DA Agonists Research Articles

Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential.

Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson's disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in thesubstantia nigraof the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them.

229. Using machine learning (ML) models to predict risk of venous thromboembolism (VTE) following spine surgery

229. Using machine learning (ML) models to predict risk of venous thromboembolism (VTE) following spine surgery

Evaluation of the Antidepressant-like Effect of Total Sterols Fraction and Stigmasterol Isolated from Leaves of Aegle marmelos and Possible Mechanism( s) of Action Involved.

Aegle marmelos Corr. (Rutaceae) commonly known as 'Indian Bael' has been used as a brain tonic traditionally. However, despite this traditional use, not enough scientific report is present that can confirm the use of this plant in neurological disorders. Thus, the total sterols fraction and stigmasterol from the leaves of Aegle marmelos were investigated for antidepressant-like effect along with their possible mechanism(s) of action by primarily performing acute toxicity study of total sterols. An acute toxicological study was carried out at a single oral dose of 2000 mg/kg. Sign of toxicity was observed by estimating biochemical and performing histopathological analysis. For the antidepressant-like effect, different doses of total sterols (50-200 mg/kg, p.o. for seven days) and stigmasterol (5- 20 mg/kg, i.p. acute) were administered in mice using TST and FST models. To evaluate the mechanism of action, mice were pretreated with GABA, 5-HT, DA, adrenergic antagonists, and glutamate agonists. Furthermore, a neurochemical study was performed following TST and molecular docking study was also performed to determine the binding affinity of stigmasterol. Total sterols fraction presents no sign of toxicity up to the oral dose of 2000 mg/kg. Oral treatment of total sterols and acute intraperitoneal treatment of stigmasterol (except 5 mg/kg) reduced the immobility time significantly. Pretreatment with pCPA (5-HT synthesis inhibitor) and NMDA (an agonist of the glutamate site) effectively reversed the immobility time of total sterols and stigmasterol (except pCPA) in TST. However, bicuculline (competitive GABA antagonist), haloperidol (D2 dopaminergic antagonist) and prazosin (α1 adrenergic antagonist) could not reverse the immobility time. Meanwhile, total sterols also effectively altered the hippocampus 5-HT and Glu levels. Also, the result of the molecular docking study depicted that stigmasterol has an affinity to the NMDA receptor. The present study suggests that the total sterols fraction did not produce any acute toxicity in rats. Also, we reported that total sterols, stigmasterol and sub-effective stigmasterol coadministration with fluoxetine significantly reduced the time of immobility in TST and FST confirmed the antidepressant-like effect of total sterols fraction and stigmasterol. Moreover, further findings suggest that the antidepressant-like effect of total sterols might be mediated by the serotonergic and glutamatergic systems. Whereas only the glutamatergic system was involved in the antidepressant activity of stigmasterol.

Genetic polymorphism of DA receptors DRD2 and DRD3 and response to non-ergot DA agonist ropinirole in newly diagnosed PD patients

Background: The interindividual variability in motor response to DAergic drugs is a critical factor conditioning the long-term outcome of PD patients. This is particularly relevant for DA receptor agonists, which are commnonly prescribed as initial treatment in early PD. As yet, the genetic determinants of the response to ropinirole have not been investigated in PD patients.

Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

5-HT2B, 5-HT7, and DA2 Receptors Mediate the Effects of 5-HT and DA on Agonistic Behavior of the Chinese Mitten Crab (Eriocheir sinensis).

