Blockade Of Dopaminergic Receptors Research Articles

Basal release and relaxation responses to 6-nitrodopamine in swine carotid, coronary, femoral, and renal arteries

Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-NG-Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D2-receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 μM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 μM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D2-like receptors.

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.

Low continuation of antipsychotic therapy in Parkinson disease \u2013 intolerance, ineffectiveness, or inertia?

BackgroundAntipsychotics are used in Parkinson disease (PD) to treat psychosis, mood, and behavioral disturbances. Commonly used antipsychotics differ substantially in their potential to worsen motor symptoms through dopaminergic receptor blockade. Recent real-world data on the use and continuation of antipsychotic therapy in PD are lacking. The objectives of this study are to (1) examine the continuation of overall and initial antipsychotic therapy in individuals with PD and (2) determine whether continuation varies by drug dopamine receptor blocking activity.MethodsWe conducted a retrospective cohort study using U.S. commercially insured individuals in Optum 2001–2019. Adults aged 40 years or older with PD initiating antipsychotic therapy, with continuous insurance coverage for at least 6 months following drug initiation, were included. Exposure to pimavanserin, quetiapine, clozapine, aripiprazole, risperidone, or olanzapine was identified based on pharmacy claims. Six-month continuation of overall and initial antipsychotic therapy was estimated by time to complete discontinuation or switching to a different antipsychotic. Cox proportional hazards models evaluated factors associated with discontinuation.ResultsOverall, 38.6% of 3566 PD patients in our sample discontinued antipsychotic therapy after the first prescription, 61.4% continued with overall treatment within 6 months of initiation. Clozapine use was too rare to include in statistical analyses. Overall therapy discontinuation was more likely for those who initiated medications with known dopamine-receptor blocking activity (adjusted hazard ratios 1.76 [95% confidence interval 1.40–2.20] for quetiapine, 2.15 [1.61–2.86] for aripiprazole, 2.12 [1.66–2.72] for risperidone, and 2.07 [1.60–2.67] for olanzapine), compared with serotonin receptor-specific pimavanserin. Initial antipsychotic therapy discontinuation also associated with greater dopamine-receptor blocking activity medication use – adjusted hazard ratios 1.57 (1.28–1.94), 1.88 (1.43–2.46), 2.00 (1.59–2.52) and 2.03 (1.60–2.58) for quetiapine, aripiprazole, risperidone, and olanzapine, respectively, compared with pimavanserin. Similar results were observed in sensitivity analyses.ConclusionsOver one-third of individuals with PD discontinued antipsychotic therapy, especially if the initial drug has greater dopamine-receptor blocking activity. Understanding the drivers of antipsychotic discontinuation, including ineffectiveness, potentially inappropriate use, clinician inertia, patient adherence and adverse effects, is needed to inform clinical management of psychosis in PD and appropriate antipsychotic use in this population.

Blockade of D1-like dopaminergic receptors suppresses Th17-cell function in multiple sclerosis

To investigate the direct effect of D1-like dopaminergic receptors antagonist on Th17-cells function in multiple sclerosis (MS) in vitro. Forty-one relapsing-remitting MS patients and twenty-five healthy subjects were examined. The functional activity of Th17-cells was assessed by the ability to produce IL-17 and IFN-γ by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells, stimulated with microbeads coated with anti-CD3/anti-CD28-antibodies. To study the involvement of D1-like dopaminergic receptors in modulation of Th17-cell function, the samples of PBMCs or CD4+ T-cells were cultured in the presence of dopamine and/or specific D1-like dopaminergic receptors antagonist (SCH23390). Cytokine levels in cell culture supernatants were measured by ELISA. The production of IL-17 and IFN-γ by stimulated PBMCs were higher in MS patients during relapse than in MS patients during clinical remission or in healthy subjects. The production of cytokines by stimulated PBMCs or CD4+ T-cells in MS patients during clinical remission and healthy subjects was comparable. Dopamine reduced the production of cytokines by PBMCs and CD4+ T-cells in all groups. Blockade of D1-like dopaminergic receptors did not affect the dopamine-mediated cytokine suppression in MS patients and healthy subjects. Blockade of D1-like dopaminergic receptors directly suppressed cytokine production by PBMCs and CD4+ T-cells in MS patients and healthy subjects. Dopamine and blockade of D1-like dopaminergic receptors have an inhibitory effect on Th17-cell function in MS. The activation of D2-like dopaminergic receptors could mediate the inhibitory effect of dopamine on Th17-cells.

