Impact of Tolvaptan Combined with Low-Dose Dopamine in Heart Failure Patients with Acute Kidney Injury.

The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 µg/kg・minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.

Slightly viscous dispersions of mucoadhesive polymers as vehicles for nasal administration of dopamine and grape seed extract-loaded solid lipid nanoparticles.

With the aim to find an alternative vehicle to the most used thermosensitive hydrogels for efficient nanotechnology-based nose-to-brain delivery approach for Parkinson's disease (PD) treatment, in this work we evaluated the Dopamine (DA) and the antioxidant grape seed-derived pro-anthocyanidins (Grape Seed Extract, GSE) co-loaded solid lipid nanoparticles (SLNs) put in slight viscous dispersions (SVDs). These SVDs were prepared by dispersion in water at low concentrations of mucoadhesive polymers to which SLN pellets were added. For the purpose, we investigated two polymeric blends, namely Poloxamer/Carbopol (PF-127/Carb) and oxidized alginate/Hydroxypropylmethyl cellulose (AlgOX/HPMC). Rheological studies showed that the two fluids possess Newtonian behaviour with a viscosity slightly higher that water. The pH values of the SVDs were mainly within the normal range of nasal fluid as well as almost no osmotic effect was associated to both SVDs. All the SVDs were capable to provide DA permeation through nasal porcine mucosa. Moreover, it was found that PF-127/Carb blend possesses penetration enhancer capability better than the Alg OX/HPMC combination. Flow cytometry studies demonstrated the uptake of viscous liquids incorporating fluorescent SLNs by human nasal RPMI 2650 cell in time-dependent manner. In conclusion, the SVD formulations may be considered promising alternatives to thermosensitive hydrogels strategy. Moreover, in a broader perspective, such SVD formulations may be also hopeful for treating various neurological diseases beyond PD treatment.

All-in-one hydrogel patches with sprayed bFGF-loaded GelMA microspheres for infected wound healing studies.

The current wound healing process faces numerous challenges such as bacterial infection, inflammation and oxidative stress. However, wound dressings used to promote wound healing, are not well suited to meet the clinical needs. Hyaluronic acid (HA) not only has excellent water absorption and good biocompatibility but facilitates cell function and tissue regeneration. Dopamine, on the other hand, increases the overall viscosity of the hydrogel and possesses antioxidant property. Furthermore, chitosan exhibits outstanding performance in antimicrobial, anti-inflammatory and antioxidant activities. Basic fibroblast growth factor (bFGF) is conducive to cell proliferation and migration, vascular regeneration and wound healing. Hence, we designed an all-in-one hydrogel patch containing dopamine and chitosan framed by hyaluronic acid (HDC) with sprayed gelatin methacryloyl (GelMA) microspheres loaded with bFGF (HDC-bFGF). The hydrogel patch exhibits excellent adhesive, anti-inflammatory, antioxidant and antibacterial properties. In vitro experiments, the HDC-bFGF hydrogel patch not only showed significant inhibitory effect on RAW cell inflammation and Staphylococcus aureus (S. aureus) growth but also effectively scavenged free radicals, in addition to promoting the migration of 3 T3 cells. In the mice acute infected wound model, the HDC-bFGF hydrogel patch adhered to the wound surface greatly accelerated the healing process via its anti-inflammatory and antioxidant activities, bacterial inhibition and pro-vascularization effects. Therefore, the multifunctional HDC-bFGF hydrogel patch holds great promise for clinical application.

What is the best treatment for hypotension in healthy dogs during anaesthesia maintained with isoflurane?