The Chinese mitten crab (Eriocheir sinensis) is a commercially important crab in China and is usually managed at high stocking densities. Agonistic behavior directly impacts crab integrity, survival, and growth and results in economic losses. In the present study, we evaluated the modulatory effects of serotonin (5-HT) and dopamine (DA) though the 5-HT2 and DA2 receptor-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway on agonistic behavior. The results showed that injection of either 10-6 mol/crab 5-HT or DA reduced the agonistic behavior of E. sinensis (P < 0.05), as did 10-10 mol/crab DA and 10-8 mol/crab 5-HT and DA (P < 0.05); however, a dose of 10-10 mol/crab 5-HT promoted agonistic behavior. 5-HT significantly increased the mRNA expression level of 5-HT7 receptor and reduced that of the DA2 receptor in the cerebral ganglion (P < 0.05). In contrast to 5-HT, DA significantly decreased 5-HT2B mRNA levels and increased 5-HT7 and DA2 receptor levels in the thoracic ganglia (P < 0.05). In addition, injections of either 5-HT or DA increased the cAMP and PKA levels in hemolymph (P < 0.05). By using in vitro culture of the thoracic ganglia, the current study showed that ketanserin (5-HT2 antagonist) and [R(-)-TNPA] (DA2 agonist) had obvious effects on the expression levels of the two receptors (P < 0.05). In vivo experiments further demonstrated that ketanserin and [R(-)-TNPA] could both significantly reduce the agonistic behavior of the crabs (P < 0.05). Furthermore, both ketanserin and [R(-)-TNPA] promoted the cAMP and PKA levels (P < 0.05). The injection of CPT-cAMP (cAMP analogue) elevated the PKA levels and inhibited agonistic behavior. In summary, this study showed that 5HT-2B and DA2 receptors were involved in the agonistic behavior that 5-HT/DA induced through the cAMP-PKA pathway in E. sinensis.

A small dose of apomorphine counteracts the deleterious effects of middle cerebral artery occlusion in different models.

The present manuscript investigates in two animal species by using two different experimental models of middle cerebral artery occlusion (permanent and transient), the neuroprotective effects of the dopamine receptor agonist apomorphine. These effects were evaluated by measuring the infarct volume and by counting muscle strength at different time points following the ischemic insult. Apomorphine at the dose of 3 mg/Kg when adminsitered at two hours following the occlusion of the middle cerebral artery was able to reduce significantly the infarct volume in the cortex of mice and the ischemic volume of the basal ganglia perfused by the perforant branches of the middle cerebral artery in the rat. In this latter case the behavioral evaluation (i.e. muscle strength) was preserved most effectively in the contralateral side at 24 and 72 hours. The present findings contribute to foster the concept that DA agonists might be useful in the treatment of cerebral ischemia. At the same time the behavioral improvement induced by DA administration following basal ganglia ischemia may be interpreted as the effects of an authentic disease modifying effect rather than a simple symtomatic relief due to a potential loss of DA containing axons in the basal ganglia. These data add on previous evidence showing analogous effects induced by the DA precursor L-DOPA. Apart from providing an evidence of a neuroprotective effect induced by increased DA stimulation the present data call for further studies aimed at comparing the effects of apomorphine with other DA agonists. In fact the quinoline moiety of apomorphine was claimed to protect neurons from a variety of insults independently from a DA agonist activity. The induction of protein clearing pathways appears to be potentially relevant for these effects.

Cluster headache and macroprolactinoma: Case report of a rare, but potential important causality

While headache is not an uncommon symptom in patients suffering from pituitary adenomas, cluster headache (CH) has rarely been reported in such cases. Headache associated with hyperprolactinemia has been reported to be responsive to dopamine agonists (DA agonists) in many patients. We report on a patient with refractory CH secondary to a macroprolactinoma who showed immediate and permanent clinical and radiologic recovery following medical treatment with DA agonists. Measurement of prolactin levels in addition to cranial magnetic resonance imaging might be considered in patients with refractory CH, until the significance of this potential causality becomes clearer.

