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Neuropharmacology Sep 2024Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and...
Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [H]raclopride on dopamine D2/3 receptors, [H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [H]UCB-J and [H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.
Topics: Animals; Swine, Miniature; Swine; Sucrose; Male; Receptor, Metabotropic Glutamate 5; Receptors, Cannabinoid; Synapses; Receptor, Cannabinoid, CB1; Receptors, Dopamine D2; Brain; Female; Receptors, Dopamine D3
PubMed: 38810925
DOI: 10.1016/j.neuropharm.2024.110018 -
Journal of Pharmacological and... 2024Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an...
Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry.
Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D), histamine 1 (H), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 μg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 μg/kg raclopride, 10 μg/kg doxepin, and 30 μg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D, H and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D, H, and mACh receptor occupancy is possible using LC-MS/MS.
Topics: Animals; Tandem Mass Spectrometry; Rats; Male; Antipsychotic Agents; Chromatography, Liquid; Receptors, Dopamine D2; Rats, Sprague-Dawley; Receptors, Muscarinic; Receptors, Histamine H1; Olanzapine; Brain; Benzodiazepines; Raclopride; Doxepin; Quinuclidinyl Benzilate; Dose-Response Relationship, Drug
PubMed: 38797366
DOI: 10.1016/j.vascn.2024.107518 -
Cortex; a Journal Devoted To the Study... Jul 2024Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation....
Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.
Topics: Humans; Receptors, Dopamine D2; Memory, Episodic; Hippocampus; Brain-Derived Neurotrophic Factor; Male; Female; Aged; Genotype; Aging; Polymorphism, Single Nucleotide; Middle Aged; Memory Disorders; Longitudinal Studies; Polymorphism, Genetic; Neuropsychological Tests; Aged, 80 and over; Intracellular Signaling Peptides and Proteins
PubMed: 38749085
DOI: 10.1016/j.cortex.2024.01.014 -
European Journal of Nuclear Medicine... May 2024Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion,...
PURPOSE
Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized.
METHODS
Based on a historical database of healthy human brain [C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex.
RESULTS
Daylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26 h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability.
CONCLUSIONS
Seasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.
PubMed: 38730083
DOI: 10.1007/s00259-024-06715-9 -
Psychopharmacology Jun 2024Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i)... (Review)
Review
RATIONALE
Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory.
OBJECTIVES
The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion.
CONCLUSIONS
The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.
Topics: Dopamine; Animals; Humans; Receptors, Dopamine D1; Receptors, Dopamine D2; Time Factors; Dopamine Antagonists; Reward; Eating; Drinking Behavior; Dopamine D2 Receptor Antagonists
PubMed: 38702473
DOI: 10.1007/s00213-024-06600-1 -
Journal of Affective Disorders Jul 2024Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating...
BACKGROUND
Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD.
METHODS
Six patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BP) with the cerebellum as reference tissue.
RESULTS
Depression and anxiety symptoms improved after 3-6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [C]raclopride BP in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01).
LIMITATIONS
This study was limited to the small sample size and lack of a healthy control group.
CONCLUSIONS
Chronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.
Topics: Humans; Receptors, Dopamine D2; Deep Brain Stimulation; Male; Positron-Emission Tomography; Female; Middle Aged; Depressive Disorder, Treatment-Resistant; Nucleus Accumbens; Adult; Raclopride; Septal Nuclei; Brain; Treatment Outcome
PubMed: 38657771
DOI: 10.1016/j.jad.2024.04.082 -
BMJ Open Apr 2024Bariatric surgery (BS) is the treatment of choice for refractory obesity. Although weight loss (WL) reduces the prevalence of obesity-related comorbidities, not all...
Portuguese observational cross-sectional clinical imaging study protocol to investigate central dopaminergic mechanisms of successful weight loss through bariatric surgery.
INTRODUCTION
Bariatric surgery (BS) is the treatment of choice for refractory obesity. Although weight loss (WL) reduces the prevalence of obesity-related comorbidities, not all patients maintain it. It has been suggested that central mechanisms involving dopamine receptors may play a role in successful WL. This protocol describes an observational cross-sectional study to test if the binding of central dopamine receptors is similar in individuals who responded successfully to BS and age- and gender-matched normal-weight healthy individuals (controls). As secondary goals, the protocol will investigate if this binding correlates with key parameters such as age, hormonal status, anthropometric metrics and neurobehavioural scores. Finally, as exploratory goals, we will include a cohort of individuals with obesity before and after BS to explore whether obesity and type of BS (sleeve gastrectomy and Roux-en-Y gastric bypass) yield distinct binding values and track central dopaminergic changes resulting from BS.