The longitudinal effect of antipsychotic burden on psychosocial functioning in first-episode psychosis patients: the role of verbal memory.

Previous literature supports antipsychotics' (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning. A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables. Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011-0.0091) and (b = 0.0026, 95% CI 0.0001-0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033-0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden. CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.

Respiratory pattern and phrenic and hypoglossal nerve activity during normoxia and hypoxia in 6-OHDA-induced bilateral model of Parkinson\u2019s disease

Respiratory disturbances present in Parkinson’s disease (PD) are not well understood. Thus, studies in animal models aimed to link brain dopamine (DA) deficits with respiratory impairment are needed. Adult Wistar rats were lesioned with injection of 6-hydroxydopamine (6-OHDA) into the third cerebral ventricle. Two weeks after hypoxic test was performed in whole-body plethysmography chamber, phrenic (PHR) and hypoglossal (HG) nerve activities were recorded in normoxic and hypoxic conditions in anesthetized, vagotomized, paralyzed and mechanically ventilated rats. The effects of activation and blockade of dopaminergic carotid body receptors were investigated during normoxia in anesthetized spontaneously breathing rats. 6-OHDA injection affected resting respiratory pattern in awake animals: an increase in tidal volume and a decrease in respiratory rate had no effect on minute ventilation. Hypoxia magnified the amplitude and minute activity of the PHR and HG nerve of 6-OHDA rats. The ratio of pre-inspiratory to inspiratory HG burst amplitude was reduced in normoxic breathing. Yet, the ratio of pre-inspiratory time to total time of the respiratory cycle was increased during normoxia. 6-OHDA lesion had no impact on DA and domperidone effects on the respiratory pattern, which indicate that peripheral DA receptors are not affected in this model. Analysis of monoamines confirmed substantial striatal depletion of dopamine, serotonin and noradrenaline (NA) and reduction of NA content in the brainstem. In bilateral 6-OHDA model changes in activity of both nerves: HG (linked with increased apnea episodes) and PHR are present. Demonstrated respiratory effects could be related to specific depletion of DA and NA.

A case of levosulpiride-induced tardive dyskinesia

Levosulpiride is chemically a substituted benzamide which acts as an atypical antipsychotic and prokinetic agent. There is dearth of study and limited research on levosulpiride-induced tardive dyskinesia (TD) and its abuse potential till date. Levosulpiride can cause TD which is related to an apparent dopaminergic hyperactivity after long-term blockade of presynaptic dopaminergic D2 receptors. So, detailed drug history should be taken to detect the rare cases of levosulpiride-induced TD and physicians should be cautious in using levosulpiride, particularly in elderly patients.

Bidirectional modulation of hippocampal synaptic plasticity by Dopaminergic D4-receptors in the CA1 area of hippocampus

Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABAA-receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening.

Dopaminergic receptor blockade changes a functional connectivity network centred on the amygdala.

Resting-state connectivity has become an increasingly important measure in characterizing the functional integrity of brain circuits in neuro-psychiatric conditions. One approach that has recently gained prominence in this regard-and which we use in this study-is to investigate how resting-state connectivity depends on the integrity of certain neuromodulator systems. Here, we use a pharmacological challenge in combination with functional magnetic resonance imaging to investigate the impact of dopaminergic receptor blockade on whole brain functional connectivity in twenty healthy human subjects. Administration of the D2-receptor antagonist haloperidol led to a profound change in functional integration in network nodes linked to the amygdala. Compared to placebo and baseline measurements, network-based statistics and pairwise connectivity analyses revealed reduced connectivity and decreased link strength between the amygdala and the bilateral posterior cingulate cortex and other cortical areas. This was complemented by less extensive but very circumscribed enhanced connectivity between the amygdala and the right putamen during D2-receptor blockade. It will be interesting to investigate whether these pharmacologically induced shifts in resting-state connectivity will similarly be evident in clinical conditions that involve a dysfunction of the dopaminergic system. Our findings might also aid in interpreting alterations in more complex states, such as those seen psychiatric conditions and their treatment. Hum Brain Mapp 37:4148-4157, 2016. © 2016 Wiley Periodicals, Inc.