Dopamine and temporal attention: An attentional blink study in Parkinson's disease patients on and off medication

The current study aimed to shed more light on the role of dopamine in temporal attention. To this end, we pharmacologically manipulated dopamine levels in a large sample of Parkinson's disease patients (n=63) while they performed an attentional blink (AB) task in which they had to identify two targets (T1 and T2) presented in close temporal proximity among distractors. We specifically examined 1) differences in the magnitude of the AB between unmedicated Parkinson patients, who have depleted levels of striatal dopamine, and healthy controls, and 2) effects of two dopaminergic medications (l-DOPA and dopamine agonists) on the AB in the Parkinson patients at the group level and as a function of individual baseline performance. In line with the notion that relatively low levels of striatal dopamine may impair target detection in general, Parkinson patients OFF medications displayed overall poor target perception compared to healthy controls. Moreover, as predicted, effects of dopaminergic medication on AB performance critically depended on individual baseline AB size, although this effect was only observed for l-DOPA. l-DOPA generally decreased the size of the AB in patients with a large baseline AB (i.e., OFF medications), while l-DOPA generally increased the AB in patients with a small baseline AB. These findings may support a role for dopamine in the AB and temporal attention, more generally and corroborate the notion that there is an optimum dopamine level for cognitive function. They also emphasize the need for more studies that examine the separate effects of DA agonists and l-DOPA on cognitive functioning.

Punding in non-demented Parkinson's disease patients: Relationship with psychiatric and addiction spectrum comorbidity

Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, non-goal oriented, repetitive activity, associated with dopaminergic replacement therapy (DRT) in patients affected by Parkinson's disease (PD) and with dopamine agonists in several conditions. We studied 25 PD patients with punding behaviors, and compared them to 130 PD controls. The psychiatric evaluation included: the Snaith-Hamilton Pleasure Scale (SHAPS); the SCales for Outcomes in PArkinson's disease-Psychiatric Complications (SCOPA-PC); the Barratt Impulsiveness Scale, Version 11 (BIS-11); the Mood Disorder Questionnaire; the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS). The occurrence of impulse control disorders (ICDs) was diagnosed through a psychiatric interview. Significantly more punding patients (96% vs. 68%; p<0.01) were in treatment with DA agonists, receiving significantly higher DA agonists levodopa equivalent daily dose (LEDD). Punding behaviors were found to be associated with psychiatric comorbidity, particularly with psychosis and bipolar disorder. In addition, higher anhedonic symptoms were reported by punders. High rate of co-occurring addictive behaviors (pathological gambling, hedonistic homeostatic dysregulation) and ICDs were found. In conclusion, presented data confirm that DRT, in a subset of PD patients, is strongly associated with addiction-like behavioral issues. Punding shares similarities with addictive behaviors and is associated to other psychiatric symptoms involving dopamine system alterations.

Dopamine inhibits the function of Gr-1+CD115+ myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity.

MDSCs accumulate in tumor-bearing animals and cancer patients and are a major factor responsible for cancer-induced immunosuppression that limits effective cancer immunotherapy. Strategies aimed at effectively inhibiting the function of MDSCs are expected to enhance host anti-tumor immunity and improve cancer immunotherapy significantly. The neurotransmitter DA has been found to have anti-cancer activity, but the underlying mechanism is poorly understood. In this study, we sought to investigate the therapeutic mechanism and efficacy of DA on the inhibition of cancer development via the regulation of MDSC functions. The regulation of the suppressive function of Gr-1(+)CD115(+) MDSCs by DA was determined by use of murine syngeneic LLC and B16 graft models treated with DA in vivo, as well as Gr-1(+)CD115(+) MDSCs isolated from these model treated with DA ex vivo. Here, we show that Gr-1(+)CD115(+) monocytic MDSCs express D1-like DA receptors. DA dramatically attenuated the inhibitory function of tumor-induced monocytic MDSCs on T cell proliferation and IFN-γ production via D1-like DA receptors and retarded tumor growth. DA and other D1 receptor agonists inhibited IFN-γ-induced NO production by MDSCs from tumor-bearing mice and cancer patients. Decreased NO production was, in part, mediated via the suppression of p-ERK and p-JNK. In conclusion, the neurotransmitter DA potently inhibits the suppressive function of MDSC and enhances anti-tumor immunity. Our finding provides a mechanistic basis for the use of DA or D1-like receptor agonists to overcome tumor-induced immunosuppression in cancer immunotherapy.

What is the effect of noise on the interval timing neural network?

