar depression. The regions identified could serve as a specific region-of-interest-for-disease template for both individual in vivo imaging studies and postmortem histopathologic exploration.

Dynamic, adaptive changes in MAO-A binding after alterations in substrate availability: an in vivo [(11)C]-harmine positron emission tomography study.

Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [(11)C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A V(T), an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.

Limbic response to psychosocial stress in schizotypy: a functional magnetic resonance imaging study.

Psychological stress causes dopamine release in the striatum and is thought to play a role in susceptibility to psychotic illness. Previous work suggests that an elevated dopaminergic response to stress may index vulnerability to psychosis in certain individuals. With functional magnetic resonance imaging, we measured stress-induced changes in brain activity in healthy individuals at elevated risk of developing psychosis. Participants were 15 controls and 25 psychometric schizotypes: 12 with positive symptom schizotypy (perceptual aberrations) and 13 with negative symptom schizotypy (physical anhedonia), as determined by questionnaires (Chapman et al., 1976; Chapman and Chapman, 1978). In the scanner, participants performed the Montreal Imaging Stress Task and a matched sensory-motor control task. Measures of self-reported stress and salivary cortisol levels were taken throughout the experiment. All three groups showed significant increases in self-reported stress and significant fMRI signal change in the striatal, limbic and cortical regions. However, the Physical Anhedonia group showed greater stress-induced striatal and limbic deactivation than the other two groups. Deactivation in the striatum was significantly correlated with Physical Anhedonia score across all subjects. Our findings suggest the presence of abnormalities in striatal response to stress in negative symptom schizotypy.

Monoamine oxidase A binding in the prefrontal and anterior cingulate cortices during acute withdrawal from heavy cigarette smoking.

CONTEXT: Greater prefrontal cortex and anterior cingulate cortex monoamine oxidase A (MAO-A) binding is associated with depressed mood. Substances in cigarette smoke, such as harman, inhibit MAO-A, and cigarette withdrawal is associated with depressed mood. Dysphoria during cigarette withdrawal predicts relapse. It is unknown whether MAO-A binding increases during early cigarette withdrawal. OBJECTIVES: To measure prefrontal and anterior cingulate cortex MAO-A binding during acute cigarette withdrawal and to assess the relationship with smoking severity, plasma levels of harman, and severity of depression. DESIGN: Study via positron emission tomography of healthy control and cigarette-smoking individuals. PATIENTS: Twenty-four healthy nonsmoking and 24 otherwise healthy cigarette-smoking individuals underwent positron emission tomography with harmine labeled with carbon 11. Healthy nonsmoking individuals underwent scanning once. Cigarette-smoking individuals underwent scanning after acute withdrawal and after active cigarette smoking. Cigarette smoking was heavy (≥25 cigarettes per day) or moderate (15-24 cigarettes per day). SETTING: Tertiary care psychiatric hospital. MAIN OUTCOME MEASURE: An index of MAO-A density, MAO-A V(T), was measured in the prefrontal and anterior cingulate cortices. RESULTS: In heavy-smoking individuals, prefrontal and anterior cingulate cortex MAO-A V(T) was greater during withdrawal (23.7% and 33.3%, respectively; repeated-measures multivariate analysis of variance, F(1,22) = 25.58, P < .001). During withdrawal from heavy smoking, prefrontal and anterior cingulate cortex MAO-A V(T) was greater than in healthy controls (25.0% and 25.6%, respectively; multivariate analysis of variance, F(2,33) = 6.72, P = .004). The difference in MAO-A V(T) in the prefrontal cortex and anterior cingulate cortex between withdrawal and active, heavy smoking covaried with change in plasma harman levels in the prefrontal cortex and anterior cingulate cortex (multivariate analysis of covariance, F(1,10) = 9.97, P = .01). The change in MAO-A V(T) between withdrawal and active, heavy smoking also covaried with severity of depression (multivariate analysis of covariance, F(1,10) = 11.91, P = .006). CONCLUSIONS: The increase in prefrontal and anterior cingulate cortex MAO-A binding and associated reduction in plasma harman level represent a novel, additional explanation for depressed mood during withdrawal from heavy cigarette smoking. This finding resolves a longstanding paradox regarding the association of cigarette smoking with depression and suicide and argues for additional clinical trials on the effects of MAO-A inhibitors on quitting heavy cigarette smoking.