5-HT1A receptor agonists buspirone and gepirone attenuate apomorphine-induced aggressive behaviour in adult male Wistar rats.
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We have studied the effects of acute serotonin (5-HT) 5-HT1A receptor agonist buspirone (0.5, 1.0, 2.5 and 5.0 mg/kg, s.c.), gepirone (5.0 and 10 mg/kg, s.c.), and 8-OH-DPAT (0.1, 0.25, and 0.5 mg/kg, i.p.) treatment on the apomorphine-induced aggressive behaviour in adult male Wistar rats. Buspirone in doses of 2.5 and 5.0 mg/kg completely blocked, gepirone (10 mg/kg) significantly attenuated the aggressiveness, and 8-OH-DPAT abolished aggressive behaviour only in the lowest dose used (0.1 mg/kg) which effect disappeared in higher doses. The antiaggressive effect of buspirone (2.5 mg/kg) and gepirone (10 mg/kg) was not reversed by a 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg). All 5-HT1A receptor agonists tested dose-dependently decreased the exploratory behaviour of experimentally naive rats, while buspirone (2.5 mg/kg) and gepirone (10 mg/kg) had only a weak effect on the locomotor activity and stereotyped behaviour in the apomorphine-pre-sensitised rats. In conclusion, our experiments demonstrate the 5-HTIA receptors may be involved in the mediation of the apomorphine-induced aggressive behaviour in adult male Wistar rats. However, the prominent antiaggressive effect of buspirone, and to a lesser extent--gepirone, seems to be mediated by some other mechanisms, evidently via the dopamine D2 receptors. (+info)
Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey.
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Despite the importance and frequency of levodopa-induced dyskinesias, little is known about their causal mechanisms. In this study, electrophysiological single-unit recordings of the neuronal activity of the globus pallidus internalis (GPi), the main basal ganglia output structure, and the globus pallidus externalis (GPe) were recorded continuously in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated subhuman primates before and after the administration of three dopamine agonists--apomorphine (a dopaminergic mixed agonist), SKF-38393 (a D1 partial agonist) and piribedil (a D2/D3 agonist)--at doses known to induce dyskinesias in the parkinsonian monkey. Changes in both the firing frequency and the firing pattern were analysed in relation to behavioural modifications. In both the normal and the parkinsonian monkey, the three agonists induced a decrease in the mean firing frequency of GPi neurones, although dyskinesias were induced only in the parkinsonian animals. In this situation, the improvement of parkinsonian motor abnormalities was correlated with the decrease in GPi firing frequency, whereas firing pattern changes were concomitant with the onset of dyskinesias. Moreover, firing frequency seemed to be decreased excessively during dyskinesias. The results indicate that the electrophysiological mechanism of dyskinesia involves an excessive decrease in GPi firing frequency and a modification of the firing pattern. However, the similarity between the induced decrease in firing frequency in normal and parkinsonian animals underlines the need for dopamine depletion in the induction of dyskinesias. (+info)
A nitric oxide-dopamine link pathway in organum vasculosum laminae terminalis of rat brain exerts control over blood pressure.
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1. Experiments were carried out to explore the possible role played by the nitric oxide (NO) and dopamine (DA) system in the organum vasculosum laminae terminalis (OVLT) of rat brain in arterial pressure regulation. 2. Intracerebroventricular (ICV) administration of NO donors such as hydroxylamine or sodium nitroprusside (SNP) caused an up to 59 mmHg decrease in blood pressure (BP) and a decrease in DA release (measured by nafion coated carbon fibre electrodes in combination with voltammetry) in the OVLT. In contrast, ICV administration of N(G)-nitro-L-arginine methyl ester (L-NAME; a constitutive NO synthase inhibitor) or 7-nitroindazol (a neuronal NO synthase inhibitor) caused an up to 98 mmHg increase in BP and an increase in DA release in the OVLT. 3. Intra-OVLT injection of amphetamine (0.1 - 0.3 mg), SKF 38393 (a DA D(1) receptor agonist; 0.01 - 0.03 mg), or apomorphine (a DA D(2,3) receptor agonist; 0.01 - 0.03 mg) caused an increase in BP. On the other hand, intra-OVLT injection of SCH23390 (a DA D(1) receptor antagonist; 0.005 - 0.020 mg) or haloperidol (0.005 - 0.020 mg) caused a decrease in BP. 4. The pressor effects induced by intra-OVLT administration of L-NAME were attenuated by pretreatment with intra-OVLT injection of haloperidol, SCF23390, or 6-hydroxydopamine. In the contrast, the hydroxylamine-, 8-Br-cGMP- or SNP-induced depressor effects were attenuated by pretreatment with intra-OVLT injection of amphetamine, SKF 38393 or apomorphine. 5. The data suggest that activation of a NO-DA link pathway within the OVLT of rat brain exerts control over blood pressure. (+info)
Action sites of rotation and unit firing induced by l-stepholidine and DA agonists in basal ganglia of 6-OHDA-lesioned rats.