Cognitive processes, such as decision making, rate calculation and planning, are strongly affected by the ability of subjects to perceive durations in the seconds-to-hours range (interval timing) [1]. A classic interval timing paradigm is the peak interval (PI) procedure which consists of interspersed reinforced and probe trials. During the reinforced trials, a stimulus such as a tone or light is turned on to signal the beginning of the to-be-timed interval and the subject’s first response after the criterion time is reinforced. During the probe trials, no reinforcement is given and the stimulus remains on for about three times the criterion time [2]. The mean response rate over a very large number of trials has a Gaussian shape whose peak measures the accuracy of criterion time estimation and the spread of the timing function measures its precision. In the vast majority of species, protocols, and manipulations to date, interval timing is both accurate and time-scale invariant, i.e. time-estimation errors increase linearly with the estimated duration [3]. We used a computational model of interval timing that mimics the activity of cortico-striatal structures involved in interval timing known as striatal beat frequency (SBF) model (Figure ​(Figure1)1) [4]. In mammals, administration of DA agonist, e.g., methamphetamine or cocaine produce an immediate, scalar (proportional), leftward shift in perceived time (responding earlier in time than under control conditions) whereas DA antagonist, e.g., haloperidol, has an opposed effect. Upon chronic administration of DA drugs, the timing functions recalibrate, i.e., they shift back to the values prior to drug administration. Once the drug is discontinued, the timing functions rebound (in a scalar manner) in the opposite direction from the initial effects of the drug, which is a signature of the clock pattern. SBF model can mimic clock patterns by adjusting the firing rates of FC neurons proportional to dopamine levels. The frequency modulation by dopaminergic drugs also produces a Gaussian-like output in SBF model. However, behavioral experiments indicate that although the average responses in PI procedure follow an almost Gaussian curve, there is always a notable skewness and a long tail of the output function. We found that frequency variability (noise) determines the deviation form the Gaussian-like output. Figure 1 (A) Schematic representation of the two main areas involved in interval timing: frontal cortex (FC) and basal ganglia (BG). (B) SBF model consists of a set of cortical oscillators, a reference memory that stores the state of the system at reinforcement ...

RLS patients can also develop compulsions on dopaminergic agonists

Introduction The aim of this study was to assess the frequency of self-reported compulsive behaviours, depressive and stress symptoms and sleep disorders in a population of Restless legs patients treated with DA agonists. Reports by Tippmann-Peikert et al. (2007) and Ritz et al. (2006) extend the risk of developing DA agonists related impulse control disorders such as gambling, heightened sexual drive or unreasonably overinvested repetitive activities to RLS patients. Materials and methods A questionnaire covering RLS severity (IRLSSG-Walters et al. 2003), mood variables, The Beck Depression Inventory II (Beck et al. 2003), a visual Analog Scale of current level of stress and sleep parameters (The MOS Sleepscale, Hays & Stewart 1992) was sent at 3 points in time over twelve months in 2005 (February, June, October) to 150 RLS patients cared for at the Quebec Memory & Motor Skills Disorders Clinic. A last section exploring changes in hobbies, development of new habits and compulsions was added at the third mailing. Results Data derived from a population of 97 patients having answered all three mailings identified 17 positive responses to compulsions. After re-evaluation only 12 (8 women and 4 men) were found to have truly compulsive behaviours. In two women, simple motor stereotyped sequences in response to sensory urge evoked the phenomenology of Gilles de La Tourette Syndrome. In two other, one male, one female, a reactivation of trichotillomania previously exhibited in childhood was observed. For the other eight patients, abnormal behavioural display was similar to complex compulsory behaviours with short-term rewarding properties such as buying clothes, buying food, eating or gambling. In addition BDI and stress scores significantly contrasted the compulsion (+) vs. compulsion (−) patients. Their MOS sub-scale sleep problem Index I and II showed significantly higher scores and finally, the augmentation phenomenon was of higher prevalence in the C + group at the time of the 3rd questionnaire. Conclusion In summary, 12 out of 97 RLS patients on stable DA agonist therapy presented with progressive dishinibition of behaviour possibly shaped by pre treatment gender and individual specificities. None had a previous diagnosis of anxious generalized disorder or obsessive compulsive disorder. They showed more dysphoric and recognized themselves as more stressed than the compulsion (-) group of RLS patients.

