Alpha-methyl-para-tyrosine Research Articles

Physiological and metabolic effects of short-term dopamine reduction in healthy horses using a tyrosine hydroxylase inhibitor (alpha-methyl-para-tyrosine)

Alpha-methyl-para-tyrosine (AMPT) is a reversible inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. This study aimed to determine whether AMPT could reduce dopamine concentrations in horses. Six healthy adult Standardbred geldings were administered AMPT (40 mg/kg BW, orally) or placebo in a randomised crossover study design. Clinical examination findings were recorded, and blood samples were collected for up to 6 h after administration of AMPT or placebo, for measurement of blood glucose, plasma ACTH and cortisol concentrations, and plasma metabolomic analysis. Plasma prolactin concentration was determined as a proxy index of central dopamine reduction. No adverse clinical effects were detected after oral administration of AMPT, with heart rate, mean arterial pressure and blood glucose concentration not differing between AMPT treatment or placebo. Plasma prolactin concentration peaked 1 h after AMPT administration before returning to baseline at 2 h (for five horses) or 6 h (for one horse). Metabolomic analysis demonstrated a reduction in plasma dopamine (0.72-fold change; P=0.016) 1 h after AMPT treatment. Plasma ACTH and cortisol concentrations were not different between AMPT and placebo over time. A few metabolites associated with ketogenesis were increased, and certain amino acids decreased, at 1 h compared with baseline, for both AMPT treatment and placebo. Therefore, AMPT was effective in reducing both central and circulating dopamine concentrations in healthy horses following a single oral dose. Further pharmacokinetic and pharmacodynamic studies are warranted to optimise the dose and duration of AMPT treatment to achieve longer-term dopamine reduction. Plasma metabolomic findings suggested an interruption to energy flux at the time of sample collection, which may be relevant to nutritional studies in horses and warrants further investigation.

Effect of short-term dopamine reduction on insulin sensitivity and post-prandial insulin and glucose responses in Standardbred horses

The role of dopamine in the regulation of insulin secretion in horses is poorly understood and requires further investigation. Pituitary pars intermedia dysfunction (PPID) is associated with decreased activity of dopaminergic neurons which normally suppress peptide hormone secretion from the pituitary pars intermedia. A high proportion of horses with PPID also have insulin dysregulation (ID), characterised by post-prandial hyperinsulinaemia and/or tissue insulin resistance, which are risk factors for the development of laminitis. The aim of this study was to investigate the effects of alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor that reduces dopamine production, on insulin sensitivity and the post-prandial insulin response to a glucose-containing meal. Six healthy Standardbred horses were enrolled in a placebo-controlled randomised crossover study, in which one dose of AMPT (40 mg/kg BW) or placebo was administered orally, prior to performing an in-feed oral glucose test (OGT) and a frequently sampled intravenous glucose tolerance test (FSIGTT). Dopamine reduction by AMPT was confirmed by an increase in plasma prolactin concentration and the lack of post-prandial increase in plasma dopamine concentration compared to placebo. Post-prandial insulin responses, both peak and AUCi, were increased after AMPT compared to placebo (P=0.048 and P=0.005, respectively), without affecting blood glucose concentrations. However, one dose of AMPT did not appear to affect tissue sensitivity as assessed by the FSIGTT. This study confirmed that dopamine plays a role in the regulation of insulin secretion in horses, as it does in other species, whereby the post-prandial release of dopamine into the circulation may inhibit pancreatic insulin secretion. Further studies are required to evaluate different dosing protocols for AMPT, and to further investigate the links between PPID, ID and laminitis risk in horses.

Behavioral Response to Catecholamine Depletion in Individuals With Schizophrenia and Healthy Volunteers.