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AIM: To elucidate the action sites of l-stepholidine (SPD) in the basal ganglia. METHODS: Counting the rotations after intra-nucleus microinjection and recording the neuron firing by microiontophoresis of SPD and DA agonists in the basal ganglia of 6-hydroxydopamine (6-OHDA)-lesioned rats. RESULTS: The DA immunoreactive substance was markedly reduced in the 6-OHDA-lesioned rats. The intra-neostriatum microinjection of apomorphine (Apo, D1/D2), SK&F 38393 (D1), and SPD elicited remarkable rotation, and the characteristics of SK&F 38393-produced rotation were of long latency and long duration. The intra-substantia nigra pars reticulata (SNR) injection of Apo, SK&F 38393, and SPD induced the rotation response, while the selective D2 agonist quinpirole hydrochloride (Ly171555) did not because of scarce D2 receptors in the SNR. The intraglobus pallidus (GP) injection of DA agonists and SPD failed to evoke rotation, but the GP nucleus still had the contribution to rotation elicited by i.p. injection of DA agonists and SPD in the 6-OHDA-lesioned rats with successive kainic acid (KA) lesion. Besides, the successive lesion of entopeduncular nucleus (EP) on rotation was less important than that of GP nucleus. The microiontophoresis of Apo and SPD into the SNR could evoke the neuron firing, but failed to activate the GP neurons, which were activated by sodium glutamate (Glu) and inhibited by gamma-aminobutyric acid (GABA). CONCLUSION: The action sites of SPD-induced rotation and neuron firing via the D1 receptors are in the neostriatum and SNR instead of GP. The direct neurocircuit through SNR is the most important for rotation of 6-OHDA-lesioned rats. (+info)
Comparison of 12-chloroscoulerine enantiomers on animal behavior to dopamine receptors.
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AIM: To compare the pharmacological characteristics of 12-chloroscoulerine (CSL) enantiomers to dopamine (DA) receptors. METHODS: Radioligand receptor binding assay with calf striatum and behavioral tests of mice or rats were used. RESULTS: In the competitive binding assay, the affinities (Ki) of l-CSL to D1 and D2 receptors were 5.7 nmol.L-1, while those of d-CSL for D1 and D2 receptors were 135 and 9150 nmol.L-1, respectively. The Ki of dl-CSL to D1 and D2 receptors were 8.9 and 9.6 nmol.L-1, respectively, which were slightly weaker than that of l-CSL. In the behavioral experiments, CSL enantiomers 5-60 mg.kg-1 antagonized the stereotypy induced by apomorphine in rats, and 5-150 mg.kg-1 produced catalepsy. The enantiomers 10-60 mg.kg-1 reduced the mice jumping behavior induced by amphetamine + levodopa. l-CSL 10-80 mg.kg-1 antagonized the spontaneous locomotor activity of normal or amphetamine-treated mice. CONCLUSION: CSL enantiomers are antagonists to DA receptors: l-CSL > dl-CSL >> d-CSL. (+info)
Inhibitory effect of dopamine on Ca(2+)-calmodulin-dependent protein kinase II activity in rat hippocampal slices.
