Release Of Endogenous Dopamine Research Articles

Modulation of striatal dopamine release in vitro by agonists of the glycine B site of NMDA receptors; interaction with antipsychotics

The N-methyl- d-aspartate (NMDA) glutamate receptor possesses an obligatory co-agonist site for d-serine and glycine, named the glycine B site. Several clinical trials indicate that glycine B agonists can improve negative and cognitive symptoms of schizophrenia when co-administered with antipsychotics. In the present study we have investigated the effects of glycine B agonists on the endogenous release of dopamine from preparations of rat striatal tissue prisms in static conditions. The glycine B agonists glycine (1 mM) and d-serine (10 μM), but not d-cycloserine (10 μM), substantially increased the spontaneous release of dopamine, but significantly reduced the release of dopamine evoked by NMDA. The effect of glycine on spontaneous release was abolished by the non-competitive NMDA antagonists 5 R,10 S-(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a, d] cyclohepten-5,10-imine (MK-801, 10 μM) and ifenprodil (5 μM), but was only partially suppressed by the competitive antagonist 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid (CPP, 10 μM). The selective inhibitor of the glial glycine transporter GlyT1 N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS, 10 μM) significantly increased the release of dopamine in an MK-801-sensitive manner. Interestingly, haloperidol (1 μM), but not clozapine (10 μM), prevented the effects of glycine. This study shows that glycine B modulators can control dopamine release by interacting with a distinctive NMDA receptor subtype with which some typical antipsychotics can interfere.

Assessment of methylphenidate-induced changes in binding of continuously infused [11C]-raclopride in healthy human subjects: correlation with subjective effects

The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders. It has been shown that information on endogenous dopamine (DA) release can be obtained noninvasively by combining positron emission tomography with a dopaminergic challenge. This approach is based on the assumption that an injected radiolabeled ligand competes with the neurotransmitter for the same receptor. Increases in DA release will therefore result in a decreased binding of the radioligand. We investigated the effect of the DA reuptake blocker methylphenidate (MP) on the binding of the D(2) receptor ligand [(11)C]-raclopride (RAC). The effect of a 0.25 mg/kg intravenous dose of MP was studied in six healthy volunteers. RAC was administered as a bolus followed by constant infusion, and subjective effects were assessed using verbal rating scales. Control scans without MP administration showed that the mean RAC binding reached stable values approximately 30 min after start of the infusion. MP administration induced a 24% decrease in RAC binding in the total striatum. Correlations were found between the MP-induced change in euphoria and the percent change in binding potential (DeltaBP) in the dorsal striatum and between baseline anxiety and DeltaBP in the dorsal and middle striatum. We also found a negative correlation between baseline BP in the dorsal striatum and change in euphoria. Our results comply with previous findings, indicating the feasibility of the bolus infusion design combined with a relatively low MP dose to study dopaminergic (dys)function.

Dopamine D1‐like receptor modulates layer‐ and frequency‐specific short‐term synaptic plasticity in rat prefrontal cortical neurons

The mesocortical dopamine (DA) input to the prefrontal cortex (PFC) is crucial for processing short-term working memory (STWM) to guide forthcoming behavior. Short-term plasticity-like post-tetanic potentiation (PTP, < 3 min) and short-term potentiation (STP, < 10 min) may underlie STWM. Using whole-cell voltage-clamp recordings, mixed glutamatergic excitatory postsynaptic currents (EPSCs) evoked by layer III or layer V stimulation (0.5 or 0.067 Hz) were recorded from layer V pyramidal neurons. With 0.5 Hz basal stimulation of layer III, brief tetani (2 x 50 Hz) induced a homosynaptic PTP (decayed: approximately 1 min). The D1-like antagonist SCH23390 (1 microm) increased the PTP amplitude and decay time without inducing changes to the tetanic response. The tetani may evoke endogenous DA release, which activates a presynaptic D1-like receptor to inhibit glutamate release to modulate PTP. With a slower (0.067 Hz) basal stimulation, the same tetani induced STP (lasting approximately 4 min, but only at 2x intensity only) that was insignificantly suppressed by SCH23390. With stimulation of layer-V-->V inputs at 0.5 Hz, layer V tetani yielded inconsisitent responses. However, at 0.067 Hz, tetani at double the intensity resulted in an STP (lasting approximately 6 min), but a long-term depression after SCH23390 application. Endogenous DA released by tetanic stimulation can interact with a D1-like receptor to induce STP in layer V-->V synapses that receive slower (0.067 Hz) frequency inputs, but suppresses PTP at layer III-->V synapses that receive higher (0.5 Hz) frequency inputs. This D1-like modulation of layer- and frequency-specific synaptic responses in the PFC may contribute to STWM processing.