Dysfunction of the dopamine system is the leading neurobiological hypothesis of schizophrenia. In this study, we tested this hypothesis in the context of aberrance salience theory of delusions using catecholamine depletion. We hypothesized that acute dopamine depletion improves both positive symptoms and salience attribution in individuals with schizophrenia. Catecholamine depletion was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 15 individuals with schizophrenia and 15 healthy volunteers. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were the Scale for the Assessment of Positive Symptoms and the Salience Attribution Test. Catecholamine depletion transiently reduced specific psychotic symptoms in symptomatic individuals with schizophrenia, namely delusions and positive formal thought disorder (interaction treatment-by-timepoint, P = .013 and P = .010, respectively). We also found trends for catecholamine depletion to increase relevant bias and adaptive salience in participants with schizophrenia while decreasing them in healthy controls (interaction group-by-treatment, P = .060 and P = .089, respectively). Exploratory analyses revealed that in participants with schizophrenia, higher relevant bias at 3 hours after the end of AMPT treatment corresponded to lower delusional symptoms (Spearman's rho = -0.761, P = .001). This study suggests that the relationship between dopamine hyperactivity and delusional symptoms in schizophrenia is mediated by impaired attribution of salience to reward-predicting stimuli.

The effects of acute dopamine depletion on resting-state functional connectivity in healthy humans

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p<.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48–1.90; p<.0001–0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p<.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed.

Neural Correlates of Impaired Reward-Effort Integration in Remitted Bulimia Nervosa.

The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward-processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa. To investigate the interaction between catecholamine functioning and behavioral, and neural responses directly, 17 remitted bulimic (rBN) and 21 healthy individuals (HC) received alpha-methyl-paratyrosine (AMPT) over 24 h to achieve catecholamine depletion in a randomized, crossover study design. We used functional magnetic resonance imaging (fMRI) and the monetary incentive delay (MID) task to assess reward-effort integration in relation to catecholaminergic neurotransmission at the behavioral and neural level. AMPT reduced the ability to integrate rewards and efforts effectively in HC participants. In contrast, in rBN participants, the reduced reward-effort integration was associated with illness duration in the sham condition and unrelated to catecholamine depletion. Regarding neural activation, AMPT decreased the reward anticipation-related neural activation in the anteroventral striatum. This decrease was associated with the AMPT-induced reduction of monetary earning in HC in contrast to rBN participants. Our findings contributed to the theory of a desensitized dopaminergic system in bulimia nervosa. A disrupted processing of reward magnitudes and effort costs might increase the probability of maintenance of bulimic symptoms.

Neural response to catecholamine depletion in remitted bulimia nervosa: Relation to depression and relapse

Bulimia nervosa has been associated with a dysregulated catecholamine system. Nevertheless, the influence of this dysregulation on bulimic symptoms, on neural activity, and on the course of the illness is not clear yet. An instructive paradigm for directly investigating the relationship between catecholaminergic functioning and bulimia nervosa has involved the behavioral and neural responses to experimental catecholamine depletion. The purpose of this study was to examine the neural substrate of catecholaminergic dysfunction in bulimia nervosa and its relationship to relapse. In a randomized, double-blind and crossover study design, catecholamine depletion was achieved by using the oral administration of alpha-methyl-paratyrosine (AMPT) over 24 h in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. In a follow-up telephone interview, bulimic relapse was assessed. Following AMPT, rBN participants revealed an increased vigor reduction and CBF decreases in the pallidum and posterior midcingulate cortex (pMCC) relative to HC participants showing no CBF changes in these regions. These results indicated that the pallidum and the pMCC are the functional neural correlates of the dysregulated catecholamine system in bulimia nervosa. Bulimic relapse was associated with increased depressive symptoms and CBF reduction in the hippocampus/parahippocampal gyrus following catecholamine depletion. AMPT-induced increased CBF in this region predicted staying in remission. These findings demonstrated the importance of depressive symptoms and the stress system in the course of bulimia nervosa.