Hypotension is a common and potentially life-threatening complication of general anaesthesia in dogs. Due to the combination of cardiovascular side effects of many anaesthetic, sedative and analgesic drugs used peri-operatively hypotension is frequently reported even in healthy dogs undergoing elective procedures. Several treatment options for hypotension have been advocated. Potential treatments include rapid administration of either crystalloid or colloid fluids; pharmacological treatments to increase cardiac output and/or systemic vascular resistance; or reduction in the delivery of the volatile anaesthetic agents. This critical appraisal considers the current evidence for which treatment is the best option for treating hypotension in healthy euvolemic dogs undergoing general anaesthesia maintained with isoflurane. Fourteen relevant studies were appraised, including 12 laboratory studies and two small clinical trials. One study demonstrated that reduction in the delivery of isoflurane may correct hypotension, but this treatment may not always be feasible. In general, rapid administration of fluids did not increase blood pressure and failed to correct hypotension. Synthetic colloids demonstrated some efficacy, but results were inconsistent between studies and large volumes may be required. Infusion of dopamine appears to be the most reliable pharmacological option consistently increasing blood pressure, cardiac output and correcting hypotension.

Effects of bee venom and dopamine-loaded nanoparticles on reserpine-induced Parkinson's disease rat model.

Parkinson's disease (PD) is a progressive chronic neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. Current PD therapeutic strategies are mainly symptomatic and can lead to motor complications overtime. As a result, alternative medicine may provide an effective adjuvant treatment for PD as an addition to or as a replacement of the conventional therapies. The aim of this work was to evaluate the effects of Bee Venom (BV) and dopamine (DA)-loaded nanoparticles in a reserpine-induced animal model of PD. After inducing PD with reserpine injection, different groups of male rats were treated with L-Dopa, BV, DA-nanoparticles. Our findings showed that BV and DA-nanoparticles administration restored monoamines, balanced glutamate/GABA levels, halted DNA fragmentation, decreased pro-inflammatory mediators (IL-1ß and TNF-α), and elevated anti-inflammatory mediators (PON1) and neurotropic factor (BDNF) levels in comparison with conventional therapy of PD. Furthermore, in a reserpine-induced PD rat model, the ameliorative effects of BV were significantly superior to that of DA-nanoparticles. These findings imply that BV and DA-nanoparticles could be useful as adjuvant treatments for PD.

Dopamine-loaded lipid based nanocarriers for intranasal administration of the neurotransmitter: A comparative study.

Both dopamine (DA) loaded Solid Lipid Nanoparticles (SLN) and liposomes (Lip), designed for intranasal administration of the neurotransmitter as an innovative Parkinson disease treatment, were already characterized in vitro in some extent by us (Trapani et al., 2018a and Cometa et al., 2020, respectively). Herein, to gain insight into the structure of SLN, X-ray Photoelectron Spectroscopy Analysis was carried out and DA-SLN (SLN 1) were found to exhibit high amounts of the neurotransmitter on the surface, whereas the external side of Glycol Chitosan (GCS) containing SLN (SLN 2) possessed only few amounts. However, SLN 2 were characterized by the highest encapsulation DA efficiency (i.e., 81%). Furthermore, in view of intranasal administration, mucoadhesion tests in vitro were also conducted for SLN and Lip formulations, evidencing high muchoadesive effect exerted by SLN 2. Concerning ex-vivo studies, SLN and Lip were found to be safe for Olfactory Ensheathing Cells and fluorescent SLN 2 were taken up in a dose-dependent manner reaching the 100% of positive cells, while Lip 2 (chitosan-glutathione-coated) were internalised by 70% OECs with six-times more lipid concentration. Hence, SLN 2 formulation containing DA and GCS may constitute interesting formulations for further studies and promising dosage form for non-invasive nose-to-brain neurotransmitter delivery.

Dopamine-loaded nanoparticle systems circumvent the blood-brain barrier restoring motor function in mouse model for Parkinson's Disease.

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disease of the central nervous system. Early treatment for PD is efficient; however, long-term systemic medication commonly leads to deleterious side-effects. Strategies that enable more selective drug delivery to the brain using smaller dosages, while crossing the complex brain-blood barrier (BBB), are highly desirable to ensure treatment efficacy and decrease/avoid unwanted outcomes. Our goal was to design and test the neurotherapeutic potential of a forefront nanoparticle-based technology composed of albumin/PLGA nanosystems loaded with dopamine (ALNP-DA) in 6-OHDA PD mice model. ALNP-DA effectively crossed the BBB, replenishing dopamine at the nigrostriatal pathway, resulting in significant motor symptom improvement when compared to Lesioned and L-DOPA groups. Notably, ALNP-DA (20 mg/animal dose) additionally up-regulated and restored motor coordination, balance, and sensorimotor performance to non-lesioned (Sham) animal level. Overall, ALNPs represent an innovative, non-invasive nano-therapeutical strategy for PD, considering its efficacy to circumvent the BBB and ultimately deliver the drug of interest to the brain.

