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Neurochemical Research May 2023Values of binding potentials (BP) of dopamine D receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due...
Values of binding potentials (BP) of dopamine D receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D receptor availabilities vary with age in vivo in humans by determining the values of BP of the specific radioligand [C]raclopride. We determined values of BP in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BP in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BP in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BP used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BP declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.
Topics: Humans; Adult; Young Adult; Dopamine; Receptors, Dopamine D2; Brain; Raclopride; Corpus Striatum; Positron-Emission Tomography; Receptors, Dopamine D3
PubMed: 36525123
DOI: 10.1007/s11064-022-03825-4 -
Journal of Physiology and Pharmacology... Jun 2022Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary...
Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary circulation, even the vascular effect of activation of the dopamine D and D subtypes in physiological and pathological conditions such as pulmonary hypertension is unknown. The objective of this study was to evaluate the vascular response of trunk pulmonary artery rings from saline and monocrotaline-treated rats in the presence of selective dopamine receptor agonists. In trunk pulmonary artery rings with intact and denuded endothelium, cumulative concentration-response curves were performed for phenylephrine, acetylcholine, and dopamine receptor agonists (apomorphine-D2-like, SKF38393-D, quinpirole-D/D, 7-OH-DPATD, and PD168077-D) alone and in the presence of corresponding selective dopamine receptor antagonists (SCH23390-D, raclopride-D/D, U99194 maleate-D, and L-745,870-D). Contractile and relaxant effects generated during the activation with phenylephrine and acetylcholine, respectively, were significantly reduced in intact and denuded endothelium trunk pulmonary artery rings from monocrotaline rats in comparison with control rats. All dopamine receptor agonists, except the 7-OH-DPAT, produced significant vascular relaxation in intact trunk pulmonary artery rings precontracted with phenylephrine in both experimental groups. Also, the vascular relaxation of SKF38393, and particularly apomorphine and PD168077 was significant in denuded endothelium trunk pulmonary artery rings from control and monocrotaline groups. Furthermore, the vasorelaxation induced by these dopamine agonists was significantly reduced in pulmonary preparations from monocrotaline-treated rats in comparison to that recorded in preparations from control rats. The effect of dopamine receptor agonists decreased significantly in the presence of the corresponding antagonist in both experimental groups. The results support that dopamine D receptor agonist induces significant vascular relaxation, whereas dopamine D receptor agonist induces vasoconstriction in intact and denuded endothelium trunk pulmonary artery rings in control and monocrotaline-induced pulmonary arterial hypertension rats.
Topics: Rats; Animals; Dopamine Agonists; Dopamine; Apomorphine; Receptors, Dopamine D2; Pulmonary Artery; Monocrotaline; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acetylcholine; Phenylephrine
PubMed: 36515630
DOI: 10.26402/jpp.2022.3.15 -
Frontiers in Human Neuroscience 2022Autonomous motivation to exercise occurs when the activity is voluntary and with a perceived inherent satisfaction from the activity itself. It has been suggested that...
BACKGROUND
Autonomous motivation to exercise occurs when the activity is voluntary and with a perceived inherent satisfaction from the activity itself. It has been suggested that autonomous motivation is related to striatal dopamine D2/3-receptor (D2/3R) availability within the brain. In this study, we hypothesized that D2/3R availability in three striatal regions (nucleus accumbens, caudate nucleus, and putamen) would be positively associated with self-reported autonomous motivation to exercise. We also examined this relationship with additional exploratory analyses across a set of extrastriatal regions of interest (ROI).
METHODS
Our sample comprised 49 older adults (28 females) between 64 and 78 years of age. The D2/3R availability was quantified from positron emission tomography using the non-displaceable binding potential of [C]-raclopride ligand. The exercise-related autonomous motivation was assessed with the Swedish version of the Behavioral Regulations in Exercise Questionnaire-2.
RESULTS
No significant associations were observed between self-reported autonomous motivation to exercise and D2/3R availability within the striatum (nucleus accumbens, caudate nucleus, and putamen) using semi-partial correlations controlling for ROI volume on D2/3R availability. For exploratory analyses, positive associations were observed for the superior ( = 0.289, = 0.023) and middle frontal gyrus ( = 0.330, = 0.011), but not for the inferior frontal gyrus, orbitofrontal cortex, anterior cingulate cortex, or anterior insular cortex.
CONCLUSION
This study could not confirm the suggested link between striatal D2/3R availability and subjective autonomous motivation to exercise among older adults. The exploratory findings, however, propose that frontal brain regions may be involved in the intrinsic regulation of exercise-related behaviors, though this has to be confirmed by future studies using a more suitable ligand and objective measures of physical activity levels.
PubMed: 36438629
DOI: 10.3389/fnhum.2022.997131 -
Reproductive Medicine and Biology 2022In humans, catecholamines (including dopamine) have been identified in semen and fallopian tubes, while dopamine D2 receptors (D2DR) are found in the sperm midpiece...