METHODS AND ANALYSIS
To address the major research question of this observational study, positron emission tomography (PET) with [C]raclopride will be used to map brain dopamine type 2 and 3 receptors (D2/3R) non-displaceable binding potential (BP) of individuals who have successfully responded to BS. Mean regional D2/3R BP values will be compared with control individuals by two one-sided test approaches. The sample size (23 per group) was estimated to demonstrate the equivalence between two independent group means. In addition, these binding values will be correlated with key parameters to address secondary goals. Finally, for exploratory analysis, these values will be compared within the same individuals (before and after BS) and between individuals with obesity and controls and types of BS.
ETHICS AND DISSEMINATION
The project and informed consent received ethical approval from the Faculty of Medicine and the Coimbra University Hospital ethics committees. Results will be disseminated in international peer-reviewed journals and conferences.
Topics: Humans; Obesity, Morbid; Cross-Sectional Studies; Portugal; Bariatric Surgery; Gastric Bypass; Obesity; Weight Loss; Positron-Emission Tomography; Receptors, Dopamine; Observational Studies as Topic
PubMed: 38569700
DOI: 10.1136/bmjopen-2023-080702 -
Neuropharmacology May 2024Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays...
Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potency in addressing this particular issue remains to be determined. Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity. CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.
Topics: Mice; Animals; Male; Cannabidiol; Hyperalgesia; Sleep Deprivation; Dopamine; Mice, Inbred C57BL; Receptors, Dopamine D2; Nucleus Accumbens; Pain; Receptors, Dopamine D1; Analgesics; Mice, Transgenic
PubMed: 38428482
DOI: 10.1016/j.neuropharm.2024.109893 -
NeuroImage. Clinical 2024Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls.
PURPOSE
Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls.
METHODS
Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (DR) availability using [C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson's disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in DR availability. We also analyzed the interregional correlation in DR availability within each group.
RESULTS
Subjects with PD showed the clearest decline in DR availability. Overall, the groups showed high interregional correlation in DR availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation.
CONCLUSION
We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also how coupled regions are across people. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region coupling might be disrupted in violence.
Topics: Humans; Overweight; Receptors, Dopamine D2; Tomography, X-Ray Computed; Positron-Emission Tomography; Corpus Striatum; Dopamine; Parkinson Disease
PubMed: 38395027
DOI: 10.1016/j.nicl.2024.103578 -
Behavioural Pharmacology Feb 2024Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also...
Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also with some serotonin 5-HT2B/7 effects. The present study examined the role of D2/3 receptors and 5-HT2B/7 receptors in amisulpride's discriminative stimulus. Selective agonists and antagonists of the above receptors were tested in adult, male C57BL/6 mice trained to discriminate 10 mg/kg amisulpride from vehicle in a two-lever drug discrimination assay. After acquisition of the two-lever discrimination, the amisulpride generalization curve yielded an ED50 = 0.56 mg/kg (95% CI = 0.42-0.76 mg/kg). Substitution tests found that the D2/3 antagonist raclopride (62.7% Drug Lever Responding), D2/3 agonist quinpirole (56.6% DLR), 5-HT7 agonist LP-44 (50.1% DLR) and 5-HT7 antagonist SB-269970 (36.7% DLR) produced various degrees of partial substitution for the amisulpride stimulus, whereas the 5-HT2B agonist BW 723C86 (17.9% DLR) and 5-HT2B antagonist SB-204741 (21.1% DLR) yielded negligible amisulpride-like effects. In combination tests with amisulpride, quinpirole decreased percent responding from 98.3% to 57.0% DLR, LP-44 decreased percent responding from 97.6% to 76.7% DLR, and BW 723C86 reduced percent responding from 95.66% to 74.11% DLR. Taken together, the results from stimulus generalization and antagonism studies suggest that amisulpride has a complex discriminative cue that involves mainly mixed D2/3 receptor antagonist/agonist effects and, to a lesser degree, mixed 5-HT7 receptor agonist/antagonist and perhaps 5-HT2B receptor antagonist effects.
Topics: Mice; Animals; Male; Antipsychotic Agents; Amisulpride; Quinpirole; Mice, Inbred C57BL; Dose-Response Relationship, Drug; Discrimination Learning; Indoles; Piperazines; Tetrahydronaphthalenes; Thiophenes
PubMed: 38375659
DOI: 10.1097/FBP.0000000000000760