Immunomodulatory Effects of Dopamine in Inflammatory Diseases

Dopamine (DA) receptor, a significant G protein-coupled receptor, is classified into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptor families, with further formation of homodimers, heteromers, and receptor mosaic. Increasing evidence suggests that the immune system can be affected by the nervous system and neurotransmitters, such as dopamine. Recently, the role of the DA receptor in inflammation has been widely studied, mainly focusing on NLRP3 inflammasome, NF-κB pathway, and immune cells. This article provides a brief review of the structures, functions, and signaling pathways of DA receptors and their relationships with inflammation. With detailed descriptions of their roles in Parkinson disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, this article provides a theoretical basis for drug development targeting DA receptors in inflammatory diseases.

PL - 022 Effects of exercise-induced fatigue on autonomic activity and dopamine metabolism in rats after D2DR modulation

Objective Objective: After injection of D2DR antagonist and agonist, the autonomic activity and striatal neurons electrical activity of rats with exercise-induced fatigue were recorded to explore the role of DA receptors in the central mechanism of exercise-induced fatigue. Methods Methods: Used male Wistar rats, randomly divided into 7 groups: control group (CG), one-time exhaustive exercise group (1FG), 3D repetitive exhaust group (3FG), and 7D repetitive exhaustion group (7FG), 7D repeated exhaustive 24h recovery group (24RG) and 7D repeated exhaustive 48h recovery group (48RG). After 1 week adaptive training in rats, rats attend 7D exhaustive treadmill exercise. Subsequently, the autonomic activity changes of each group with D2DR antagonists and agonists were observed in open filed. Used glass microelectrode extracellular recording technique to observe the dorsolateral striatum neurons change of the rats injected with D2DR antagonist spiperone. Real-time PCR (RT-PCR) molecular biology methods were used to measure the expression of D1DR and D2DR in the striatum after exercise-induced fatigue. To investigate the role of DA neurotransmitter and receptor on central mechanism of exercise-induced fatigue. Results Results: (1) With the increase of treadmill exercise load, the total distance of each group became shorter, and the recovery phase gradually recovered to a quiet level. The maximum exercise speed of rats in 7FG was significantly higher than 1FG (P<0.05).The average exercise speed of rats in each group was significantly lower than CG (P<0.05).The average speed of 7FG and 24RG were significantly lower than 1FG(P<0.05). the average movement speed of the 48RG was higher than 7FG;(2) After D2DR antagonist injection, the exhaustive time of rats was significantly lower than CG(P<0.01), while the exhaustive time of D2DR agonist intervention was significantly increased (P<0.01).The active areas of the rats in the open field were concentrated in the corners and margins. The distance of normal rats in 60 min was about 159 m. The activity of rats decreased after D2DR antagonist intervention, the movement distance of rats in CG、1FG and 48RG were significant reduced;(3) After injection of D2DR antagonist, The excitability of dorsolateral striatum neurons were affected by 56.10%, 9.76% (4/41) increased excitability, and 46.34% (19/41) decreased, the inhibitory effect of D2DR agonist was higher than excitatory effects (P<0.05);(4) RT-PCR data showed that there was no significant change in the expression of D1DR in the striatum after exercise-induced fatigue, and D2DR was significantly higher than the CG (P<0.01). Conclusions Conclusion:(1) With the increase of fatigue in rats, the total distance of exercise in each group gradually decreased;(2) Exercise-induced fatigue affects the expression of DA receptors in the striatum;(3) D2DR antagonists and agonists can affect the locomotor ability of rats;(4) D2DR antagonist can inhibit striatal neurons in rats with exercise-induced fatigue, suggesting that D2DR may be one of the drug intervention targets of exercise-induced fatigue.(NSFC: 31401018, SKXJX: 2014014).

The Hypoactivity Associated with the Repeated Exposure to Atrazine Is Related to Decreases in the Specific Binding to D1-DA Receptors in the Striatum of Rats

The herbicide atrazine (ATR) has a potential toxic effect on the neuronal circuits of the brain, specifically on two major dopaminergic pathways: the nigrostriatal and mesolimbic circuits. In this work, we repeatedly exposed adult male Sprague-Dawley rats to 6 injections of 100 mg ATR/kg of body weight (for two weeks) and one saline injection two days after ATR administration. Locomotor activity was assessed for 15 minutes and/or 2 hours after ATR or saline injection and 2 months after the final ATR administration. The specific binding of [3H]-SCH23390 to D1-DA receptors and that of [3H]-Spiperone to D2-DA receptors in the dorsal and ventral striatum were assessed 2 days and 2 months after ATR treatment. ATR administration resulted in immediate, short- and long-term hypoactivity and reduced specific binding of [3H]-SCH23390 in the dorsal striatum of rats evaluated 2 months after the last ATR injection. The specific binding of [3H]-SCH23390 in the ventral striatum and the specific binding of [3H]-Spiperone in the dorsal and ventral striatum remained unchanged at 2 days or 2 months after ATR treatment. These results, together with previous findings of our group, indicate that the nigrostriatal system is a preferential target for ATR exposure.