Chronic estrogen and progesterone treatment inhibits ketamine-induced disruption of prepulse inhibition in rats

Ketamine is a dissociative anesthetic and antagonist of N-methyl-d-aspartate receptors (NMDAr). Hypofunction of NMDAr may underlie some schizophrenia symptoms and the psychotomimetic effects of ketamine have been used to model this hypofunction. Gender differences exist in the age of onset and symptom profile of schizophrenia and sex steroid hormones have been successfully trialed as adjunctive treatment in this illness; however, the mechanism of action of these hormone treatment strategies remains unclear. The aim of this study was therefore to investigate the effect of sex steroid hormones on ketamine-induced disruption of prepulse inhibition (PPI), an endophenotype of schizophrenia. Female ovariectomized (OVX) rats did not show altered effects of ketamine compared to intact rats. There were also no significant changes in the effect of ketamine on PPI in OVX rats implanted with a high dose of estrogen. In contrast, in OVX rats implanted with a low dose of estrogen plus progesterone, the effect of 10mg/kg ketamine was significantly reduced. There were no parallel changes in startle amplitude. These results differ from previous studies on the effect of sex steroid hormones on the disruption of PPI by treatment with the NMDAr antagonist, MK-801, or dopaminergic drugs, such as apomorphine. We speculate that this differential effect of sex steroids on the action of ketamine is mediated by mechanisms other than dopaminergic stimulation or NMDA receptor blockade, for example GABAA receptors. These results extend our understanding of the effects of sex steroid hormones on PPI and their use as potential treatments in schizophrenia.

P.2.a.005 Blockade of D1 dopaminergic receptors corrects depression-like behaviour in gonadectomised rats treated with a low dose of testosterone

P.2.a.005 Blockade of D1 dopaminergic receptors corrects depression-like behaviour in gonadectomised rats treated with a low dose of testosterone

Dracaena arborea extracts delay the pro-ejaculatory effect of dopamine and oxytocin in spinal male rats.

Dracaena arborea is a medicinal plant with ethnopharmacological aphrodisiac reputation. In the present study, the effect of an intravenous administration of aqueous and ethanolic extracts from the dried roots of this plant on the ejaculatory pattern of spinal cord-transected and urethane-anaesthetized rats was investigated. In addition, the effects of these extracts were also determined on dopamine and oxytocin-induced ejaculation. Systemic administration of aqueous and ethanolic extracts (5, 20, 60, 100 mg kg(-1)) of D. arborea did not activate fictive ejaculation, whereas dopamine (0.1 μM kg(-1)) and oxytocin (0.5 UI kg(-1)) provoked ejaculation evidenced by the rhythmic contractions of the bulbospongiosus muscles accompanied with penile erection and sometimes with expulsion of the seminal plugs. Pretreatment of spinal rats with D. arborea extracts dose-dependently blocked the pro-ejaculatory activity of dopamine and oxytocin. In conclusion, the present study shows that the bioactive substances present in the extracts of D. arborea inhibit the activity of the bulbospongiosus muscles through the blockade of dopaminergic and oxytocinergic receptors in rats.

Effect of Extracts and Isolated Pure Compounds of <i>Spondias Mombin</i> (l. Anacardiaceae) Leaves on Gross Exploratory Behaviors in Mice.

