Dopamine D4 receptor gene expression plays important role in extinction and reinstatement of cocaine-seeking behavior in mice.

Dopamine D4 receptor (DRD4) dysregulation is associated with a variety of behaviors including novelty-seeking, approach avoidance, and ADHD. DRD4 has also been shown to interact with the environment to produce changes in behavior and longevity. The present study sought to examine the role of DRD4 on cocaine-seeking behavior in the conditioned place preference (CPP) test and determine its effects on extinction and reinstatement in adult wild-type (WT), heterozygous (HT), and knockout (KO) mice. Results revealed that all mice, regardless of sex or genotype, developed a similar acquisition for a cocaine place preference. Female DRD4 KO mice failed to extinguish their preference for the cocaine-paired chamber following the extinction period. Male DRD4 KO mice failed to reinstate their preference after a priming dose following successful extinction. No differences in locomotor activity were observed within drug treatment conditions due to genotype, and female mice displayed reduced locomotor activity during CPP conditioning compared to male mice. The observed effects illustrate the role DRD4 gene expression has on extinction and reinstatement, but not acquisition, of cocaine-seeking behavior.

Dopamine receptor DR2 expression in B cells is negatively correlated with disease activity in rheumatoid arthritis patients.

OBJECTIVE: Dopamine receptor (DR) signaling is involved in the pathogenesis of autoimmune diseases. We aimed to measure the expression levels of DR1-5 on B cells from patients with rheumatoid arthritis (RA) and to analyze the relationship between DRs and clinical manifestations, inflammatory biomarkers, functional status and disease activity. METHODS: A total of 29 patients with RA, 12 healthy donors and 12 patients with osteoarthritis (OA) were recruited in this study. Flow cytometry was used to measure the levels of DR1-5 expressed on B cells. The relationships between B cell DR expressions and clinical features in RA patients were analyzed using the Spearman correlation test. RESULTS: The expression levels of B cell DR1-5 in both the RA and OA groups were lower than those in healthy controls. After 3 months of medication, all five receptors were elevated in RA patients, with DR2 and DR3 being significantly increased from the baseline. DR2 expression on B cells was negatively correlated with inflammatory biomarkers and disease activity. CONCLUSION: RA patients had lower expression level of DR2 on B cells compared to the healthy controls, and the level of DR2 negatively correlated with the disease activity. DR2 and DR3 might be novel predictors of patient responses to disease modifying antirheumatic drug therapy.

Adenosine and dopamine receptors coregulate photoreceptor coupling via gap junction phosphorylation in mouse retina.

Gap junctions in retinal photoreceptors suppress voltage noise and facilitate input of rod signals into the cone pathway during mesopic vision. These synapses are highly plastic and regulated by light and circadian clocks. Recent studies have revealed an important role for connexin36 (Cx36) phosphorylation by protein kinase A (PKA) in regulating cell-cell coupling. Dopamine is a light-adaptive signal in the retina, causing uncoupling of photoreceptors via D4 receptors (D4R), which inhibit adenylyl cyclase (AC) and reduce PKA activity. We hypothesized that adenosine, with its extracellular levels increasing in darkness, may serve as a dark signal to coregulate photoreceptor coupling through modulation of gap junction phosphorylation. Both D4R and A2a receptor (A2aR) mRNAs were present in photoreceptors, inner nuclear layer neurons, and ganglion cells in C57BL/6 mouse retina, and showed cyclic expression with partially overlapping rhythms. Pharmacologically activating A2aR or inhibiting D4R in light-adapted daytime retina increased photoreceptor coupling. Cx36 among photoreceptor terminals, representing predominantly rod-cone gap junctions but possibly including some rod-rod and cone-cone gap junctions, was phosphorylated in a PKA-dependent manner by the same treatments. Conversely, inhibiting A2aR or activating D4R in daytime dark-adapted retina decreased Cx36 phosphorylation with similar PKA dependence. A2a-deficient mouse retina showed defective regulation of photoreceptor gap junction phosphorylation, fairly regular dopamine release, and moderately downregulated expression of D4R and AC type 1 mRNA. We conclude that adenosine and dopamine coregulate photoreceptor coupling through opposite action on the PKA pathway and Cx36 phosphorylation. In addition, loss of the A2aR hampered D4R gene expression and function.

Disease-specific expression of the serotonin-receptor 5-HT(2C) in natural killer cells in Alzheimer's dementia.

Alzheimer's dementia (AD) is a degenerative brain disorder characterized mainly by cholinergic failure, but other neuro-transmitters are also deficient especially at late stages of the disease. Misfolded ß-amyloid peptide has been identified as a causative agent, however inflammatory changes also play a pivotal role. Even though the most prominent pathology is seen in the cognitive functions, specific abnormalities of the central nervous system (CNS) are also reflected in the periphery, particularly in the immune responses of the body. The aim of this study was to characterize the dopaminergic and serotonergic systems in AD, which are also markedly disrupted along with the hallmark acetyl-choline dysfunction. Peripheral blood mono-nuclear cells (PBMCs) from demented patients were judged against comparison groups including individuals with late-onset depression (LOD), as well as non-demented and non-depressed subjects. Cellular sub-populations were evaluated by mono-clonal antibodies against various cell surface receptors: CD4/CD8 (T-lymphocytes), CD19 (B-lymphocytes), CD14 (monocytes), and CD56 (natural-killer (NK)-cells). The expressions of dopamine D(3) and D(4), as well as serotonin 5-HT(1A), 5-HT(2A), 5-HT(2B) and 5-HT(2C) were also assessed. There were no significant differences among the study groups with respect to the frequency of the cellular sub-types, however a unique profound increase in 5-HT(2C) receptor exclusively in NK-cells was observed in AD. The disease-specific expression of 5-HT(2C), as well as the NK-cell cyto-toxicity, has been linked with cognitive derangement in dementia. These changes not only corroborate the existence of bi-directional communication between the immune system and the CNS, but also elucidate the role of inflammatory activity in AD pathology, and may serve as potential biomarkers for less invasive and early diagnostic purposes as well.