Targeting β-arrestin2 in the treatment of l-DOPA–induced dyskinesia in Parkinson’s disease

Parkinson’s disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursorl-3,4-dihydroxyphenylalanine (l-DOPA), but its prolonged use causes dyskinesias referred to asl-DOPA–induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PDl-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson’s symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronicl-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine–treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect ofl-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.

Perspectives of D1 dopamine antagonists using in treatment of nervous and psychic disorders with (+)-SCH-23390 as an example

The effect of dopamine (DA), its agonists and antagonists on the amplitude of GABA-activated currents of isolated multipolar spinal cord neurons (both motoneurons and interneurons) of larva of the lamprey Lampetra planeri by means of patch-clamp method in the whole cell configuration was studied. (+)-SCH-23390, a D1-DA receptors antagonist was shown to block dopamine effects on GABA-activated currents by 63.0 ± 4.7 % and by 77.1 ± 2.0 %. Effects of (-)quinpirol, a D2-DA receptors agonist, on GABA-activated currents were blocked by means of (+)-SCH-23390 by 78.8 ± 0.4 % and by 85.0 ± 5.7 %. Because of chemoactivated currents are in full accordance with a gradual scale, the results on blocking D1-DA receptors by (+)-SCH-23390 are ideal ones and that is the possible basis to further clinical aprobation of (+)-SCH-23390 for treatment of epilepsy, neurotic reactions and depression.

Neurochemical and Behavioral Features in Genetic Absence Epilepsy and in Acutely Induced Absence Seizures

The absence epilepsy typical electroencephalographic pattern of sharp spikes and slow waves (SWDs) is considered to be due to an interaction of an initiation site in the cortex and a resonant circuit in the thalamus. The hyperpolarization-activated cyclic nucleotide-gated cationic Ih pacemaker channels (HCN) play an important role in the enhanced cortical excitability. The role of thalamic HCN in SWD occurrence is less clear. Absence epilepsy in the WAG/Rij strain is accompanied by deficiency of the activity of dopaminergic system, which weakens the formation of an emotional positive state, causes depression-like symptoms, and counteracts learning and memory processes. It also enhances GABAA receptor activity in the striatum, globus pallidus, and reticular thalamic nucleus, causing a rise of SWD activity in the cortico-thalamo-cortical networks. One of the reasons for the occurrence of absences is that several genes coding of GABAA receptors are mutated. The question arises: what the role of DA receptors is. Two mechanisms that cause an infringement of the function of DA receptors in this genetic absence epilepsy model are proposed.

Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling

Dopamine (DA) D2-like autoreceptors are an important component of the DA system, but their influence on postsynaptic DA signaling is not well understood. They are, directly or indirectly, involved in drug abuse and in treatment of schizophrenia and attention deficit hyperactive disorder: DA autoreceptors influence the behavioral effect of cocaine and methylphenidate and may be the target of antipsychotic medications such as haloperidol. DA autoreceptors are active at two levels: Somatodendritic autoreceptors mainly influence firing rate of DA neurons, and presynaptic autoreceptors control release of neurotransmitter at axonal terminals. Here we develop a mathematical model that captures the dynamics of this dual autoregulation system. Our model predicts a biphasic autoreceptor response between DA terminals and somatodendritic regions that influences the postsynaptic integration of DAergic firing patterns. We applied our model to study how DA uptake inhibition affects the translation of DA cell firing into activation of postsynaptic DA receptors. While uptake inhibition increased tonic activation of low-affinity postsynaptic receptors, high-affinity state receptors saturated and thus became insensitive to phasic DA signaling. This effect had remarkable regional specificity: While high-affinity DA receptors saturated at low levels of uptake inhibition in nucleus accumbens, they only saturated at higher levels of uptake inhibition in dorsal striatum. Based on high-affinity receptor saturation, the model predicted that removal of autoreceptor control would lead to cocaine hypersensitivity.

Corticostriatal Plastic Changes in Experimental L-DOPA-Induced Dyskinesia

In Parkinson’s disease (PD), alteration of dopamine- (DA-) dependent striatal functions and pulsatile stimulation of DA receptors caused by the discontinuous administration of levodopa (L-DOPA) lead to a complex cascade of events affecting the postsynaptic striatal neurons that might account for the appearance of L-DOPA-induced dyskinesia (LID). Experimental models of LID have been widely used and extensively characterized in rodents and electrophysiological studies provided remarkable insights into the inner mechanisms underlying L-DOPA-induced corticostriatal plastic changes. Here we provide an overview of recent findings that represent a further step into the comprehension of mechanisms underlying maladaptive changes of basal ganglia functions in response to L-DOPA and associated to development of LID.