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AIM: To study the effect of dopamine (DA) on Ca(2+)-calmodulin dependent protein kinase II (CCDPK II) activity in rat hippocampus. METHODS: Using rat hippocampal slices as an in vitro model, the activity of CCDPK II was examined by the method of 32P-incorporation. RESULTS: Exogenous DA reduced CCDPK II activity in hippocampal slices in a concentration- and time-dependent manner. Removal of extracellular calcium antagonized the DA-induced inhibition of CCDPK II activity, partially or completely. The activity of CCDPK II was markedly decreased by apomorphine (a nonselective DA receptor agonist), SKF38393 (a selective D1-like DA receptor agonist), or quinpirole (a selective D2-like DA receptor agonist). The inhibition of CCDPK II activity induced by exogenous DA was abolished by preincubation with Sch-23390, a selective D1-like DA receptor antagonist, or domperidone, a selective D2-like DA receptor antagonist. CONCLUSION: DA has an inhibitory effect on CCDPK II activity in rat hippocampus, related to stimulation of D1-like and D2-like receptors and calcium influx. (+info)
Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells.
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BACKGROUND AND PURPOSE: Grafts of MHP36 cells have previously been shown to reduce dysfunction after global ischemia in rats. To test their efficacy after focal ischemia, MHP36 cells were grafted 2 to 3 weeks after transient intraluminal middle cerebral artery occlusion (tMCAO) in rats. METHODS: MHP36 cells were implanted into the hemisphere contralateral to the lesion, with 8 deposits of 3 microL of cell suspension (25 000 cells per microliter). Sham grafted rats received equivalent volumes of vehicle. Three groups, sham-operated controls (n=11), MCAO+sham grafts (n=10), and MCAO+MHP36 grafts (n=11), were compared in 3 behavioral tests. RESULTS: In the bilateral asymmetry test, MCAO+MHP36 grafted rats exhibited neglect before grafting but subsequently showed no significant dysfunction, whereas MCAO+sham grafted rats showed stable sensorimotor deficits over 18 weeks relative to controls. MCAO+sham grafted rats demonstrated spontaneous motor asymmetry and increased rotational bias after injection of dopamine agonists. MCAO+MHP36 and control groups exhibited no bias in either spontaneous or drug-induced rotation. In contrast to motor recovery, MCAO+MHP36 grafted rats showed no improvement relative to MCAO+sham grafted rats in spatial learning and memory in the water maze. MCAO produced large striatal and cortical cavitations in both occluded groups. Lesion volume was significantly reduced (P<0.05) in the MCAO+MHP36 grafted group. The majority of MHP36 cells were identified within the intact grafted hemisphere. However, MHP36 cells were also seen in the cortex, striatum, and corpus callosum of the lesioned hemisphere. CONCLUSIONS: MHP36 cells may improve functional outcome after MCAO by assisting spontaneous reorganization in both the damaged and intact hemispheres. (+info)
Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats.
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RATIONALE: Orphanin FQ (OFQ; also known as nociceptin), the endogenous ligand of the opioid receptor-like receptor, injected intracerebroventricularly (i.c.v.) decreases basal motor activity and basal extracellular levels of dopamine (DA) in the nucleus accumbens (Nuc Acc) in rats. OBJECTIVE: The present study was designed to determine if OFQ similarly attenuates cocaine-induced motor stimulation and to determine if this effect is dependent on attenuation of the increase in extracellular DA. METHODS: After a 1-h adaptation period, rats were injected with either artificial cerebrospinal fluid or OFQ (3-30 nmol, i.c.v.) 5 min prior to cocaine (10 mg/kg, i.p.) or apomorphine (3 mg/kg, i.p.) administration and the total distance traveled was measured for a further 1 h. In a separate experiment, changes in extracellular DA were monitored by microdialysis following cocaine and OFQ treatment in anesthetized rats. RESULTS: OFQ dose-dependently attenuated both basal and cocaine-induced motor stimulation. OFQ (30 nmol, i.c.v.) also attenuated both the basal and the cocaine-induced increase in extracellular DA in the Nuc Acc. OFQ, at the highest dose, also decreased the motor stimulation induced by apomorphine. CONCLUSIONS: Our results suggest that the modulatory effect of OFQ on locomotor activity is not solely due to its inhibitory action on extracellular DA in the Nuc Acc. (+info)