CASSIA SIAMEA INDUCED HEPATITIS, A CASE REPORT OF PHYTOMEDICINE SIDE EFFECT

CASSIA SIAMEA INDUCED HEPATITIS, A CASE REPORT OF PHYTOMEDICINE SIDE EFFECT

Pharmacokinetic-Pharmacodynamic Analysis of Antipsychotics-induced Extrapyramidal Symptoms based on Receptor Occupancy Theory Incorporating Endogenous Dopamine Release

We aimed to analyze the risks of extrapyramidal symptoms (EPS) induced by typical and atypical antipsychotic drugs using a common pharmacokinetic-pharmacodynamic (PK-PD) model based on the receptor occupancy. We collected the data for EPS induced by atypical antipsychotics, risperidone, olanzapine and quetiapine, and a typical antipsychotic, haloperidol from literature and analyzed the following five indices of EPS, the ratio of patients obliged to take anticholinergic medication, the occurrence rates of plural extrapyramidal symptoms (more than one of tremor, dystonia, hypokinesia, akathisia, extrapyramidal syndrome, etc.), parkinsonism, akathisia, and extrapyramidal syndrome. We tested two models, i.e., a model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition and a model not considering the endogenous dopamine release, and used them to examine the relationship between the D2 receptor occupancy of endogenous dopamine and the extent of drug-induced EPS. The model incorporating endogenous dopamine release better described the relationship between the mean D2 receptor occupancy of endogenous dopamine and the extent of EPS than the other model, as assessed by the final sum of squares of residuals (final SS) and Akaike's Information Criteria (AIC). Furthermore, the former model could appropriately predict the risks of EPS induced by two other atypical antipsychotics, clozapine and ziprasidone, which were not incorporated into the model development. The developed model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition may be useful for the prediction of antipsychotics-induced EPS.

Glutamate-Evoked Alterations of Glial and Neuronal Cell Morphology in the Guinea Pig Retina

Neuronal activity is accompanied by transmembranous ion fluxes that cause cell volume changes. In whole mounts of the guinea pig retina, application of glutamate resulted in fast swelling of neuronal cell bodies in the ganglion cell layer (GCL) and the inner nuclear layer (INL) (by approximately 40%) and a concomitant decrease of the thickness of glial cell processes in the inner plexiform layer (IPL) (by approximately 40%) that was accompanied by an elongation of the glial cells, by a thickening of the whole retinal tissue, and by a shrinkage of the extracellular space (by approximately 18%). The half-maximal effect of glutamate was observed at approximately 250 mum, after approximately 4 min. The swelling was caused predominantly by AMPA-kainate receptor-mediated influx of Na+ into retinal neurons. Similar but transient morphological alterations were induced by high K+ and dopamine, which caused release of endogenous glutamate and subsequent activation of AMPA-kainate receptors. Apparently, retinal glutamatergic transmission is accompanied by neuronal cell swelling that causes compensatory morphological alterations of glial cells. The effect of dopamine was elicitable only during light adaptation but not in the dark, and glutamate and high K+ induced strong ereffects in the dark than in the light. This suggests that not only the endogenous release of dopamine but also the responsiveness of glutamatergic neurons to dopamine is regulated by light-dark adaptation. Similar morphological alterations (neuronal swelling and decreased glial process thickness) were observed in whole mounts isolated immediately after experimental retinal ischemia, suggesting an involvement of AMPA-kainate receptor activation in putative neurotoxic cell swelling in the postischemic retina.

