Silver(I) Coordination Polymers: Photocatalytic Properties and Enhanced Treatment Activity of Haloperidol on Children Tic Disorder by Regulating Neurotransmitter Content.

In this article, the characterization, synthesis, as well as the photocatalysis dye degradation performance of two novel silver(I) coordination polymers, namely, [Ag(L)(Hbdc)]n (1, L = 1,4-Bis(5,6-dimethylbenzimidazol-1-yl)butane, H2bdc = 1,4-Benzenedicarboxylic acid) and [Ag2(L)(hip)]n (2, H2hip = 5-Hydroxyisophthalic acid), were investigated. Fascinatingly, the photocatalytic performance of Complexes 1 and 2 have been investigated, wherein Complex 2 is considered an excellent photocatalyst for degrading Rhodamine B/methyl violet/methylene blue mixed organic dyes. Furthermore, the treatment activities of Complexes 1 and 2 on Tic disorder (TD) were assessed when used with haloperidol, and biochemical studies were conducted to reveal the mechanism in detail. Initially, the enzyme-linked immunosorbent assay was carried out to determine the dopamine and high vanillic acid contents in the striatum of the TD animal model. Subsequently, the reverse transcription-polymerase chain reaction was utilized to determine the relative expression of dopamine 1 and 2 receptor.

Variation in the ß-endorphin, oxytocin, and dopamine receptor genes is associated with different dimensions of human sociality.

There is growing evidence that the number and quality of social relationships have substantial impacts on health, well-being, and longevity, and, at least in animals, on reproductive fitness. Although it is widely recognized that these outcomes are mediated by a number of neuropeptides, the roles these play remain debated. We suggest that an overemphasis on one neuropeptide (oxytocin), combined with a failure to distinguish between different social domains, has obscured the complexity involved. We use variation in 33 SNPs for the receptor genes for six well-known social neuropeptides in relation to three separate domains of sociality (social disposition, dyadic relationships, and social networks) to show that three neuropeptides (ß-endorphin, oxytocin, and dopamine) play particularly important roles, with each being associated predominantly with a different social domain. However, endorphins and dopamine have a much wider compass than oxytocin (whose effects are confined to romantic/reproductive relationships and often do not survive control for other neuropeptides). In contrast, vasopressin, serotonin, and testosterone play only limited roles.

Steroid hormone (20-hydroxyecdysone) modulates the acquisition of aversive olfactory memories in pollen forager honeybees.

Here, we examine effects of the steroid hormone, 20-hydroxyecdysone (20-E), on associative olfactory learning in the honeybee, Apis mellifera. 20-E impaired the bees' ability to associate odors with punishment during aversive conditioning, but did not interfere with their ability to associate odors with a food reward (appetitive learning). The steroid had a significant impact also on the expression of amine-receptor genes in centers of the brain involved in the formation and recall of associative olfactory memories (mushroom bodies). 20-E increased expression of the dopamine receptor gene, Amdop2, and reduced the expression of the putative dopamine/ecdysone receptor gene, Amgpcr19. Interestingly, Amgpcr19 tended to be highly expressed in the brains of foragers that exhibited strong aversive learning, but expressed at lower levels in bees that performed well in appetitive learning assays. In 2-d-old bees, transcript levels of the same gene could be reduced by queen mandibular pheromone, a pheromone that blocks aversive learning in young worker bees. As ecdysteroid levels rise to a peak ∼2 d after adult emergence and then fall to low levels in foragers, we examined aversive learning also in young worker bees. Aversive learning performance in 2-d-old bees was consistently poor. The results of this study indicate that learning in honeybees can be modulated by ecdysteroids. They highlight, in addition, a potential involvement of the putative dopamine/ecdysone receptor, AmGPCR19, in hormonal regulation of associative olfactory learning in the honeybee.

Antifibrotic effect of combined treatment with neuroleptic drug and immobilized hyaluronidase in pulmonary fibrosis.