EDS in Parkinson’s disease: pharmacology and new mouse model

Excessive daytime sleepiness (EDS) can affect 20–50% of patients with Parkinson’s disease (PD), and sudden onset of sleep attacks (SA) in PD behind the wheel often leads to fatal car accidents. Although non-treated PD patients exhibit EDS and SA, SA in PD is often associated with use of DA agonists, especially the recent non-ergot DA D2/3 agonists. We have therefore initiated a pharmacological study to study the pharmacodynamics of the D2/3 agonists on sleep. Male rats underwent surgery for EEG and EMG electrodes. Vehicle was injected (i.p.) 5 min before the beginning of lights-off period (ZT12) on day 1, and sleep was recorded for 24-h. On day 2, quinpirole (Qu: 30 μ g or 1000 μ g/kg), a non-ergot DA D2/3 agonist, was injected. Amounts of sleep parameters for the 24-h following Qu administration were compared to those following vehicle injections. Change in the extracellular DA levels after drug administration was also measured in the prefrontal cortex. Low dose of Qu significantly increased SWS and REM sleep, and decreased wakefulness. On the contrary, high dose of Qu significantly enhanced wakefulness which lasted for 3–4 h followed by a large increase in sleep that lasted until the end of the active period. This increase in sleep was much larger than the sleep loss in the initial hours, and was also much larger than sleep rebound seen after the total sleep deprivation of 4-h (ZT12-16). A low dose of Qu reduced DA release immediately by 60%, and the level gradually returned to the baseline over 7-h. A high dose of Qu produced much longer reduction in DA release, and the effect lasted for 12-h. Interestingly, the recovery of DA release started to occur at 4 h after the high dose injection, and the slope of the recovery after 4 h is identical to the slope that occurred after the low quinpirole dose administration (which accompanied sleep induction). D2/3 agonists reduce dopamine release by acting on pre-synaptic D2/3 autoreceptors, while high doses predominantly activate postsynaptic D2 receptors. The results of microdialysis experiments suggest that a shift from postsynaptic (excitatory) to presynaptic (inhibitory) action may occur 4 h after the administration of a high dose of Qu. This mechanism may partially explain the D2/D3 agonist-induced excessive sleepiness seen in human patients and we are testing this hypothesis using a new mouse model of PD with cre-loxP recombinant conditional knockout of DA neurons. Research supported by R21 NS072942.

Treatment of antipsychotic-induced hyperprolactinemia with bromocriptine: A case report

INTRODUCTION Previous literature has highlighted an increase in morbidity and mortality associated with antipsychotic use in persons with severe mental illnesses (SMI), which include schizophrenia and bipolar disorder. Drug-induced hyperprolactinemia is a function of dopamine blockade in the anterior pituitary. Elevated prolactin levels are often accompanied by symptoms of decreased libido and erectile dysfunction (ED) in men, and galactorrhea and amenorrhea in women. However, the extent to which antipsychotic (AP) use is associated with sexual dysfunction has not been extensively reported. Hyperprolactinemia may also increase the risk for osteopenia.

The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat.

L-DOPA continues to be the primary treatment for patients with Parkinson's disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT1A receptor dependent manner. In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D1 receptor agonist SKF81297 and the D2 receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802's effects was evaluated using WAY-100635, a 5-HT1A receptor antagonist. Results confirmed the dose-dependent (20 > 10 > 5mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of anti-parkinsonian efficacy at 10mg/kg. BMY-14802 at 10 and 20mg/kg also reduced dyskinesia induced by both D1 and D2 receptor agonists. Additionally, BMY-14802's anti-dyskinetic effects against L-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5mg/kg). Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD.