Cardiac sympathetic activity in 22q11.2 deletion syndrome

Aim22q11.2 deletion syndrome (22q11.2DS) affects catechol-O-methyl-transferase (COMT), which involves the degradation of norepinephrine (NE). Clinically, adults with 22q11.2DS are at increased risk for sudden unexpected death. Although the causes are likely multifactorial, increased cardiac sympathetic activity with subsequent fatal arrhythmia, due to increased levels of NE, should be considered as a possible mechanism predisposing to this premature death. The purpose of this study was to determine whether cardiac sympathetic activity is increased in 22q11.2DS, both at baseline and following an acute NE depletion with alpha-methyl-para-tyrosine (AMPT). MethodsFive adults with 22q11.2DS and five age- and sex-matched healthy controls underwent 2 sessions with either AMPT or placebo administration before 123I-mIBG scintigraphy. Heart-to-mediastinum ratios (H/M) were determined from the images 15min (early) and 4h (late) after administration of 123I-mIBG and the washout (WO) was calculated as an indicator of adrenergic drive. ResultsAt baseline there were no significant differences in both early and late H/M between 22q11.2DS and controls. However, there was a significant difference in WO between 22q11.2DS and controls (−4.92±2.8 and −10.44±7.2, respectively; p=0.027), but a “negative WO” does not support an increased sympathetic drive. In addition there was a trend towards a higher late H/M after AMPT administration compared to baseline which was more pronounced in 22q11.2DS. ConclusionThis study for the first time suggests normal cardiac sympathetic activity in adults with 22q11.2DS assessed by 123I-mIBG scintigraphy. Although there is a small difference in adrenergic drive compared to healthy subjects, this most likely does not explain the increased unexpected death rate in the 22q11.2 DS population.

The Role of BDNF, Leptin, and Catecholamines in Reward Learning in Bulimia Nervosa

Background:A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin.Methods:Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 hour after a standardized breakfast.Results:AMPT–induced differences in plasma BDNF levels were positively correlated with the AMPT–induced differences in reward learning in the whole sample (P=.05). Across conditions, plasma brain derived neurotrophic factor levels were higher in remitted bulimia nervosa subjects compared with controls (diagnosis effect; P=.001). Plasma BDNF and leptin levels were higher in the morning before compared with after a standardized breakfast across groups and conditions (time effect; P<.0001). The plasma leptin levels were higher under catecholamine depletion compared with placebo in the whole sample (treatment effect; P=.0004).Conclusions:This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with remitted bulimia nervosa and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both remitted bulimia nervosa and controls.

Noradrenaline-induced release of newly-synthesized accumbal dopamine: differential role of alpha- and beta-adrenoceptors.

Previous studies have shown that intra-accumbens infusion of isoproterenol (ISO), a beta-adrenoceptor-agonist, and phenylephrine (PE), an alpha-adrenoceptor-agonist, increase the release of accumbal dopamine (DA). In the present study we analyzed whether the ISO-induced release of DA is sensitive to pretreatment with the DA synthesis inhibitor alpha-methyl-para-tyrosine (AMPT). Earlier studies have shown that the PE-induced release of DA is derived from DA pools that are resistant to AMPT. In addition to PE, the alpha-adrenoceptor-antagonist phentolamine (PA) was also found to increase accumbal DA release. Therefore, we investigated whether similar to the DA-increasing effect of PE, the DA increase induced by PA is resistant to AMPT. Pretreatment with AMPT prevented the ISO-induced increase of accumbal DA. The accumbal DA increase after PA was not reduced by the DA synthesis inhibitor, independently of the amount of DA released. These results show that mesolimbic beta-, but not alpha-adrenoceptors, control the release of accumbal newly-synthesized DA pools. The DA-increasing effects of PE have previously been ascribed to stimulation of presynaptic receptors located on noradrenergic terminals, whereas the DA-increasing effects of PA and ISO have been ascribed to an action of these drugs at postsynaptic receptors on dopaminergic terminals. The fact that AMPT did not affect the accumbal DA response to PE and PA, whereas it did prevent the accumbal DA increase to ISO, supports our previously reported hypothesis that the noradrenergic neurons of the nucleus accumbens containing presynaptic alpha-adrenoceptors impinge upon the dopaminergic terminals in the nucleus accumbens containing postsynaptic adrenoceptors of the alpha but not of the beta type. The putative therapeutic effects of noradrenergic agents in the treatment of DA-related disorders are shortly discussed.

Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [(123)I]-IBZM (radiotracer for dopamine D2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [(123)I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.