Sensory stimulation accelerates dopamine release in the basal ganglia

We report herein the modulation of dopamine release in the basal ganglia during peripheral electrical stimulation in animals. The endogenous dopamine release during electrical stimulation was measured in anesthetized cats by positron emission tomography (PET) using the D2 receptor agonist [ 11C]-raclopride. Binding potential (BP) parametric maps were calculated using a simplified reference region model. The regional dopamine release evoked by electrical stimulation was estimated both by region of interest (ROI) analysis and statistical parametric mapping (SPM 99). Both ROI analysis and statistical parametric mapping showed significant release of endogenous dopamine in the nucleus accumbens and the striatum contralateral to the stimulated side as compared to the resting condition as well as the ipsilateral side. Accordingly, we suggest that the activity of the dopaminergic neurons in the midbrain projecting to the nucleus accumbens and the striatum is modulated by the input from the afferent nerves. This provides an in vivo evidence for the importance of the basal ganglia in the processing of peripheral information required for normal movement. This may also explain the clinically observed sensory system abnormalities in patients with movement disorders.

Effect of sensory stimulus on striatal dopamine release in humans and cats: a [ 11C]raclopride PET study

Background : Sensory stimulation of the forelimb extremities constitutes a well-established experimental model that has consistently shown to activate dopamine (DA) neurotransmission in the mammals’ forebrain. Objectives: To visualize in vivo this modification of striatal DA release in healthy human volunteers using Positron Emission Tomography (PET) and [ 11C]raclopride. Experiments in humans were paralled by experiments in anesthetized cats. Changes in endogenous DA release were assessed through its competition with [ 11C]raclopride binding (BP raclo), a radioligand probing DA D2-receptors. Results: In humans no significant difference of BP raclo in caudate (with sensory stimulation: 2.0 ± 0.3 versus without sensory stimulation: 2.2 ± 0.3; P = 0.3) or putamen (2.6 ± 0.3 versus 2.6 ± 0.2; P = 0.9) ipsilateral to the stimulus was disclosed as a result of sensory stimulation. Similarly, no change of BP raclo was observed contralaterally to the stimulation in the caudate nucleus (with sensory stimulation: 2.0 ± 0.4 versus without sensory stimulation: 2.1 ± 0.2; P = 0.5) and the putamen (2.5 ± 0.4 versus 2.6 ± 0.2; P = 0.4). In cats the same results were obtained in the ipsilateral to stimulation striatum (with sensory stimulation: 2.5 ± 0.03 versus without sensory stimulation: 2.4 ± 0.05; P = 0.7). No change was also observed contralaterally to the stimulation (2.4 ± 0.04 versus 2.5 ± 0.06; P = 0.6). The [ 11C]raclopride binding remained unchanged by sensory stimuli in both humans and cats. Conclusion: This suggests that the DA release induced by sensory stimulus is mostly extrasynaptic whereas the synaptic DA release is probably small, which fits well with the absence of [ 11C]raclopride displacement. The mechanism of this extrasynaptic DA release could be related to a local action of glutamate on dopaminergic terminals via a thalamo-cortico-striatal loop. Present results also underline homology between cat and human responses to sensory stimuli and validate the use of cat brain to find physiological concepts in humans.

Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has been used as a treatment for neuropsychiatric disorders such as depression and Parkinson's disease (PD). Despite the growing interest in therapeutic application of rTMS, precise mechanisms of its action remain unknown. With respect to PD, activation of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism underlying the therapeutic effects; however, modulating effects of rTMS over the primary motor cortex (M1) on the dopaminergic system have not been studied. MethodsWe used [11C]raclopride positron emission tomography to measure changes of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight anesthetized monkeys. ResultsrTMS over the right M1 induced a reduction of [11C]raclopride binding potential (BP) in the bilateral ventral striatum, including the nucleus accumbens, and a significant increase of BP in the right putamen; no significant BP reduction was found in the dorsal striatum. These data indicate that rTMS over the motor cortex induces a release of endogenous dopamine in the ventral striatum. ConclusionsOur results suggest that therapeutic mechanisms of rTMS may be explained in part by an activation of the mesolimbic dopaminergic pathway, which plays critical roles in rewards, reinforcement, and incentive motivation.