Evidence for the Nitric Oxide Pathway as a Potential Mode of Action in Fenoldopam-induced Vascular Injury

Fenoldopam, a dopaminergic DA1 agonist, induces vasodilatation via nitric oxide (NO), and this may be associated with mesenteric arterial injury. NO is produced from the enzymatic action of nitric oxide synthase (NOS), which is regulated by the shear-stress mediating protein caveolin-1. Profound vasodilatation and accompanied decreased shear are early events that could initiate vascular injury. Therefore, it is of interest to determine the role of caveolin-1 and the NO pathway in fenoldopam-induced vascular injury. At sites of fenoldopam-induced mesenteric arterial injury, decreased caveolin-1 expression and apoptosis were prominent immunohistochemical findings. An additional finding at these sites of injury were loss and/or reduced expression of caveolin-1 regulated structural proteins, connexin-43, (gap junction) ZO-1, and claudin (tight junctions). Because functional loss of caveolin-1 is associated with increased NOS activity and vasodilatation via NO, studies were conducted to show a NO donor produced vascular lesions in the mesenteric arteries morphologically similar to those induced by fenoldopam. Moreover, the incidence and severity of fenoldopam-induced vascular injury were reduced when an NOS inhibitor or a scavenger of NO-generated free radicals were coadministered with fenoldopam. Collectively, these data suggest that caveolin-1 and its regulated NO pathway may play an important role in vasodilatory drug-induced vascular injury.

Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats

The present study investigated gender differences in the effects of presynaptic and postsynaptic DA agonists on latent inhibition in the passive avoidance paradigm. During the preexposure phase, 32 male and 32 female Wistar rats were exposed to a passive avoidance box (or a different context) and received drug injections in three trials: the control group received an injection of 10% ascorbic acid in a different context. The experimental groups received injections of 10% ascorbic acid (latent inhibition [LI] group), 1mg/kg of the postsynaptic DA D1/D2 agonist apomorphine (APO group), and 1.5mg/kg of the presynaptic DA agonist methamphetamine (METH group) in a passive avoidance box. All experimental groups were placed in the light compartment of the passive avoidance box and were allowed to enter into the dark compartment to receive a footshock (1mA, 2s) in five trials over 5 days. The latency to enter into the dark compartment was recorded in these five trials. The latent inhibition occurred in the female LI group but not in the male LI group. Regardless of gender, the APO group exhibited an increase in latent inhibition. Male rats in the METH group exhibited a decrease in latent inhibition, but female rats in the METH group exhibited an increase in latent inhibition, indicating that the METH group exhibited sexual dimorphism. The gender factor interacted only with the METH group and not the LI or APO group. The present paper discusses whether gender, the postsynaptic DA D1/D2 agonist APO, and presynaptic DA agonist METH may be related to schizophrenia.

The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion

The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by d-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated d-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction.

Differential DAergic Control of D1 and D2 Receptor Agonist Over Locomotor Activity and GABA Level in the Striatum

The basal ganglia, a group of nuclei, are associated with a variety of functions, including motor control. The striatum, which is the major input station of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. The striatum is made up 96% of medium spiny neurons which are GABAergic cells. GABAergic cells are known to contain DA receptors which divide into two main branches- the D1 receptor (D1R)-expressing direct pathway and the D2 receptor (D2R)-expressing indirect pathway. The role of these two efferent pathways has not been clear in control of motor behaviors. To establish the influence of the different DA subtypes on GABAergic systems in the striatum, D1 selective receptor agonist (SKF 38393) and D2 selective receptor agonist (Quinpirole) were administered to mice. SKF 38393 and quinpirole were administered intraperitoneally in a volume of 0, 1, 5, 10 (mg/kg) and motor activity was assessed for 60 min immediately after the injection of DA agonists. Mice were sacrificed after behavioral test and the striatum in the brain were dissected for analysis of GABA level with HPLC. Both SKF 38393 and quinpirole dose-dependently increased locomotor activity but, GABA level in the striatum was clearly different in two agonists. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal GABAergic motor behaviors.