Dopamine receptors in human peripheral blood lymphocytes: changes in mRNA expression in opioid addiction.

Gradual adaptations of the brain to repeated drug exposure may induce addiction. Brain mesolimbic dopaminergic pathway is the site of the effect of addictive drugs. The dopamine receptors in peripheral blood lymphocytes may reflect the status of homologous brain receptors. In the present study, the effects of opioid addiction on mRNA expression of dopamine D(3), D(4) and D(5) receptors in human peripheral blood lymphocytes were investigated, using a real-time PCR method. Four groups each comprising 30 individuals were enrolled in the study: opioid addicted, methadone maintained, long-term abstinent and normal subjects. The results indicated that dopamine D(3) receptor mRNA expression was increased in addicted and methadone maintained subjects by a factor of 1.74 and 1.98, respectively, but no change was observed in the abstinent group. The dopamine D(4) receptor mRNA expression was reduced in abstinent and addicted subjects (but not in the methadone group) and reached 0.44 and 0.53 the amount of the control group, respectively. Expression of dopamine D(5) receptor mRNA showed a significant reduction in abstinent subjects (0.41 the amount of the control group). However, in the addicted and methadone maintained groups, the change of expression level was not statistically significant. It can be concluded that persisting deficiency of dopamine D(4) and D(5) receptors may be a risk factor urging individuals to addiction, and methadone may exert its therapeutic effects through normalizing mRNA expression of these receptors. The dopamine D(3) receptor may have a negative feedback role in addiction; however, we have no explanation for the persisting up-regulation of this receptor in methadone subjects.

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI.

RATIONALE: Lysergic acid diethylamide (LSD) differs from other types of hallucinogens in that it possesses direct dopaminergic effects. The exact nature of this component has not been elucidated. OBJECTIVE: The present study sought to characterize the effects of several dopamine D(4) agonists and antagonists on the discriminative stimulus effect of LSD at two pretreatment times and 2,5-dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT(2A/2C) agonist. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with LSD-30 (0.08 mg/kg, i.p., 30-min pretreatment time), LSD-90 (0.16 mg/kg, i.p., 90-min pretreatment time), and DOI (0.4 mg/kg, i.p., 30-min pretreatment time) as discriminative stimuli. Substitution and combination tests with the dopamine D(4) agonists, ABT-724 and WAY 100635, were performed in all groups. Combination tests were run using the dopamine D(4) antagonists A-381393 and L-745,870 and two antipsychotic drugs, clozapine and olanzapine. RESULTS: WAY 100635 produced full substitution in LSD-90 rats, partial substitution in LSD-30 rats, and saline appropriate responding in DOI-trained rats. ABT-724 partially mimicked the LSD-90 and LSD-30 cues, but produced no substitution in DOI-trained rats. In combination tests, both agonists shifted the dose-response curve of LSD leftward, most potently for the LSD-90 cue. The D(4) antagonists significantly attenuated both the LSD-90 and LSD-30 cue, but had no effect on the DOI cue. CONCLUSION: Dopamine D(4) receptor activation plays a significant modulatory role in the discriminative stimulus effects in LSD-90-trained rats, most markedly for the later temporal phase of LSD, but has no effect on the cue produced by DOI.

Abnormal motor function and the expression of striatal dopamine D2 receptors in manganese-treated mice.

Manganese (Mn) plays an important role in the etiology of several neurobehavioral disorders, but there is a lack of data regarding its specific effects on neurotransduction, especially dopaminergic neurotransduction. We investigated the relationship between motor deficits and alterations in the expression of tyrosine hydroxylase (TH) and dopamine D2-like receptors (DR), including the three dopaminergic subtypes, D2, D3, and D4, in low- and high-dose Mn-treated mice. After administration of Mn (intraperitoneal injections of 20 or 40 mg/kg MnCl(2).4H(2)O once per day for 5 d), motor activity and expression of TH and DR were examined in the striatum of the mouse brain. Mn treatment resulted in significant decrease in coordination and/or impaired motor learning after 5 d of treatment and this effect remained until 10 d after the end of Mn treatment. The expression of dopamine D2-like receptor D2 (DRD2), but not TH, DRD3, or DRD4, in the striatum was dose-dependent, and statistically significant increases were seen at the mRNA and protein levels. These findings indicate that Mn-induced motor deficits may be modulated in part by the expression of DRD2 in the striatum. In addition, our results suggest that the disturbance of dopaminergic neurotransmission mediated by DRD2 may be involved in the pathogenesis of Mn neurotoxicity.