A circadian clock in the fish retina regulates dopamine release via activation of melatonin receptors

Although many biochemical, morphological and physiological processes in the vertebrate retina are controlled by a circadian (24 h) clock, the location of the clock and how the clock alters retinal function are unclear. For instance, several observations have suggested that dopamine, a retinal neuromodulator, may play an important role in retinal rhythmicity but the link between dopamine and a clock located within or outside the retina remains to be established. We found that endogenous dopamine release from isolated goldfish retinae cultured in continuous darkness for 56 h clearly exhibited a circadian rhythm with high values during the subjective day. The continuous presence of melatonin (1 nM) in the culture medium abolished the circadian rhythm of dopamine release and kept values constantly low and equal to the night-time values. The selective melatonin antagonist luzindole (1 microM) also abolished the dopamine rhythm but the values were high and equal to the daytime values. Melatonin application during the late subjective day introduced rod input and reduced cone input to fish cone horizontal cells, a state usually observed during the subjective night. In contrast, luzindole application during the subjective night decreased rod input and increased cone input. Prior application of dopamine or spiperone, a selective dopamine D(2)-like antagonist, blocked the above effects of melatonin and luzindole, respectively. These findings indicate that a circadian clock in the vertebrate retina regulates dopamine release by the activation of melatonin receptors and that endogenous melatonin modulates rod and cone pathways through dopamine-mediated D(2)-like receptor activation.

Impact of apomorphine on BOLD signal during movement in normals.

Our group investigated modulatory effects of apomorphine on cerebral activation patterns during finger tapping movements in six healthy right-handed volunteers using an established fMRI protocol. Apomorphine application disclosed a reduction of cerebral activation to the contralateral precentral and postcentral gyrus and ipsilateral cerebellum, with a prominent net reduction of BOLD signal in cerebellar areas. These findings contradict those of similar studies performed on dopaminergic function and Parkinson's disease (PD), which predominantly found augmentation of cerebral activation patterns in normal volunteers and PD patients after dopaminergic stimulation. One conceivable explanation for our singular results would be preferred binding of apomorphine to presynaptic dopaminergic receptors, leading to inhibition of endogenous dopamine release and resultant diminished dopaminergic stimulation, reflected in diminished cerebral activation patterns. These findings warrant future consideration and further investigation of possible central inhibitory effects of dopaminergic therapy in functional imaging studies of the dopaminergic system in general and PD in particular.

Atypical Antipsychotics: Mechanism of Action

Atypical Antipsychotics: Mechanism of Action

Nociceptin/orphanin fq modulation of rat midbrain dopamine neurons in primary culture

Previous microdialysis studies have identified a suppressive effect of the novel opioid peptide nociceptin (also known as orphanin FQ) on dopamine release from mesolimbic neurons. In order to further evaluate the locus of this action, we investigated nociceptin's action in an in vitro model system, namely midbrain dopamine neurons in primary culture. Immunohistochemical analysis revealed abundant tyrosine hydroxylase- and GABA-immunoreactive neurons, with a strong correlation between tyrosine hydroxylase content and basal endogenous dopamine release. Nociceptin (0.01–100 nM) suppressed basal dopamine release by up to 84% (EC 50=0.65 nM). This action was reversible by drug removal and attenuated by co-application of the non-peptidergic ORL1 antagonist, Compound B. Nociceptin had no significant effect on dopamine release evoked by direct depolarization of the terminals with elevated extracellular K +, suggesting that nociceptin suppresses dopamine release by modulating the firing rate of the dopamine neurons. Nociceptin also suppressed GABA release from the cultures (45% maximal inhibition; EC 50=1.63 nM). Application of the GABA-A antagonist, bicuculline, elevated extracellular dopamine concentrations but the dopamine release inhibiting property of nociceptin persisted in the presence of bicuculline. The NMDA receptor antagonist, d(−)-2-amino-5-phosphononpentanoic acid (AP-5) had no effect on basal dopamine release and failed to modify nociceptin's inhibitory effects. Thus, nociceptin potently modulates dopamine release from midbrain neurons most likely as a result of a direct suppression of dopamine neuronal activity.

