Attenuation of dopamine-induced GABA release in problem gamblers.

INTRODUCTION: We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS: [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS: The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS: Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.

Behavioural effects of phenylalanine-free amino acid tablet supplementation in intellectually disabled adults with untreated phenylketonuria.

AIM: To evaluate the effects of phenylalanine (Phe)-free essential amino acid (AA) tablets enriched in tyrosine and tryptophan on the performance of intellectually disabled adult patients with untreated phenylketonuria (PKU). METHODS: Phe-free AA tablets and placebo tablets were administered to 19 untreated PKU subjects on a normal diet for 6 mo in a prospective double-blinded crossover study. The adaptive behaviour of the patients was tested prior to the study and at 6 and 12 mo after the start, using a simplified version of the Vineland Adaptive Behaviour Scale. For each sub-domain, the patients were rated either "0" (for poor performance) or "1" (for good performance). Neurological signs and symptoms and specific behavioural characteristics were recorded monthly by caretakers. Every 6 mo, neurological examination of the patients was performed, and the caretakers were interviewed. The statistical significance of the results was tested by means of the Fisher's exact and Wilcoxon tests. RESULTS: The most significant changes were an improved concentration and the development of a meaningful smile, which were observed in 44% and 43% of the patients on AA tablet treatment, respectively, but not patients on placebo. Other important but less significant changes included increased awareness of external stimuli (63%) and less self-injury (43%), and 40% were smiling and laughing occasionally. The mean overall rating increased from an initial value of 6.3 to 10.1 in patients when on AA tablet treatment (p=0.002), and to 7.0 in patients when on placebo (p=0.068). The difference between active AA treatment and placebo was statistically significant (p=0.027). CONCLUSIONS: This pilot study suggests that Phe-free AA tablets enriched in tyrosine and tryptophan may improve the quality of life in some intellectually disabled adults with untreated PKU.

The mental self.

In meditation both the quality and the contents of consciousness may be voluntarily changed, making it an obvious target in the quest for the neural correlate of consciousness. Here we present the results of a positron emission tomography study of yoga nidra relaxation meditation when compared with the normal resting conscious state. Meditation is accompanied by a relatively increased perfusion in the sensory imagery system: hippocampus and sensory and higher order association regions, with decreased perfusion in the executive system: dorsolateral prefrontal cortex, anterior cingulate gyrus, striatum, thalamus, pons, and cerebellum. To identify regions active in both systems we performed a principal component analysis of the results. This separated the blood flow data into two groups of regions, explaining 25 and 18% of their variance: One group corresponded to the executive system, and the other to the systems supporting sensory imagery. A small group of regions contributed considerably to both networks: medial parietal and medial prefrontal cortices, together with the striatum. The inclusion of the striatum and our subsequent finding of increased striatal dopamine binding to D2 receptors during meditation suggested dopaminergic regulation of this circuit. We then investigated the neural networks supporting episodic retrieval of judgments of individuals with different degrees of self-relevance, in the decreasing order: self, best friend, and the Danish queen. We found that all conditions activated a medial prefrontal - precuneus/posterior cingulate cortex, thalamus, and cerebellum. This activation occurred together with the activation of the left lateral prefrontal/temporal cortex. The latter was dependent on the requirement of retrieval of semantic information, being most pronounced in the "queen" condition. Transcranial magnetic stimulation, targeting precuneus, was then applied to the medial parietal region to transiently disrupt the normal function of the circuitry. We found a decreased efficiency of retrieval of self-judgment compared to the judgment of best friend. This shows that the integrity of the function of precuneus is essential for self-reference, but not for reference to others.

Increased dopamine tone during meditation-induced change of consciousness.

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level.