PURPOSE
In humans, catecholamines (including dopamine) have been identified in semen and fallopian tubes, while dopamine D2 receptors (D2DR) are found in the sperm midpiece region. How dopamine dose affects human sperm function and whether dopamine treatment is useful in assisted reproductive technology is unclear.
METHODS
Sperm samples were obtained from patients with normal semen parameters undergoing fertility treatment. We investigated the effects of dopamine treatment on tyrosine phosphorylation and sperm motility. Sperm motility was analyzed using the computer-assisted sperm analysis (CASA) system.
RESULTS
This study revealed that various dopamine concentrations (0.1-100 μM) did not increase sperm tyrosine phosphorylation. Progressive motility increased substantially when treated with high concentrations of dopamine (10 and 100 μM) and was blocked by raclopride (a D2DR antagonist). After 24-h sperm culture, the addition of 10 μM dopamine significantly increased curvilinear velocity and amplitude of lateral head displacement, which are indicators of hyperactivation.
CONCLUSION
Dopamine did not affect tyrosine phosphorylation, but increased sperm motility. High concentrations of dopamine were more effective to accelerate sperm motility in cases where sperm motile capacity was low.
PubMed: 36310655
DOI: 10.1002/rmb2.12482 -
Psychopharmacology Dec 2022The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical...
RATIONALE
The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches.
OBJECTIVES
In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae.
METHODS
Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format.
RESULTS
METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems.
CONCLUSIONS
These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.
Topics: Animals; Zebrafish; Methamphetamine; Larva; Dopamine; Seizures; Excitatory Amino Acid Antagonists
PubMed: 36269378
DOI: 10.1007/s00213-022-06252-z -
Brain Research Dec 2022Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male...
Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male and female rats with spared nerve injury (SNI) model of neuropathy. SNI induced mechanical hypersensitivity that was stronger in females. Reversible blocking of the CeA with muscimol (GABA receptor agonist) induced a reduction of mechanical hypersensitivity that did not differ between males and females. Following spinal co-administration of atipamezole (α-adrenoceptor antagonist), the reduction of mechanical hypersensitivity by CeA muscimol was attenuated more in males than females. In contrast, following spinal co-administration of raclopride (dopamine D2 receptor antagonist) the reduction of hypersensitivity by CeA muscimol was attenuated more in females than males. The reduction of mechanical hypersensitivity by CeA muscimol was equally attenuated in males and females by spinal co-administration of WAY-100635 (5-HT receptor antagonist) or bicuculline (GABA receptor antagonist). The CeA muscimol induced attenuation of ongoing pain-like behavior (conditioned place preference test) that was reversed by spinal co-administration of atipamezole in both sexes. The results support the hypothesis that CeA contributes to mechanical hypersensitivity and ongoing pain-like behavior in SNI males and females. Disinhibition of descending controls acting on spinal α-adrenoceptors, 5-HT, dopamine D2 and GABA receptors provides a plausible explanation for the reduction of mechanical hypersensitivity by CeA block in SNI. The involvement of spinal dopamine D2 receptors and α-adrenoceptors in the CeA muscimol-induced reduction of mechanical hypersensitivity is sexually dimorphic, unlike that of spinal α-adrenoceptors in the reduction of ongoing neuropathic pain.
Topics: Female; Rats; Male; Animals; Muscimol; Receptors, GABA-A; Neuralgia; Amygdala; Receptors, Neurotransmitter; GABA-A Receptor Antagonists; Receptors, Adrenergic
PubMed: 36265669
DOI: 10.1016/j.brainres.2022.148128 -
Toxicology and Applied Pharmacology Dec 2022The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early...
The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D receptors in both schizophrenia and addiction, we further tested their role by exposing mice to raclopride. Adolescent mice that were either exposed to nicotine (24 mg/Kg/day) or not, received single daily raclopride (0.5 mg/kg, s.c.) or saline followed by phencyclidine injections (10 mg/Kg, s.c.) during open field testing for 6 consecutive days (Acquisition phase, ACQ). Phencyclidine and nicotine challenges (Sensitization Test, ST) were carried out after a 5-day withdrawal. Ambulation escalated in response to repeated phencyclidine exposure during ACQ and was increased after phencyclidine challenge, evidencing development and expression of locomotor sensitization. Raclopride prevented phencyclidine-evoked development of sensitization. However, raclopride pre-exposure during ACQ only shortened its expression in phencyclidine-challenged mice. Nicotine failed to interfere with phencyclidine stimulatory effects during ACQ but potentiated raclopride inhibition during the first ACQ days. During ST, nicotine history shortened the expression of phencyclidine-evoked sensitization. Nicotine challenge had no impact on locomotion, which is consistent with a lack of nicotine/phencyclidine cross-sensitization. In conclusion, our results show that nicotine does not worsen, and may even ameliorate phencyclidine-sensitized psychotic-like behavior in adolescent mice. The potentiation of raclopride-mediated inhibition further suggests that nicotine transiently improves the therapeutic efficacy of medication on psychotic symptoms through mechanisms that converge on D receptors.