Apomorphine reduces BOLD signal in fMRI during voluntary movement in Parkinsonian patients.

Our group investigated modulatory effects of apomorphine on cerebral activation patterns during finger tapping movements in seven Parkinson's disease (PD) patients off medication. Cerebral activation was measured according to an established fMRI protocol. Apomorphine application disclosed a reduction of cerebral activation patterns to the contralateral precentral gyrus affecting both clinically affected and unaffected sides; tapping with the unaffected hand additionally revealed activation in the contralateral postcentral gyrus. These findings contradict those of similar functional imaging studies performed in PD to date, which variously found augmentation of cerebral activation patterns in Parkinsonian patients after dopaminergic stimulation. One conceivable explanation for our singular results would be preferred binding of apomorphine to presynaptic dopaminergic receptors, leading to inhibition of endogenous dopamine release and resultant diminished dopaminergic stimulation, reflected in diminished cerebral activation patterns. These findings warrant future consideration and further investigation of possible central inhibitory effects of dopaminergic therapy in functional imaging studies in PD.

Endogenous dopamine release after pharmacological challenges in Parkinson's disease.

Using (11)C-raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinson's disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in (11)C-raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by (18)F-dopa uptake. Localization of significant changes in (11)C-raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease.

Dopamine release during sequential finger movements in health and Parkinson's disease: a PET study.

Parkinson's disease is associated with slowness, especially of sequential movements, and is characterized pathologically by degeneration of dopaminergic neurons, particularly targeting nigrostriatal projections. In turn, nigrostriatal dopamine has been suggested to be critical for the execution of sequential movements. The objective of this study was to investigate in vivo, with [(11)C]raclopride, PET changes in regional brain levels of dopamine in healthy volunteers and Parkinson's disease patients during the execution of paced, stereotyped sequential finger movements. Striatal [(11)C]raclopride binding reflects dopamine D(2) receptor availability and is influenced by synaptic levels of endogenous dopamine. During execution of a pre-learned sequence of finger movements, a significant reduction in binding potential (BP) of [(11)C]raclopride was seen in both caudate and putamen in healthy volunteers compared with a resting baseline, consistent with release of endogenous dopamine. Parkinson's disease patients also showed attenuated [(11)C]raclopride BP reductions during the same motor paradigm in striatal areas less affected by the disease process. These findings confirm that striatal dopamine release is a component of movement sequencing and show that dopamine release can be detected in early Parkinson's disease during a behavioural manipulation.

Concomitant effect of acetylcholine and dopamine on carotid chemosensory activity in catecholamine depleted cats.