Previous studies have reported several neuro-physiological effects of crude extracts of Spondias mombin leaves, which is widely used by traditional medical practitioners in Nigeria for the treatment of neuro-psychiatric disorders. However the neuro-physiological effects of fractionated extracts and pure isolates, with the pharmacological mechanisms responsible for these effects have remained largely unexplored. This study elucidated the neurotransmitter systems and receptors involved in the effects of extracts, and isolated compounds of Spondias mombin leaves in mice (n = 5 - 6) after intraperitoneal (i.p.) route of administration on gross explorative behaviors in mice. The crude ethanolic extract of Spondias mombin leaves was fractionated using the partitioning method to obtain the ethylacetate, butanolic and aqueous fractions. Open column chromatographic fractionation of the ethylacetate fraction yielded seven sub-fractions, out of which the pure coumaroyl, quercetin and gallic acid derivatives were obtained after purification on Sephadex LH-20. The ethanolic extract, butanolic, ethylacetate fractions, ethylacetate subfractions and pure isolates of the Spondias mombin leaves were tested on open field locomotion and head dipping behaviors in mice using standard pharmacological tools. The results showed that the ethanolic and butanolic extracts decreased open field locomotion, while ethylacetate fraction increased open field locomotion at lower doses, but decreased it at higher doses. Subfractions S1 - S7 decreased open field locomotion except S2 ,which had no effect on open field locomotion. The three pure isolates decreased open field locomotion. Pre-treatment with yohimbine, atropine and propranolol had no effect on the coumaroyl derivatibe-induced effect on open field behavior, naloxone reversed this effect while haloperidol potentiated the inhibitory effects of the three pure isolates on open field locomotion. Ethanolic and butanolic decreased head dipping behavior in a dose dependent manner, while ethylacetate fraction increased head dips at lower doses, but decreased it at higher doses. Subfractions S1 - S7 decreased the number of head dips except S2, which had no effect. Coumaroyl derivative had no effect, but gallic acid and quercetin derivatives decreased the number of head dips. Yohimbine, atropine, propranolol and haloperidol potentiated the inhibitory effect of gallic acid and quercetin derivatives on head dips, whereas naloxone reversed the effect of coumaroyl and quercetin derivatives on head dips. It can be inferred that blockade of opioid receptors consistently reversed the effect of coumaroyl derivative on open field locomotion and head dipping behaviors, while blockade of dopaminergic receptors consistently facilitated the effects of the three pure isolates on open field locomotion and head dipping behaviors. It is suggested that the opioid and dopaminergic neurotransmitter systems are strongly involved in the behavioral effects of pure isolates of Spondias mombin leaves in mice.Keywords : Receptors; Neurotransmitters; Explorative Behaviors; Coumaroyl, Gallic Acid; Quercertine; Spondias mombin

Modulation of haloperidol-induced catalepsy in rats by GABAergic neural substrate in the inferior colliculus

Not only is the inferior colliculus (IC) a highly important center of integration within the central auditory pathway, but it may also play a modulatory role in sensory-motor circuitry. Previous evidence from our laboratory relating the IC to motor behavior shows that glutamate-mediated mechanisms within the IC modulate haloperidol-induced catalepsy. The high density of GABAergic receptors in the IC led to this study of a possible link between these receptors, haloperidol-induced catalepsy, and a possible involvement of the blockade of dopaminergic receptors. Catalepsy was evaluated by positioning both forepaws of rats on an elevated horizontal wooden bar and recording the time that the animal maintained this position. The present study shows that haloperidol-induced catalepsy was enhanced by local microinjection into the IC of midazolam (20nmol/0.5μl), a benzodiazepine receptor agonist, whereas animals receiving a microinjection of bicuculline (40 or 80ng/0.5μl), a GABAergic antagonist, showed a reduction in the time of catalepsy. However, the microinjection of haloperidol (2.5 or 5.0μg/0.5μl) bilaterally into the IC did not induce catalepsy. Therefore, our results suggest the involvement of the IC in the modulation of catalepsy induced by haloperidol, even though the dopaminergic mechanisms of the IC are unable to induce catalepsy when blocked by the direct microinjection of haloperidol. It is thus possible that the IC plays a role in sensorimotor gating and that GABA-mediated mechanisms are involved.

Drug-Induced Parkinsonism

Drug-induced parkinsonism (DIP) is the second-most-common etiology of parkinsonism in the elderly after Parkinson's disease (PD). Many patients with DIP may be misdiagnosed with PD because the clinical features of these two conditions are indistinguishable. Moreover, neurological deficits in patients with DIP may be severe enough to affect daily activities and may persist for long periods of time after the cessation of drug taking. In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs. The clinical manifestations of DIP are classically described as bilateral and symmetric parkinsonism without tremor at rest. However, about half of DIP patients show asymmetrical parkinsonism and tremor at rest, making it difficult to differentiate DIP from PD. The pathophysiology of DIP is related to drug-induced changes in the basal ganglia motor circuit secondary to dopaminergic receptor blockade. Since these effects are limited to postsynaptic dopaminergic receptors, it is expected that presynaptic dopaminergic neurons in the striatum will be intact. Dopamine transporter (DAT) imaging is useful for diagnosing presynaptic parkinsonism. DAT uptake in the striatum is significantly decreased even in the early stage of PD, and this characteristic may help in differentiating PD from DIP. DIP may have a significant and longstanding effect on patients' daily lives, and so physicians should be cautious when prescribing dopaminergic receptor blockers and should monitor patients' neurological signs, especially for parkinsonism and other movement disorders.