The cerebral haemodynamic response to somatosensory stimulation in preterm newborn lambs is reduced with dopamine or dobutamine infusion.

BACKGROUND: In the adult brain, increases in neural activity lead to increases in local blood flow. However, in the preterm neonate, studies of cerebral functional haemodynamics have yielded inconsistent results, including negative responses suggesting decreased perfusion and localised tissue hypoxia, probably due to immature neurovascular coupling. Furthermore, the impact of vasoactive medications, such as dopamine and dobutamine used as inotropic therapies in preterm neonates, on cerebrovascular responses to somatosensory input is unknown. We aimed to characterise the cerebral haemodynamic functional response after somatosensory stimulation in the preterm newborn brain, with and without dopamine or dobutamine treatment. METHODS: We studied the cerebral haemodynamic functional response in 13 anaesthetised preterm lambs, using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb) following left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. The 4.8 and 7.8 s stimulations were repeated during dopamine or dobutamine infusion. RESULTS: Stimulation always produced a somatosensory evoked response. Majority of preterm lambs demonstrated positive functional responses (i.e. increased ΔoxyHb) in the contralateral cortex following stimulus trains of all durations. Dopamine increased baseline oxyHb and total Hb, whereas dobutamine increased baseline deoxyHb. Both dopamine and dobutamine reduced the evoked ΔoxyHb responses to 4.8 and 7.8 s stimulations. CONCLUSIONS: Somatosensory stimulation increases cerebral oxygenation in the preterm brain, consistent with increased cerebral blood flow due to neurovascular coupling. Notably, our results show that dopamine/dobutamine reduces oxygen delivery relative to consumption in the preterm brain during somatosensory stimulations, suggesting there may be a risk of intermittent localised tissue hypoxia which has clear implications for clinical practice and warrants further investigation.

Mediatory role of the dopaminergic system through D1 receptor on glycine-induced hypophagia in neonatal broiler-type chickens.

The present study aimed to examine the mediatory role of the dopaminergic system in the food intake induced by intracerebroventricular (ICV) injection of glycine in neonatal 3-h feed-deprived (FD3) meat-type chickens. In the first and second experiments, birds were ICV injected using low and high doses of glycine (50, 100 and 200 nmol) and strychnine (50, 100 and 200 nmol), respectively. In experiments 3-9, the behaviorally subeffective doses of dopamine (10 nmol), 6-OHDA (2.5 nmol), SCH 23,390 (D1 antagonist; 5 nmol), AMI-193 (D2 antagonist; 5 nmol), NGB2904 (D3 antagonist; 6.4 nmol) and L-741,742 (D4 antagonist; 6 nmol) were, respectively, co-administrated with glycine (200 nmol) in FD3 5-day-old chicks to investigate possible interplay of dopamine receptors in glycine-induced feeding behavior. Then, cumulative food intake based on body weight percentage (%BW) was determined at 30, 60 and 120 min after the injection. According to the results, dopamine significantly boosted the hypophagia induced by glycine at all-time intervals (p ≤ 0.001). These results combined with the previous findings suggest an interplay between dopamine and glycine in chicken's brain in which D1 receptor-mediated food intake induced by glycine.

Hypotension in Preterm Infants (HIP) randomised trial.