Using the model of lung fibrosis induced by intratracheal administration of bleomycin we studied anti-fibrotic activity of combined treatment with neuroleptic haloperidol and hyaluronidase immobilized on polyethylene oxide using electron-beam synthesis. It was shown that successive administration of immobilized hyaluronidase and the neuroleptic drug inhibits deposition of collagen fibers in the bleomycin-treated lungs. Combined treatment with the test compounds reduced swelling of the alveolar epithelium, exudation and infiltration of the alveolar interstitium and alveolar passages by inflammatory cells, and desquamation of alveolocytes into alveolar lumen, so that the alveolar-capillary membrane function was preserved.

The striatum and pain modulation.

The aim of this review was to give a general aspect of the sensorial function of the striatum related to pain modulation, which was intensively studied in our laboratory. We analyse the effect of electrical and chemical stimulation of the striatum on the orofacial pain, especially that produced by tooth pulp stimulation of the lower incisors. We demonstrated specific sites within the nucleus which electrical or chemical stimulation produced inhibition of the nociceptive jaw opening reflex. This analgesic action of the striatum was mediated by activation of its dopamine D(2) receptors and transmitted through the indirect pathways of the basal ganglia and the medullary dorsal reticular nucleus (RVM) to the sensorial nuclei of the trigeminal nerve. Its mechanism of action was by inhibition of the nociceptive response of the second order neurons of the nucleus caudalis of the V par.

Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men.

CONTEXT: In animals, repeated exposure to stimulant drugs leads to an enhanced drug-induced psychomotor response and increased dopamine release. This phenomenon, known as sensitization, may confer vulnerability to drug addiction or drug-induced psychosis in humans. A similar phenomenon, referred to as endogenous sensitization, is also believed to play a role in the emergence of positive symptoms in patients with schizophrenia. OBJECTIVE: To determine whether behavioral and neurochemical sensitization occur in healthy individuals after limited exposure to amphetamine in the laboratory. DESIGN: Open-label, 1-year follow-up of repeated amphetamine administration in healthy volunteers. SETTING: Department of Psychiatry, McGill University, and McConnell Brain Imaging Center, Montreal Neurological Institute. PARTICIPANTS: Ten healthy men (mean +/- SD age, 25.8 +/- 1.8 years). INTERVENTION: Three single doses of amphetamine (dextroamphetamine sulfate, 0.3 mg/kg by mouth) were administered on days 1, 3, and 5. MAIN OUTCOME MEASURES: Using positron emission tomography and [11C]raclopride, we measured dopamine release in response to amphetamine on the first exposure (day 1) and 14 days and 1 year after the third exposure. RESULTS: The initial dose of amphetamine caused dopamine release in the ventral striatum (a reduction in [11C]raclopride binding). Consistent with a sensitization-like phenomenon, 14 and 365 days after the third dose of amphetamine there was a greater psychomotor response and increased dopamine release (a greater reduction in [11C]raclopride binding), relative to the initial dose, in the ventral striatum, progressively extending to the dorsal caudate and putamen. A high novelty-seeking personality trait and self-rating assessments indicating impulsivity predicted proneness to sensitization. CONCLUSIONS: Sensitization to stimulants can be achieved in healthy men in the laboratory. This phenomenon is associated with increased dopamine release and persists for at least 1 year.

Reconstitution of affinity-purified dopamine D2 receptor binding activities by specific lipids.

The role of lipids in maintaining ligand binding properties of affinity-purified bovine striatal dopamine D2 receptor was investigated in detail. The receptor, purified on a haloperidol-linked Sepharose CL6B affinity column, exhibited low [3H]spiroperidol binding unless reconstituted with soybean phospholipids. In order to understand the role of individual phospholipids in maintaining the receptor binding activity, the purified preparation was reconstituted separately with individual phospholipids and assayed for [3H]spiroperidol binding. Except for phosphatidylcholine and phosphatidylethanolamine, that respectively restored 30 and 20% binding as compared to that obtained with soybean lipids, reconstitution with other lipids had very little effect. When various combinations of phospholipids were used for reconstitution, a phosphatidylcholine and phosphatidylserine mixture seemed to almost fully restore the receptor binding. A mixture of phosphatidylcholine and phosphatidylethanolamine was as effective as phosphatidylcholine alone in reconstituting ligand binding; however, when phosphatidylserine was also included in the mixture, there was a pronounced increase in binding (about 2-fold compared to the soybean lipids and about 6-fold compared to the phosphatidylcholine-phosphatidylethanolamine mixture). Substitution of other phospholipids or cholesterol for phosphatidylserine in phosphatidylcholine and phosphatidylethanolamine mixture had little effect. Maximal reconstitution of [3H]spiroperidol binding was obtained with phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine mixture (2:2:1, w/w) at a concentration of 0.5 mg/ml. The reconstituted receptor exhibited high affinity binding for [3H]spiroperidol which was comparable to that obtained with membrane or solubilized preparations. Various dopaminergic antagonists and agonists showed appropriate order of potency for the reconstituted receptor. The presently described reconstitution data suggest a role of specific phospholipids in preserving the binding properties of dopamine D2 receptor and should prove useful in studies on functional reconstitution of the receptor.