Behavioral Responses to Catecholamine Depletion in Unmedicated, Remitted Subjects with Bulimia Nervosa and Healthy Subjects

BackgroundBulimia nervosa (BN) has been associated with dysregulation of the central catecholaminergic system. An instructive way to investigate the relationship between catecholaminergic function and psychiatric disorder has involved behavioral responses to experimental catecholamine depletion (CD). The purpose of this study was to examine a possible catecholaminergic dysfunction in the pathogenesis of bulimia nervosa. MethodsCD was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 18 remitted female subjects with BN (rBN) and 31 healthy female control subjects. The study design consisted of a randomized, double blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were bulimic symptoms assessed by the Eating Disorder Examination—Questionnaire. Measures were assessed before and 26, 30, 54, 78, 102 hours after the first AMPT or placebo administration. ResultsIn the experimental environment (controlled environment with a low level of food cues) rBN subjects had a greater increase in eating disorder symptoms during CD compared with healthy control subjects (condition × diagnosis interaction, p < .05). In the experimental environment, rBN subjects experienced fewer bulimic symptoms than in the natural environment (uncontrolled environment concerning food cues) 36 hours after the first AMPT intake (environment × diagnosis interaction, p < .05). Serum prolactin levels increased significantly, and to a comparable degree across groups, after AMPT administration. ConclusionsThis study suggests that rBN is associated with vulnerability for developing eating disorder symptoms in response to reduced catecholamine neurotransmission after CD. The findings support the notion of catecholaminergic dysfunction as a possible trait abnormality in BN.

Angiotensin II stimulates sympathetic neurotransmission to adipose tissue

Angiotensin II (AngII) facilitates sympathetic neurotransmission by regulating norepinephrine (NE) synthesis, release, and uptake. These effects of AngII contribute to cardiovascular control. Previous studies in our laboratory demonstrated that chronic AngII infusion decreased body weight of rats. We hypothesized that AngII facilitates sympathetic neurotransmission to adipose tissue and may thereby decrease body weight. The effect of chronic AngII infusion on the NE uptake transporter and NE turnover was examined in metabolic (interscapular brown adipose tissue, ISBAT; epididymal fat, EF) and cardiovascular tissues (left ventricle, LV; kidney) of rats. To examine the uptake transporter saturation isotherms were performed using [3H]nisoxetine (NIS). At doses that lowered body weight, AngII significantly increased ISBAT [3H]NIS binding density. To quantify NE turnover, alpha-methyl-para-tyrosine (AMPT) was injected in saline-infused, AngII-infused, or saline-infused rats that were pair-fed to food intake of AngII-infused rats. AngII significantly increased the rate of NE decline in all tissues compared to saline. The rate of NE decline in EF was increased to a similar extent by AngII and by pair feeding. In rats administered AngII and propranolol, reductions in food and water intake and body weight were eliminated. These data support the hypothesis that AngII facilitates sympathetic neurotransmission to adipose tissue. Increased sympathetic neurotransmission to adipose tissue following AngII exposure is suggested to contribute to reductions in body weight.

Reduction in total plasma ghrelin levels following catecholamine depletion: Relation to bulimic and depressive symptoms

There is increasing preclinical and clinical evidence of the important role played by the gastric peptide hormone ghrelin in the pathogenesis of symptoms of depression and eating disorders. To investigate the role of ghrelin and its considered counterpart, peptide tyrosine tyrosine (PYY), in the development of bulimic and depressive symptoms induced by catecholamine depletion, we administered the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine (AMPT) in a randomized, double-blind, placebo-controlled crossover, single-site experimental trial to 29 healthy controls and 20 subjects with fully recovered bulimia nervosa (rBN). We found a decrease between preprandial and postprandial plasma ghrelin levels (p<0.0001) and a postprandial rise in plasma PYY levels (p<0.0001) in both conditions in the entire study population. Plasma ghrelin levels decreased in the entire study population after treatment with AMPT compared to placebo (p<0.006). AMPT-induced changes in plasma ghrelin levels were negatively correlated with AMPT-induced depressive symptoms (p<0.004). Plasma ghrelin and plasma PYY levels were also negatively correlated (p<0.05). We did not observe a difference in ghrelin or PYY response to catecholamine depletion between rBN subjects and healthy controls, and there was no correlation between plasma ghrelin and PYY levels and bulimic symptoms induced by catecholamine depletion. These findings suggest a relationship between catecholamines and ghrelin with depressive symptoms.