Cytochemical and Ultrastructural Characteristics of BHK-21 Cells Exposed to Dopamine

BHK-21 cells were incubated in medium containing dopamine (DA) and catecholamine contents were then measured using the Falck cytochemical method. As compared with controls, significant increases were seen in the fluorescence of cells and these were proportional to the concentration and duration of exposure to DA and more marked in cells in suspension than in attached cells. Parallel electron microscopic studies showed that the increased fluorescence intensity of the cytoplasm correlated with the presence of dense networks of fibrils which were identified on the basis of morphological characteristics as microfilaments consisting of F-actin. Prior blockade of dopaminergic receptors with haloperidol did not alter the subsequent effects of DA on fluorescence intensity or cell ultrastructure. These data suggest that, in conditions of chronic exposure, DA can penetrate into the cytoplasm, inducing actin polymerization and becoming bound to the newly formed actin cytoskeleton. Structurally, this can be apparent as hypertrophy of the cytoskeleton and its derivatives, with significant influences on the overall structure of the cell.

Off‐line concomitant release of dopamine and glutamate involvement in taste memory consolidation

It has been postulated that memory consolidation process requires post-learning molecular changes that will support long-term experiences. In the present study, we assessed with in vivo microdialysis and capillary electrophoresis whether such changes involve the release of neurotransmitters at post-acquisition stages. Using conditioned taste aversion paradigm we observed spontaneous off-line (i.e. in absence of stimulation) dopamine and glutamate reactivation within the insular cortex about 45 min after the stimuli association. These increments did not appear in control groups that were unable to acquire the task, and it seems to be dependent on amygdala activity since its reversible inactivation by tetrodotoxin impaired cortical off-line release of both neurotransmitters and memory consolidation. In addition, blockade of dopaminergic D1 and/or NMDA receptors before the off-line activity impaired long- but not short-term memory. These results suggest that off-line extracellular increments of glutamate and dopamine have a significant functional role in consolidation of taste memory.

Enhanced serum prolactin concentration after metoclopramide stimulation in idiopathic oligozoospermia and azoospermia.

The aim of the study was to evaluate the hormonal pattern in men with idiopathic oligozoospermia and azoospermia. Material consisted of 13 sterile men, 21-34 years old (the mean - 27 years). Three of 13 patients had the third degree oligozoospermia, 3 - extreme oligozoospermia and 7 - azoospermia. The control group consisted of 11 healthy men who were found to have normozoospermia. In all patients and in control subjects the estimation of LH, FSH, prolactin (PRL), testosterone and dihydrotestosterone (DHT) in basal conditions and also PRL determination at 15, 30, 60 min after stimulation with metoclopramide (MCP 10 mg i.v.) were performed by radioimmunoassay. The results indicate that men with idiopathic oligo- or azoospermia have significantly higher prolactin level in response to dopaminergic receptor blockade with metoclopramide and significantly lower serum testosterone and DHT concentrations.

Effects of long term losartan treatment on D2 receptor modulation of breathing in the dystrophic hamster in air and following intermittent hypoxic bouts

Angiotensin II (A) acting through A1 receptors and hypoxia release dopamine in several brain regions and the carotid body. Blockade of dopaminergic receptors (D2) modulates ventilation in the hamster. We tested the hypothesis that two months of losartan (L, an A1 receptor blocker, 50 mg/kg) treatment would affect D2‐modulated control of breathing during exposure to air and five minutes each of three bouts of 10% O2 interspersed with air (IH) differently compared to tap water‐treated dystrophic (D) hamsters. Ventilation was evaluated in conscious control (C), CL, D and DL hamsters injected with vehicle or domperidone, a D2 receptor antagonist (Dom) that does not cross the blood‐brain barrier. During baseline air exposure, frequency (f) was higher in the C versus the D groups. Dom normalized f and increased tidal volume in the DL group relative to CL. Dom doubled minute ventilation (MV) in DL relative to the D group, but did not affect C or CL groups. To evaluate the effects of IH, the ratio of MV during the third bout of IH to baseline (H/B) was determined. In DL, Dom relative to vehicle had no effect on MV H/B but in D hamsters Dom increased MV H/B (1.2 ± 0.12 vs. 1.8 ± 0.14, P=0.02). Losartan had no effect on MV H/B in the control groups. These results suggest that in dystrophic hamsters breathing air or hypoxia losartan alters D2‐modulated control of breathing by acting on the carotid body.