| 1. |
- Andersson, Mikael, et al.
(författare)
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Subchronic haloperidol increases CB(1) receptor binding and G protein coupling in discrete regions of the basal ganglia.
- 2005
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 82:2, s. 264-72
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Tidskriftsartikel (refereegranskat)abstract
- The present study was designed to test whether chronic neuroleptic treatment, which is known to alter both expression and density of dopamine D(2) receptors in striatal regions, has effects upon function and binding level of the cannabinoid CB(1) receptor in the basal ganglia by using receptor autoradiography. As predicted, subchronic haloperidol treatment resulted in increased binding of (3)H-raclopride and quinpirole-induced guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) in the striatum when compared to that measured in control animals. This increased D(2) receptor binding and function after 3 days washout was normalized after a 2-week washout period. Effect of haloperidol treatment was studied for CB(1) receptor binding and CP55,940-stimulated [(35)S]GTPgammaS in the striatum, globus pallidus, and substantia nigra. (3)[H]CP55,940 binding levels were found in rank order from highest to lowest in substantia nigra > globus pallidus > striatum. Furthermore, subchronic haloperidol treatment resulted in elevated binding levels of (3)[H]CP55,940 in the striatum and the substantia nigra and CB(1) receptor-stimulated [(35)S]GTPgammaS bindings in the substantia nigra after 3 days washout. These increased binding levels were normalized at 1-4 weeks after termination of haloperidol treatment. Haloperidol treatment had no significant effect on CB(1) receptor or [(35)S]GTPgammaS binding levels in globus pallidus. The results help to elucidate the underlying biochemical mechanism of CB(1) receptor supersensitivity after haloperidol treatment.
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| 2. |
- Asser, Andres, et al.
(författare)
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Acute effects of methcathinone and manganese in mice : A dose response study
- 2019
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Ingår i: Heliyon. - : ELSEVIER SCI LTD. - 2405-8440. ; 5:9
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Tidskriftsartikel (refereegranskat)abstract
- An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.
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| 3. |
- Björk, Karl, et al.
(författare)
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Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors
- 2010
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Ingår i: Addiction Biology. - : Wiley-Blackwell. - 1355-6215 .- 1369-1600. ; 15:3, s. 299-303
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Tidskriftsartikel (refereegranskat)abstract
- The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways, but intracellular mediators of such interactions are poorly understood. Here we report that an acute ethanol challenge induces a robust phosphorylation of two key signal transduction kinases, AKT and DARPP-32, in the striatum of mice. Ethanol-induced AKT phosphorylation was blocked by the opioid receptor antagonist naltrexone but unaffected by blockade of dopamine D2 receptors via sulpiride. In contrast, DARPP-32 phosphorylation was abolished by both antagonists. These data suggest that ethanol acts via two distinct but potentially synergistic striatal signaling cascades. One of these is D2-dependent, while the other is not. These findings illustrate that pharmacology of ethanol reward is likely more complex than that for other addictive drugs.
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| 4. |
- Terasmaa, Anton
(författare)
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Dopamine D2 receptor G protein coupling and it's regulation
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dopamine (DA) receptors belong to the superfamily of G protein coupled receptors. The D2 DA receptor is negatively coupled with adenylate cyclase via pertussis toxin sensitive (Gi/o) G proteins. In the brain the D2 DA receptor is mainly expressed in the caudate-putamen, the nucleus accumbens and the olfactory tubercle but also in the substantia nigra and the ventral tegmental area. The nigrostriatal dopaminergic system innervates the dorsal striatum. Most of the dorsal striatal D2 DA receptors are localized on the cell bodies of striatopallidal inhibitory GABAergic neurons that send their projections to the globus pallidus. DA D2 agonists inhibit striatopallidal GABA-ergic neurons thereby increasing motor activity since in this way the indirect pathway of the basal ganglia mediating motor inhibition will be inhibited. Degeneration of the nigrostriatal DA neurons causes a marked decrease in striatal DA levels and inhibition of motor functions. These changes are associated with a marked supersensitivity development in the striatal D2 receptors. In a hemiparkinsonian rat model with 6-hydroxydopamine (6-OHDA) induced unilateral lesions of the nigrastriatal DA system D2 agonists induce a strong contralateral rotational behaviour in very low doses due to preferential activation of the supersensitive D2 receptors on the DA denervated side. The aim of this study was to characterize in the above model potential changes in the coupling of the D2 receptor to the Gi/o protein that may play a role in the D2 receptor supersensitivity development. [35S]-guanosine 5'-0-(gamma-thio) triphosphate ([35S]GTP-gamma-S) binding as a method for direct visualization of G protein activation by receptors was adapted to study D2short receptors and their signalling in CHO cells transfected with the D2 receptor. Pharmacological characterization of 18 dopaminergic ligands revealed a good correlation of potencies of all ligands to modulate [35S]GTP-gamma-S binding with their potencies to inhibit [3H]raclopride binding. Also efficacies of dopaminergic ligands at D2 receptor were characterized. It was found that serotonin and other serotoninergic agonists have partial agonistic activity at the D2 receptor expressed in CHO cells. Studies on [35 [35S]GTP-gamma-S, [3 H]DA and [3H]-raclopride binding were used to investigate the cross regulation between G proteins and D2 DA receptors expressed in CHO cells. The obtained results indicate that not only analogues of GTP but a] so GDP and GMP turned D2 DA receptors into a low affinity state for DA. On the other hand, activation of the D2 receptor by DA caused a decrease in the binding affinity for GDP, but not for analogues of GTP. According to these results, the high-affinity state of agonist binding can be achieved only when no nucleotides are bound in the agonist receptor-G protein complex. The role of G-proteins in D2 receptor supersensitivity was studied in striatal membranes from rats with unilateral 6OHDA induced lesions of the nigrostriatal DA cells. The number of [ 3 H]raclopride binding sites was increased in the DA denervated striatum, but no changes in ligand binding affinities and in proportion of high-affinity agonist binding sites could be detected. The number and the affinity of [35S]GTP-gamma-S binding sites was unaltered after the striatal DA denervation, whereas the binding affinity of GDP was decreased in the DA denervated versus the intact striatum. It is proposed that the decrease in GDP binding affinity to D2 DA receptor-coupled G proteins is an important factor in D2 receptor supersensitivity appearing after degeneration of the striatal DA terminals. DSP4 induced lesions of locus coeruleus (LC) noradrenergic neurons influence the ascending mesencephalic DA systems by reducing striatal DA turnover and inducing behavioural supersensitivity to dopaminergic drugs, the latter effect being similar to that observed after the loss of striatal DA terminals. The density of striatal D2 receptors was increased following DSP4 treatment as also is the case after DA denervation of the striatum. In contrast, such NA lesions had no effect on D2 receptor G protein coupling as found after DA denervation. It is known that Ca2+/calmodulin suppresses the D2 receptor signaling by interacting with the calmodulin binding motif of the D2 receptor located in the N-terminal part of the third intracellular loop of the D2 receptor. This motif is also part of the A2A/D2 heterodimer interface and A2A strongly antagonizes the D2 signalling within the A2A/D2 heterodimer. It is demonstrated that in the A2A/D2 cotransfected, but not in the D2 alone transfected CHO cells, expressing endogenous calmodulin, Ca2+ substantially increases the basal and DA stimulated [35S]GTP-gamma-S binding. These results may be explained on the basis of a competition between calmodulin and A2A for their overlapping binding motifs at the D2 receptor. The results illustrate the dynamic interplay of A2A/D2 heterodimers and the D2 interacting protein in control of the D2 signalling.
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