Catecholamine depletion in first-degree relatives of individuals with mood disorders: An [18F]fluorodeoxyglucose positron emission tomography study

Catecholamine depletion with alpha-methylparatyrosine (AMPT) has previously been shown to induce depressive symptoms in currently remitted patients with major depressive disorder (MDD) but not healthy controls. Thus sensitivity to catecholamine depletion has been hypothesized to be an endophenotype of MDD. Here we tested this hypothesis in the context of a randomized, double-blinded, placebo-controlled design by measuring changes in mood in a group of psychiatrically-healthy individuals at risk of mood disorders by virtue of family history (high-risk subjects, HRs). In addition, we tested whether HRs differed from healthy controls with no family-history of mood disorders (low-risk controls, LRs) in their cerebral metabolic response when undergoing catecholamine depletion. Eight healthy LRs (6 males, mean age = 34.1 ± 7.1) and 6 healthy HRs (3 males, mean age = 29.3 ± 4.6) participated in two, 3-day-long identical sessions during which they completed standardized measures of depression, anxiety and fatigue and an [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scan. On one occasion participants received 4 weight-adjusted doses of AMPT and on the other occasion participants received 4 doses of placebo. The LR and HR groups did not differ from each other in their mood during sham depletion. However, during the period of peak catecholamine depletion, the HR group reported significantly more depression, anxiety and fatigue than the LR group. A region-of-interest analysis showed that during catecholamine depletion versus placebo the combined LR and HR groups displayed a significant increase in cerebral metabolic rate in the left and right ventral striata, left and right amygdalae, and left and right hippocampi (FWE-corrected p < 0.05). Whole brain voxel-wise analyses indicated significantly increased glucose metabolism in the left and right putamina (FWE-corrected p < 0.05) in the combined LR and HR groups in the AMPT versus the placebo session. In the LR group, alone, no significant elevation in glucose metabolism was observed in the regions-of-interest in the catecholamine depletion versus placebo condition. In the HR group, alone, the region-of-interest analysis showed a significant increase in cerebral metabolic rate in the left and right ventral striata (FWE-corrected p < 0.05). No regions-of-interest showed significantly different metabolism in the HR group versus the LR group in the placebo condition, however compared with the LR group, the HR group displayed nominally increased glucose metabolism in the left amygdala during catecholamine depletion (SVC-corrected p = 0.05). A region-of-interest analysis for the interaction contrast confirmed that catecholamine depletion had differential effects on HR and LR participants. Compared with the LR group, the HR group displayed significantly increased glucose metabolism in the left ventral striatum, left amygdala, and left lateral orbitofrontal cortex (OFC) (FWE-corrected p < 0.05). Our results suggest that sensitivity to catecholamine depletion may be a phenotypic marker of vulnerability to mood disorders that is characterized at the neurophysiological level by disinhibition of the striatum and its efferent projections comprising the limbic–cortical–striatal–pallidal–thalamic circuitry.

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]–DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]–IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

Dopamine-Related Deficit in Reward Learning After Catecholamine Depletion in Unmedicated, Remitted Subjects with Bulimia Nervosa

Disturbances in reward processing have been implicated in bulimia nervosa (BN). Abnormalities in processing reward-related stimuli might be linked to dysfunctions of the catecholaminergic neurotransmitter system, but findings have been inconclusive. A powerful way to investigate the relationship between catecholaminergic function and behavior is to examine behavioral changes in response to experimental catecholamine depletion (CD). The purpose of this study was to uncover putative catecholaminergic dysfunction in remitted subjects with BN who performed a reinforcement-learning task after CD. CD was achieved by oral alpha-methyl-para-tyrosine (AMPT) in 19 unmedicated female subjects with remitted BN (rBN) and 28 demographically matched healthy female controls (HC). Sham depletion administered identical capsules containing diphenhydramine. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were reward learning in a probabilistic reward task analyzed using signal-detection theory. Secondary outcome measures included self-report assessments, including the Eating Disorder Examination-Questionnaire. Relative to healthy controls, rBN subjects were characterized by blunted reward learning in the AMPT--but not in placebo--condition. Highlighting the specificity of these findings, groups did not differ in their ability to perceptually distinguish between stimuli. Increased CD-induced anhedonic (but not eating disorder) symptoms were associated with a reduced response bias toward a more frequently rewarded stimulus. In conclusion, under CD, rBN subjects showed reduced reward learning compared with healthy control subjects. These deficits uncover disturbance of the central reward processing systems in rBN related to altered brain catecholamine levels, which might reflect a trait-like deficit increasing vulnerability to BN.