OBJECTIVE: To determine whether restricting the use of inotrope after diagnosis of low blood pressure (BP) in the first 72 hours of life affects survival without significant brain injury at 36 weeks of postmenstrual age (PMA) in infants born before 28 weeks of gestation. DESIGN: Double-blind, placebo-controlled randomised trial. Caregivers were masked to group assignment. SETTING: 10 sites across Europe and Canada. PARTICIPANTS: Infants born before 28 weeks of gestation were eligible if they had an invasive mean BP less than their gestational age that persisted for ≥15 min in the first 72 hours of life and a cerebral ultrasound free of significant (≥ grade 3) intraventricular haemorrhage. INTERVENTION: Participants were randomly assigned to saline bolus followed by either a dopamine infusion (standard management) or placebo (5% dextrose) infusion (restrictive management). PRIMARY OUTCOME: Survival to 36 weeks of PMA without severe brain injury. RESULTS: The trial terminated early due to significant enrolment issues (7.7% of planned recruitment). 58 infants were enrolled between February 2015 and September 2017. The two groups were well matched for baseline variables. In the standard group, 18/29 (62%) achieved the primary outcome compared with 20/29 (69%) in the restrictive group (p=0.58). Additional treatments for low BP were used less frequently in the standard arm (11/29 (38%) vs 19/29 (66%), p=0.038). CONCLUSION: Though this study lacked power, we did not detect major differences in clinical outcomes between standard or restrictive approach to treatment. These results will inform future studies in this area. TRIAL REGISTRATION NUMBER: NCT01482559, EudraCT 2010-023988-17.

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel.

The endocannabinoid system is a promising target to mitigate pain as the endocannabinoids are endogenous ligands of the pain-mediating receptors-cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Herein, we report on a class of lipids formed by the epoxidation of N-arachidonoyl-dopamine (NADA) and N-arachidonoyl-serotonin (NA5HT) by epoxygenases. EpoNADA and epoNA5HT are dual-functional rheostat modulators of the endocannabinoid-TRPV1 axis. EpoNADA and epoNA5HT are stronger modulators of TRPV1 than either NADA or NA5HT, and epoNA5HT displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. These epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1ß, TNF-α and nitrous oxide and raise anti-inflammatory IL-10 cytokine in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of anandamide. Detailed kinetics and molecular dynamics simulation studies provide evidence for this potentiation using the epoxygenase human CYP2J2. Taken together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are potent, multi-faceted molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors.

On-Demand Reversible UV-Triggered Interpenetrating Polymer Network-Based Drug Delivery System Using the Spiropyran-Merocyanine Hydrophobicity Switch.

A reversible switchable on-demand UV-triggered drug delivery system (DDS) based on interpenetrating polymer networks (IPNs) with silicone as the host polymer and spiropyran (SP)-functionalized guest polymer is designed and demonstrated. The photo-responsive IPNs provide a new triggered drug delivery concept as they exploit the change in intermolecular interactions (work of adhesion) among the drug, matrix, and solvent when the incorporated hydrophobic SP moieties transform into the hydrophilic merocyanine form upon light irradiation without degradation and disruption of the DDS. The change in how the copolymer composition (hydrophilicity and content) and the lipophilicity of the drug (log P) affect the release profile was investigated. A thermodynamic model, based on Hansen solubility parameters, was developed to design and optimize the polymer composition of the IPNs to obtain the most efficient light-triggered drug release and suppression of the premature release. The developed IPNs showed excellent result for dopamine, l-dopa, and prednisone with around 90-95% light-triggered release. The model was applied to study the release behavior of drugs with different log P and to estimate if the light-induced hydrophobic-to-hydrophilic switch can overcome the work of adhesion between polymers and drugs and hence the desorption and release of the drugs. To the best of our knowledge, this is the first time that work of adhesion is used for this aim. Comparing the result obtained from the model and experiment shows that the model is useful for evaluating and estimating the release behavior of specific drugs merocyanine, IPN, DDS, and spiropyran.

Clinical features and outcome of septic shock in dogs: 37 Cases (2008-2015).