Carotid body chemotransduction mechanisms involve many neurotransmitters that are synthetized, stored, and released from the chemoreceptor cell. Acetylcholine (ACh) and dopamine (DA) are the main transmitters studied to date. It has been suggested that, at least in cats, ACh is an excitatory whereas DA is an inhibitory transmitter in the carotid body (as review see Eyzaguirre and Zapata, 1884; Fidone et al., 1997; Fitzgerald, 2000). However, their role on chemosensory activity in response to hypoxia is still debated. Recently, in catecholamine-depleted cats where the storage and release of carotid body DA was greatly impeded by the use of ∝-methyl-paratyrosine and reserpine (Bairam and Marchai, in press), DA infiision was showed to inhibit the carotid sinus nerve chemosensory discharge rate (CSND) while ACh reversed the effect under basal condition. In response to hypoxia, DA slowed the initial increase of CSND whereas ACh accelerated it, while neither drug altered the steady-state chemosensory discharge under hypoxic conditions. One interpretation of these results was that DA infusion prevented the expression of ACh excitatory effect during hypoxia as it was infused methyl-paratyrosine maintained throughout ACh administration. Using a similar model of adult cats pre-treated with oc-methyl-paratyrosine and reserpine (Bairam and Marchai, in press), we investigated the effect of 1) ACh infusion on CSND response to different inspiratory oxygen concentrations (Fi02) and 2) DA infusion while ACh is maintained. This protocol of drug administration should reveal the excitatory role of ACh on CSND under basal condition particularly in hypoxia. Indeed, the methyl-paratyrosine with oc-methyl-paratyrosine and reserpine, which inhibits and depletes catecholamine synthesis and storage (Leitner and Roumy, 1986; Fitzgerald et al., 1983), should minimize the effects of endogenous release of DA on CSND.KeywordsArterial Blood PressureCarotid BodyExcitatory EffectDrug InfusionInspiratory Oxygen ConcentrationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

In Vivo Detection of Striatal Dopamine Release during Reward: A PET Study with [ 11C]Raclopride and a Single Dynamic Scan Approach

Anew simple method is proposed to detect, using PET and [ 11C]raclopride, changes in striatal extracellular dopamine concentration during a rewarded effortful task. This approach aimed to increase the sensitivity in detection of these effects. It requires a single-dynamic PET study and combines the classic kinetic compartmental model with the general linear model of SPM to provide statistical inference on changes in [ 11C]raclopride time–activity curve due to endogenous dopamine release during two short periods of activation. Kinetic simulations predicted that 100% dopamine increase during two 5-min periods starting at 30 and 60 min after the injection can be detected. Moreover the effects of dopamine release on the [ 11C]raclopride time-activity-curve are different from those induced by CBF increase. These simulated curves were used to construct the statistical linear model and to test voxel-by-voxel in healthy subjects the hypothesis that dopamine is released in the ventral striatum during periods of unexpected monetary gains, but not during periods of unexpected monetary loss. The experimental results are in line with the expected results although the amplitude of the effects due to dopamine release is moderate. The advantages and the limits of this method as well as the relevance of the results for dopamine involvement in reward processing are discussed.

Direct, real-time assessment of dopamine release autoinhibition in the rat caudate–putamen

Inhibition of endogenous dopamine release by photo-released dopamine (i.e., autoinhibition) was characterized in the rat caudate–putamen using combined caged-dopamine photolysis and fast-scan cyclic voltammetry. Coronal brain slices (400 μm thick) were perfused with caged-dopamine (150–200 μM in artificial cerebrospinal fluid). Ultraviolet illumination of increasing duration (25–250 ms, ∼100 μm beam diameter) was focused at the tip of the recording electrode to uncage increasing amounts of exogenous dopamine at the recording sites (0.5–5 μM); a single biphasic electrical stimulus was delivered 0.1–10 s later to induce endogenous dopamine release. The concentrations of both endogenous and exogenous dopamine were determined using voltammetry, thus enabling determination of concentration-dependent inhibition of the endogenous release by the latter. While unaffected by control ultraviolet illumination, endogenous dopamine release was rapidly inhibited by photo-released dopamine in a concentration-dependent manner. Photo-application of 3–5 μM exogenous dopamine inhibited the endogenous release by 90–100% (electrical stimulus applied 1 s after photolysis initiation), an effect prevented by 2 μM sulpiride. The autoinhibition was dependent on the time between photolysis onset and electrical stimulation. Terminal dopamine autoreceptor stimulation led to robust inhibition of endogenous dopamine release with a latency of ∼200 ms and effective duration of less than 5 s. The percent autoinhibition was a skewed, U-shaped function of photolysis/electrical stimulation intervals with the peak inhibition at 1 s. This study directly demonstrates that autoreceptor-mediated inhibition of terminal dopamine release in caudate–putamen is designed to provide a rapid, robust, yet short-lasting modulation of terminal dopamine release.

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.