Poster #22 HYPERACTIVATION IN WORKING MEMORY CIRCUITS IN SIBLINGS OF SCHIZOPHRENIA PATIENTS: AN FMRI STUDY

Dysphoria is an integral part of the symptomatology of a variety of clinical states, though there is little empirical data available on the qualitative and quantitative aspects of this phenomenon. The purpose of the study was to administer alphamethyl paratyrosine (AMPT), a catecholamine depleting agent as a chemical probe to induce dysphoria, and document the ensuing changes in mental status. AMPT (4–5 g/day) was administered to a group of medication-free schizophrenic patients (n = 13) over a 48 hour period, and changes in their mental status were monitored at 12 hour intervals with the Profile of Mood States (POMS), Addiction Research Center Inventory (ARCI), Drug Attitude Inventory (DAI) and other standardized rating scales. All of the subjects experienced dysphoric responses of variable severity. The profile of changes included blunted pleasure responsivity, clouded thinking, loss of motivation and lowered vigilance. Subtle subjective changes were experienced soon after the first dose of AMPT and the dysphoria steadily worsened, resulting in social withdrawal and personal distress. Subjective responses were the earliest to manifest, followed by akathisia, akinesia and rigidity. We conclude that AMPT induced dopamine depletion is a safe, rapid, reliable and reversible method of studying dysphoric states in humans. The technique is helpful in examining the phenomenology of dysphoria, the temporal relationship between subjective and behavioural consequences of dopamine depletion, and the role of dopamine in mediating subtle aspects of pleasure responsivity, which is in turn crucial to the understanding of treatment non-adherence in schizophrenia and the origins of comorbid substance abuse.

The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

PurposeFunctional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients.MethodsIn FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [123I]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs.ResultsThe HV subjects comprised 12 women and 8 men (mean age 31 ± 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 ± 5 years). The FD patients had a lower left plus right average striatal binding potential (BPNP) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BPNP in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects.ConclusionThese preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathways.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-011-2015-6) contains supplementary material, which is available to authorized users.

Further Electrochemical and Behavioural Evidence of a Direct Relationship Between Central 5-HT and Cytoskeleton in the Control of Mood

Reduced activity of CNS serotonin is reported in unipolar depression and serotonin is the major target of recent antidepressant drugs. However, an acute depletion of serotonin in healthy individuals does not induce depressive symptoms suggesting that depression does not correlate with the serotonin system only. Neuronal plasticity (structural adaptation of neurons to functional requirements) includes synthesis of microtubular proteins such as tyrosinated isoform of α-tubulin and presence of serotonin as regulator of synaptogenesis. In depression neuronal plasticity is modified.Here, in rats submitted to a behavioural test widely used to predict the efficacy of antidepressant drugs (forced swimming test: FST) a significant decrease of both cerebral tyrosinated α-tubulin expression and serotonin levels is monitored. Moreover, treatment with para-chlorophenylalanine (PCPA, compound that specifically depletes brain serotonin) but not alpha-methyl para tyrosine (α-MPT, compound that blocks synthesis of catechols: chemicals also implicated in depression) significantly reduced tyrosinated α-tubulin. Thus, a direct relationship between serotonin and tyrosinated α-tubulin appears to be present both in “physiological” and in “pathological” states. In addition, data obtained in animals submitted to FST and/or treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine further support the interrelationship between central serotonin and cytoskeleton. These data propose that direct relationship between serotonin and tyrosinated α-tubulin could be considered within the mechanism(s) involved in the pathogenesis of depression.

Lower Level of Endogenous Dopamine in Patients With Cocaine Dependence: Findings From PET Imaging of D 2 /D 3 Receptors Following Acute Dopamine Depletion

Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.