OBJECTIVES: To describe patient characteristics of dogs with septic shock, investigate markers of disease severity, and assess treatment impact on outcome. DESIGN: Retrospective study. SETTING: Single center, university veterinary teaching intensive care unit. ANIMALS: Thirty-seven dogs with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean number of organ dysfunction was 3.24 ± 1.0, and included cardiovascular (100%), respiratory (73%), hematologic (68%), renal (49%), and hepatic (32%) dysfunction. The gastrointestinal tract was the most common source of sepsis. Mean blood pressure prior to resuscitation was 50 ± 8 mm Hg. All dogs were given IV fluids before vasopressor therapy with a mean rate of 12.1 ± 11.0 mL/kg/h. All dogs were given antimicrobials, administered within a mean of 4.3 ± 5.7 hours after diagnosis. Dopamine or norepinephrine was administered IV, respectively in 51.3% and 37.8% of dogs, with a mean duration of hypotension of 2.6 ± 3.0 hours. Mortality rate was 81.1%. Survivors were more likely to have a feeding tube (P = 0.007) and to have gastrointestinal sepsis (P = 0.012), and less likely to have respiratory dysfunction (P < 0.001). APPLEFull scores (P = 0.014) and time to antimicrobial therapy (P = 0.047) were identified as predictors of mortality. Treatment bundles consisting of 7 interventions that may improve outcomes in people with septic shock were evaluated. Survivors received 4.1 ± 1.3 interventions, whereas nonsurvivors received 2.4 ± 1.4 (P = 0.003). CONCLUSIONS: Septic shock in dogs confers a guarded prognosis. Early antimicrobial therapy and the utilization of treatment bundles may increase survivability in dogs with septic shock. More research is warranted to investigate the impact of specific interventions on survival.

Intrathecal and intracerebroventricular dopamine for Parkinson's disease.

While CDD directly to the CSF can provide a constant delivery of the dopaminergic drug resulting in a more stable treatment effect without the limitations of traditional oral therapy without peripheral effects, it is still young and longitudinal data is lacking. These experimental therapies show promise and further investigation into their efficacy and safety could extend the frontiers for management of PD.

The Effect of Levosimendan on Two Distinct Rodent Models of Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by motor symptoms related to the deficiency in dopamine levels, and cognitive symptoms that are similar in nature to those manifested during Alzheimer's disease. Levosimendan, on the other hand, is a calcium sensitizer and phosphodiesterase inhibitor that was shown to possess neuroprotective, memoryenhancing, and anti-apoptotic properties. OBJECTIVE: In the current study, the possible protective effect of levosimendan was investigated in two animal models of Parkinson's disease. METHODS: Both intracerebral injection 6-hydroxydopamine (6-OHDA) and the direct injection of lipopolysaccharide (LPS) into the substantia nigra were used as models to induce Parkinson's-like behavior. Levosimendan (12 µg/kg intraperitoneally once weekly) was started 7 days before or 2 days after lesioning of the animals. At day 14 post-lesioning, animals were subjected to apomorphine challenge, which was correlated with dopamine levels in the striatum and tyrosine hydroxylase (TH)-positive nigral cells. RESULTS: Results showed that levosimendan restored the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells when administered 7 days before, but not two days after 6-OHDA lesioning. In the LPS model of PD, the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells were restored when levosimendan was administered 7 days before as well as two days after lesioning. CONCLUSION: Levosimendan seems to provide a promising agent with potential clinical value for PD.

Form-Deprivation and Lens-Induced Myopia Are Similarly Affected by Pharmacological Manipulation of the Dopaminergic System in Chicks.

Purpose: Animal models have demonstrated a link between decreases in retinal dopamine levels and the development of form-deprivation myopia (FDM). However, the consistency of dopamine's role in the other major form of experimental myopia, that of lens-induced myopia (LIM), is less clear, raising the question as to what extent dopamine plays a role in human myopia. Therefore, to better define the role of dopamine in both forms of experimental myopia, we examined how consistent the protection afforded by dopamine and the dopamine agonist 6-amino-5,6,7,8-tetrahydronaphthalene-2,3-diol hydrobromide (ADTN) is between FDM and LIM. Methods: Intravitreal injections of dopamine (0.002, 0.015, 0.150, 1.500 µmol) or ADTN (0.001, 0.010, 0.100, 1.000 µmol) were administered daily to chicks developing FDM or LIM. Axial length and refraction were measured following 4 days of treatment. To determine the receptor subtype by which dopamine and ADTN inhibit FDM and LIM, both compounds were coadministered with either the dopamine D2-like antagonist spiperone (0.005 µmol) or the D1-like antagonist SCH-23390 (0.005 µmol). Results: Intravitreal administration of dopamine or ADTN inhibited the development of FDM (ED50 = 0.003 µmol and ED50 = 0.011 µmol, respectively) and LIM (ED50 = 0.002 µmol and ED50 = 0.010 µmol, respectively) in a dose-dependent manner, with a similar degree of protection observed in both paradigms (P = 0.471 and P = 0.969, respectively). Coadministration with spiperone, but not SCH-23390, inhibited the protective effects of dopamine and ADTN against the development of both FDM (P = 0.214 and P = 0.138, respectively) and LIM (P = 0.116 and P = 0.100, respectively). Conclusions: pharmacological targeting of the retinal dopamine system inhibits FDM and LIM in a similar dose-dependent manner through a D2-like mechanism.