Topics: Mice; Animals; Phencyclidine; Nicotine; Raclopride; Locomotion; Motor Activity; Receptors, Dopamine
PubMed: 36252887
DOI: 10.1016/j.taap.2022.116282 -
IEEE Transactions on Radiation and... Apr 2022PET imaging of small animals is often used for assessing biodistribution of a novel radioligand and pharmacology in small animal models of disease. PET acquisition and...
PET imaging of small animals is often used for assessing biodistribution of a novel radioligand and pharmacology in small animal models of disease. PET acquisition and processing settings may affect reference region or image-derived input function (IDIF) kinetic modeling estimates. We examined four different factors in comparing quantitative results: 1) effect of reconstruction algorithm, 2) number of MAP iterations, 3) strength of the MAP prior, and 4) Attenuation and scatter. The effect of these parameters has not been explored for small-animal reference region and IDIF kinetic modeling approaches. Dynamic PET/CT scans were performed in 3 species with 3 different tracers: house sparrows with [C]raclopride, rats with [F]AS2471907 (11HSD1) and mice with [C]UCB-J (SV2A). FBP yielded lower kinetic modeling estimates compared to 3D-OSEM-MAP reconstructions, in sparrow and rat studies. Target resolutions (MAP prior strength) of 1.5 and 3.0mm demonstrated reduced in rats but only 3.0mm reduced BP in sparrows. Therefore, use of the highest target resolution (0.8mm) is warranted. We demonstrated using kinetic modeling that forgoing CT-based attenuation and scatter correction may be appropriate to improve animal throughput when using short-lived radioisotopes in sparrows and mice. This work provides recommendations and a framework for future optimization of kinetic modeling for preclinical PET methodology with novel radioligands.
PubMed: 36185820
DOI: 10.1109/trpms.2021.3088606 -
Communications Biology Sep 2022Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between...
Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between blink rates, measured after oral placebo) (PL) and after a challenge with oral methylphenidate (MP; 60 mg) and striatal D1 receptor (D1R) (measured at baseline) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R ([C]NNC112) (BL-D1R) and D2R availability ([C]raclopride) after PL (PL-D2R) and after MP (MP-D2R) were quantified in the striatum as non-displaceable binding potential. MP reduced the number of blinks and increased the time participants kept their eyes open. Correlations with dopamine receptors were only significant for the eye blink measures obtained after MP; being positive for BL-D1R in putamen and MP-D2R in caudate (PL-D2R were not significant). MP-induced changes in blink rates (PL minus MP) were negatively correlated with BL-D1R in caudate and putamen. Our findings suggest that eye blink measures obtained while stressing the dopamine system might provide a more sensitive behavioral biomarker of striatal D1R or D2R in healthy volunteers than that obtained at baseline or after placebo.
Topics: Corpus Striatum; Dopamine; Humans; Methylphenidate; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 36163254
DOI: 10.1038/s42003-022-03979-5 -
Neuropharmacology Dec 2022Adrenergic receptors (AR) in the ventral tegmental area (VTA) modulate local neuronal activity and, as a consequence, dopamine (DA) release in the mesolimbic forebrain....
Adrenergic receptors (AR) in the ventral tegmental area (VTA) modulate local neuronal activity and, as a consequence, dopamine (DA) release in the mesolimbic forebrain. Such modulation has functional significance: intra-VTA blockade of α-AR attenuates behavioral responses to salient environmental stimuli in rat models of drug seeking and conditioned fear as well as phasic DA release in the nucleus accumbens (NAc). In contrast, α-AR in the VTA has been suggested to act primarily as autoreceptors, limiting local noradrenergic input. The regulation of noradrenaline efflux by α-AR could be of clinical interest, as α-AR agonists are proposed as promising pharmacological tools in the treatment of PTSD and substance use disorder. Thus, the aim of our study was to determine the subtype-specificity of α-ARs in the VTA capable of modulating phasic DA release. We used fast scan cyclic voltammetry (FSCV) in anaesthetized male rats to measure DA release in the NAc after combined electrical stimulation and infusion of selected α-AR antagonists into the VTA. Intra-VTA microinfusion of idazoxan - a non-subtype-specific α-AR antagonist, as well as BRL-44408 - a selective α-AR antagonist, attenuated electrically-evoked DA in the NAc. In contrast, local administration of JP-1302 or imiloxan (α- and α-AR antagonists, respectively) had no effect. The effect of BRL-44408 on DA release was attenuated by intra-VTA DA D antagonist (raclopride) pre-administration. Finally, we confirmed the presence of α-AR protein in the VTA using western blotting. In conclusion, these data specify α-, but not α- or α-AR as the receptor subtype controlling NA release in the VTA.
Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Autoreceptors; Dopamine; Idazoxan; Male; Norepinephrine; Nucleus Accumbens; Raclopride; Rats; Receptors, Adrenergic, alpha-1; Ventral Tegmental Area
PubMed: 36116534
DOI: 10.1016/j.neuropharm.2022.109258