A proposed mechanism for diurnal/nocturnal bruxism: hypersensitivity of presynaptic dopamine receptors in the frontal lobe.

There are many reports in the literature concerning nocturnal bruxism, however, diurnal (non-sleep)/nocturnal bruxism is rarely mentioned. We report three patients with diurnal/nocturnal bruxism. They differed from the usual features of nocturnal bruxism in hypoperfusion of the left frontal lobe, a poor response to l-dopa or bromocriptine therapy and a favourable response to metoclopramide. Hypersensitive presynaptic dopamine receptors may be the underlying pathology responsible for this type of bruxism. Regional differences in dopamine receptor pharmacology may explain the perplexing relationship of bruxism to both hyper- and hypo-dopaminergic states.

Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats.

Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats.

Reconstitution of solubilised brain D2 dopamine receptors into phospholipid vesicles.

D2 dopamine receptors have been solubilised from bovine caudate nucleus using cholate/sodium chloride in the presence of soyabean phospholipid. Reconstitution of the receptors into soyabean phospholipid vesicles has been achieved by dialysis to remove detergent and salt. The receptors are truly reconstituted as judged by sedimentation, electron microscopy, heat stability and analysis on sucrose density gradients. The ligand-binding properties of the reconstituted receptors resemble those of the solubilised preparation.

Dopaminergic inhibition of adenylate cyclase correlates with high affinity agonist binding to anterior pituitary D2 dopamine receptors.

Dopamine (DA) and the dopaminergic agonists n-propylnorapomorphine (NPA), 2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN) and apomorphine (APO) inhibit forskolin-stimulated adenylate cyclase activity in a dose-dependent fashion by more than 40% in membrane preparations of the porcine anterior pituitary gland. These agonists exhibit apparent dissociation constants that follow an expected dopaminergic order of potency (NPA greater than ADTN greater than or equal to APO greater than DA). The inhibition is dependent on guanine nucleotides and is reversible by dopaminergic antagonists (spiroperidol greater than (+)-butaclamol much greater than (-)-butaclamol). The potencies of these agonists in inhibiting forskolin-stimulated adenylate cyclase activity correlate with the agonist dissociation constants (KH) for binding to the high affinity receptor state (RH) in porcine anterior pituitary membranes (De Lean et al., Mol. Pharmacol. 1982, 22, 290-297) and the EC50 for inhibition of prolactin release from rat anterior pituitary cells in culture (Caron et al., J. Biol. Chem. 1978, 253, 2244-2253). Furthermore, the intrinsic activities of dopamine and the other agonists for inhibition of forskolin-stimulated adenylate cyclase are similar and correlate well with the ability of these agents to induce a comparable proportion (50%) of the receptor in a high affinity state. Together these data provide additional support for the physiological relevance of the high affinity agonist binding state of the D2 receptor in mediating the decrease in prolactin secretion via attenuation of adenylate cyclase.

Estrogen regulation of rat anterior pituitary adenylate cyclase.

The effect of chronic estrogen treatment on the stimulation and dopamine inhibition of anterior pituitary (AP) adenylate cyclase (AC) activity was examined. Treatment of ovariectomized female rats with estradiol for 21 days resulted in a 450% increase in AP weight compared to ovariectomized controls. Stimulation of AC by guanine nucleotides (GN) (1 nM-0.1 mM) and vasoactive intestinal peptide (1 microM) was reduced by 50%. Stimulation of AC by fluoride ions was unchanged by estradiol treatment. Stimulation above basal by forskolin was reduced by variable amounts (23-50%), and depended on the concentration of forskolin used. Inhibition of AC mediated by D2-dopamine receptors was decreased by 45%. Estrogen treatment had no effect on the toxin-catalyzed incorporation of [32P]ADP into stimulatory and inhibitory GN regulatory proteins. These results indicate that the effect of estrogen on the anterior pituitary include modulation of stimulated, dopamine-inhibited and basal AC activity.