Noradrenaline enhances the excitatory effects of dopamine on medial prefrontal cortex pyramidal neurons in rats.

AIM: Our previous studies showed that exposure to acute restraint stress enhanced cocaine-induced conditioned place preference (cocaine-CPP) and suggested the possibility that co-activation of adrenergic transmission boosts the increase in medial prefrontal cortex (mPFC) neuronal activity by the activation of dopaminergic transmission. To examine this possibility, the effects of the co-treatment with dopamine (DA) and noradrenaline (NA) on mPFC neurons were compared with those of treatment with DA alone using whole-cell patch-clamp recordings. METHODS: The effects of DA alone and a mixture of DA and NA on the membrane potentials and spontaneous excitatory postsynaptic currents (sEPSCs) were examined by electrophysiological recordings of mPFC pyramidal neurons in brain slices of male Sprague Dawley rats. Extracellular DA and NA levels in the mPFC during and after restraint stress exposure were also examined by in vivo microdialysis. RESULTS: Dopamine significantly produced depolarizing effects on mPFC neurons and tended to increase sEPSC frequency. Co-administration of NA with DA produced stronger depolarizing effects and significantly increased sEPSC frequency. The findings suggest that the additional depolarizing effect of NA on DA-responsive neurons, rather than the excitation of DA-nonresponsive neurons by NA, contributes to the stronger effect of co-treatment of NA with DA. CONCLUSION: The present study suggests that NA released by restraint stress exposure cooperates with DA to stimulate DA-responsive neurons in the mPFC, thereby causing the stress-induced enhancement of cocaine-CPP.

Topical application of dopaminergic compounds can inhibit deprivation myopia in chicks.

PURPOSE: Animal models have demonstrated a link between dysregulation of the retinal dopamine system and the development of experimental myopia (short-sightedness). However, pharmacological investigations of dopamine in animal models rely heavily on intravitreal or systemic administration, which have several limitations for longer-term experiments. We therefore investigated whether administration of dopamine as a topical eye drop can inhibit the development of form-deprivation myopia (FDM) in chicks. We also examined whether chemical modification of dopamine through deuterium substitution, which might enhance stability and bioavailability, can increase dopamine's effectiveness against FDM when given topically. METHODS: Dopamine or deuterated dopamine (Dopamine-1,1,2,2-d4 hydrochloride) was administered as a daily intravitreal injection or as daily topical eye drops to chicks developing FDM over an ascending dose range (min. n = 6 per group). Axial length and refraction were measured following 4 days of treatment. RESULTS: Both intravitreal (ED50 = 0.002µmoles) and topical application (ED50 = 6.10µmoles) of dopamine inhibited the development of FDM in a dose-dependent manner. Intravitreal injections, however, elicited a significantly higher level of protection relative to topical eye drops (p < 0.01). Deuterated dopamine inhibited FDM to a similar extent as unmodified dopamine when administered as intravitreal injections (p = 0.897) or topical eye drops (p = 0.921). CONCLUSIONS: Both intravitreal and topical application of dopamine inhibit the development of FDM in a dose-dependent manner, indicating that topical administration may be an effective avenue for longer-term dopamine experiments. Deuterium substitution does not alter the protection afforded by dopamine against FDM when given as either an intravitreal injection or topical eye drop.

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism.

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher "complexity" and lower "texture". Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA.

Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.