Effects of ceruletide on perioral movements and the dopamine receptor-adenylate cyclase system in rats chronically treated with fluphenazine.

The effects of repeated administration of ceruletide (100 micrograms/kg/perday, i.p. for 3 days) on perioral movements and the striatal dopamine receptor adenylate cyclase system were examined in rats chronically treated with fluphenazine enanthate (FPZ) (25 mg/kg i.m. every 3 weeks for 30 weeks) and sesame oil-treated (control) rats. After the tenth injection of fluphenazine, the rats started to display five types of perioral movements (teeth chattering, chewing, tongue protrusion, mouth opening and perioral tremors). Moreover, increases in SCH23390 binding and spiperone binding to striatal membranes, were found in the FPZ-treated rats. Furthermore, dopamine receptor-coupled adenylate cyclase activity was potentiated in striatal membranes. High amplitude EMG discharges (8-10 Hz), recorded from the masseter in the FPZ-treated rats occurred concurrently with perioral tremors. Repeated ceruletide (CLT) injections abolished perioral movements, and reversed both the elevated SCH23390 binding and the dopamine stimulated adenylate cyclase (AC) activity to the control level. The effect of CLT on perioral movements, D1 receptors and dopamine-stimulated AC activity continued for 6 days after the final CLT injection. These findings suggest that systemically administered CLT affects the D1 receptor adenylate cyclase system and that an increase of the D1 receptor mechanism may play an important role in the pathogenesis of tardive dyskinesia.

Dopamine D-1 but not D-2 receptor stimulation of the dorsal striatum potentiates apomorphine-induced jaw movements in rats.

The effects of bilateral injections of selective D-1 and D-2 agonists and antagonists into the dorsal striata on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. A phototransducer attached to the lower mandible automatically detected jaw movements. YM-09151-2 (0.2 and 0.5 micrograms) and cis(Z)-flupentixol (0.5 and 1 microgram) injected into the dorsal striatum increased the frequency of jaw movements after apomorphine (0.2 mg/kg i.v.). The effects were prevented by administration of SCH23390 (1 microgram) with YM-09151-2 (0.5 microgram) or cis(Z)-flupentixol (1 microgram). Injection of SCH23390 (1 microgram) alone into the dorsal striatum failed to alter the apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Local application of the selective D-1 agonists, SKF38393 (5 micrograms) and SKF75670 (10 micrograms), into the dorsal striatum potentiated the apomorphine (0.2 mg/kg i.v.)-induced jaw movements, while a D-2 agonist, quinpirole (10 micrograms), injected into the same site attenuated these movements. These data are suggestive of an oppositional D-1: D-2 receptor interaction in the dorsal striatum.

Occlusal disharmonies modulate central catecholaminergic activity in the rat.

Occlusal disharmonies have classically been thought to be involved in the etiopathogenesis of bruxism, as have, more recently, alterations in central neurotransmission, particularly dopaminergic neurotransmission. However, the connection between these two factors has still not been established. In this study, we assessed the effects of diverse occlusal disharmonies, maintained for either 1 day or 14 days, on neurochemical indices of dopaminergic and noradrenergic activity in the striatum, frontal cortex, and hypothalamus of the rat. The in vivo activity of tyrosine hydroxylase, determined as the accumulation of 3,4-dihydroxyphenylalanine (DOPA), 30 min after the administration of 3-hydroxybenzylhydrazine, a DOPA decarboxylase inhibitor, and dopamine and noradrenaline contents were quantified by high-performance liquid chromatography with electrochemical detection. The wearing of an acrylic cap on both lower incisors for 1 day induced a significant increase in DOPA accumulation in the regions analyzed, with parallel increases in dopamine levels in the hypothalamus and dopamine and noradrenaline in the frontal cortex. After the cap was maintained for 14 days, DOPA accumulation tended to return to control values, except in the left striatum, thereby causing an imbalance between hemispheres. In contrast, 1 or 14 days after the lower left and the upper right incisors were cut, less pronounced changes in catecholaminergic neurotransmission were found in the brain areas studied. Moreover, the cutting of one lower incisor did not modify either DOPA accumulation or dopamine and noradrenaline contents in the striatum or hypothalamus. These results provide experimental evidence of a modulation of central catecholaminergic neurotransmission by occlusal disharmonies, being dependent on the nature of the incisal alteration and on the time during which it was maintained.

Interactive role of adenosine and dopamine in the opiate withdrawal syndrome.

Adenosine reduces opioid withdrawal symptoms by activating A(1) adenosine receptors, probably by inhibiting excitatory amino acid release. Since blockade of A(2A) adenosine receptors seems to enhance dopaminergic striatopallidal transmission, we evaluated the role of the purinergic system in the opiate withdrawal syndrome by using two A(1) receptor agonists [ N(6)-cyclohexyladenosine, CHA and 2-chloro- N(6)-cyclopentyladenosine, CCPA], and two A(2A) receptor antagonists (SCH 58261 and 8-(3-chlorostyryl)caffeine, CSC). Male adult rats received increasing doses of morphine sulphate suspended in 5 ml/kg of a sustained release preparation (40-100 mg/kg s.c.) daily for 4 days and 20 h after the last administration, the withdrawal syndrome was evoked by naloxone (5 mg/kg i.p.). Animals were observed for 30 min for signs of opiate withdrawal. Other groups of rats were implanted with concentric probes for microdialysis and dopamine levels were measured in the nucleus accumbens. CHA and CCPA (0.05, 0.1 or 0.5 mg/kg i.p.) significantly reduced "wet-dog" shakes, diarrhoea, teeth chattering, jumping and writhing. SCH 58261 and CSC (0.1, 0.5 or 1 mg/kg i.p.), given 10 min before naloxone, also reduced signs of opiate withdrawal. CHA plus SCH 58261 and CCPA plus CSC greatly enhanced the reduction of withdrawal signs observed with CHA and CCPA or CSC and SCH 58261 alone. In vivo microdialysis showed that naloxone significantly decreased DA release; this effect was prevented by pretreatment with systemic SCH 58261 and CSC, but not with CHA and CCPA. Our results demonstrate that A(1) and A(2A) adenosine receptors mediate the effect induced by adenosine in opiate withdrawal syndrome and suggest that adenosine A(1) agonists and adenosine A(2A) antagonists may be beneficial in the treatment of this syndrome.

Characteristics of 3H-cis-flupenthixol binding in rat striatum.

Characteristics of membrane receptor binding by 3H-cis-flupenthixol were examined in rat striatum. Using modifications of standard dopamine receptor binding techniques, it was possible to obtain 70% specific binding with 3H-cis-flupenthixol. Association and dissociation rates were very rapid, with equilibrium reached in 2 min and half-time of dissociation being 1 min. Analysis of saturation and competition studies using cis-flupenthixol and spiroperidol indicated that cis-flupenthixol binds to two striatal receptors with apparent KD's of 0.7 and 4.8 nM. It is suggested these represent D1 and D2 dopamine receptors respectively. The further characterization of the properties of cis-flupenthixol binding presented here should enable more detailed studies of multiple dopamine receptors to be designed.

A full repetitive jaw movement response after 70% depletion of caudate D1 receptors.

Repetitive jaw movements (RJM in the rat can be produced in a dose-dependent manner with the selective D1 agonist, SKF 38393. Administration of the protein coupling agent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to rats pretreated with a D2 receptor blocker resulted in a 70-30% reduction of D1 dopamine receptors, but only a 10% reduction of D2 receptors in the rat caudate. Twenty-four hours following EEDQ, the RJM response to SKF 38393 was assessed. The massive selective reduction of the D1 receptor density was found not to modify the rate of RJM induced by SKF 38393 in that dose response curves in control and EEDQ-treated rats were essentially identical. These data provide evidence to indicate that there is a functional D1 receptor reserve for D1-mediated RJM behavior.