ergoline and vanoxerine

Paraquat (1,1'-dimethyl-4,4'-bipyridinium, PQ) is a herbicide to possibly induce Parkinson's disease (PD), since a strong correlation has been found between the incidence of the disease and the amount of PQ used. In this study, we examined PQ toxicity in rat organotypic midbrain slice cultures. PQ dose dependently reduced the number of dopaminergic neurons in cultured slices. Since this damage was prevented by GBR-12909, the dopamine transporter could be an initial step of the PQ induced dopaminergic neurotoxicity. The sequential treatments with lower PQ and 1-methyl-4-phenyl pyridinium (MPP+) doses, where each dose alone was not lethal, markedly killed dopamine neurons, suggesting that the exposure of a lower dose of PQ could lead to the vulnerability of dopaminergic neurons. This cell death was prevented by the inhibitors of NMDA, nitric oxide synthase (NOS), cycloheximide and caspase cascade. Neurons expressing NOS were identified inside and around the regions where dopamine neurons were packed. The cell death induced by the sequential treatments with PQ and MPP+ was also rescued by L-deprenyl and dopamine D2/3 agonists. These results strongly support that the constant exposure to low levels of PQ would lead to the vulnerability of dopaminergic neurons in the nigrostriatal system by the excitotoxic pathway, and might potentiate neurodegeneration caused by the exposure of other substances and aging.

Topics: 1-Methyl-4-phenylpyridinium; Analysis of Variance; Animals; Animals, Newborn; Azepines; Cabergoline; Caspases; Cell Count; Cycloheximide; Dizocilpine Maleate; Dopamine Agonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ergolines; Excitatory Amino Acid Antagonists; Herbicides; Immunohistochemistry; Mesencephalon; NADPH Dehydrogenase; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Organ Culture Techniques; Paraquat; Piperazines; Protein Synthesis Inhibitors; Quinoxalines; Rats; Rats, Wistar; Selegiline; Tyrosine 3-Monooxygenase

Subjects that respond more to a novel environment show a greater locomotor response to drugs of abuse such as cocaine and amphetamine. The current study was performed to examine differences between high (HR) and low (LR) responding rats to a novel environment following administration of amphetamine, a selective dopamine uptake blocker (GBR-12909), a nonselective dopamine agonist (apomorphine), and selective dopamine D1 and D2/D3 agonists. A behavioral checklist and a rating scale were used to determine the behavioral arousal caused by administration of amphetamine (0, 0.5, 2.0, and 8.0 mg/kg), GBR-12909 (0, 1.25, 5.0, and 20.0 mg/kg), apomorphine (0, 0.1, 0.3, and 1 mg/kg), SKF 39393 (0, 2.5, 10, and 40 mg/kg), or quinpirole (0, 0.05, 0.5, and 5.0 mg/kg). The five drugs produced behavioral activation profiles distinct from each other. Following amphetamine administration, both HR and LR subjects showed dose dependent increases in behavioral arousal. The behaviors primarily affected were sniffing, locomotor activity, rearing, and oral activity. HR rats showed a greater overall behavioral response to amphetamine administration compared with LR rats and there were differences in specific behaviors between the two groups. Following GBR-12909 administration, all subjects showed dose dependent increases in sniffing, locomotor activity, and rearing. Differences between HR and LR were observed in sniffing, locomotor activity, and rearing behaviors. HR and LR both showed dose dependent increases in behavior following apomorphine administration. HR showed greater behavioral activation after apomorphine than LR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamine; Animals; Apomorphine; Behavior, Animal; Dopamine Agonists; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Environment; Ergolines; Individuality; Male; Piperazines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3

The discriminative stimulus effects of cocaine were studied in rats trained to discriminate 10.0 mg/kg cocaine from vehicle in a shock avoidance paradigm. Rats used could discriminate 10.0 mg/kg cocaine from vehicle within an average of 20 sessions after the start of discrimination training. Cocaine produced dose-dependent stimulus effects at 1.0- to 10.0-mg/kg doses. Cocaine (10.0 mg/kg) generalized to the dopamine reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methyoxy]ethyl]-4-(3-phenylpropyl)piperaz ine 2HCl (GBR 12909) (30.0 mg/kg), methamphetamine (0.3 mg/kg), apomorphine (0.3 mg/kg), and the D2 dopamine agonist quinpirole (0.1 mg/kg), but not to the D1 dopamine agonist SK&F38393 (3.0-30.0 mg/kg). 1-Phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine-7,8-diol HCl (SK&F38393) (10.0 mg/kg) combined with several doses (1.0-10.0 mg/kg) of cocaine shifted the stimulus generalization curve for cocaine to the left. Haloperidol (0.1 and 0.3 mg/kg), the D1 dopamine antagonist 7-chloro-2,3,4,5-tetrahydro-3-methyl-phenyl-1-H-benzazepine-7-ol maleate (SCH23390) (0.01-0.3 mg/kg), and the D2 dopamine antagonist S(-)-sulpiride (20.0 and 40.0 mg/kg) only partially blocked the stimulus effects of cocaine. Haloperidol (0.3 mg/kg) combined with SCH23390 (0.03 mg/kg) completely blocked the stimulus effects of cocaine. In addition, haloperidol (0.3 mg/kg) blocked the stimulus effects of quinpirole (0.1 mg/kg), in common with cocaine. These data suggest that both D1 and D2 dopamine receptors contribute to the discriminative stimulus effects of cocaine.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Avoidance Learning; Benzazepines; Cocaine; Discrimination Learning; Discrimination, Psychological; Dopamine Agents; Dose-Response Relationship, Drug; Electroshock; Ergolines; Haloperidol; Male; Methamphetamine; Neurotransmitter Uptake Inhibitors; Piperazines; Quinpirole; Rats; Sulpiride

We investigated the involvement of dopamine D1 and D2 receptor subtypes in the effects of GBR 12909, a selective dopamine uptake inhibitor, on latent learning in the performance of a water-finding task and on locomotor activity in mice. GBR 12909 (10 and 20 mg/kg) impaired latent learning, and this effect was counteracted by the dopamine D2 receptor antagonist, (-)-sulpiride (20 and 40 mg/kg), but not by the dopamine D1 receptor antagonist, SCH 23390 (0.025 and 0.05 mg/kg). The dopamine D2 receptor agonist, quinpirole (0.5 and 1 mg/kg) and the dopamine D1 receptor agonist, SKF 38393 (20 mg/kg) impaired latent learning, but both effects were less than that of GBR-12909. The effect of quinpirole, but not of GBR 12909, on latent learning was potentiated by combination with SKF 38393. In contrast to its effect on learning, SCH 23390 (0.025 and 0.05 mg/kg) was more effective to suppress the stimulant effect of GBR 12909 on locomotor activity than was (-)-sulpiride (40 and 80 mg/kg). These findings suggest that both dopamine D1 and D2 receptors play an important role in the action of endogenously released dopamine in latent learning and locomotor activity, and that while the dopamine D2 receptor is involved predominantly in latent learning, both dopamine D1 and D2 receptors play a critical role in locomotor activity.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Dopamine Agents; Drinking Behavior; Ergolines; Exploratory Behavior; Haloperidol; Learning; Male; Mice; Mice, Inbred Strains; Motor Activity; Neurotransmitter Uptake Inhibitors; Piperazines; Quinpirole; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulpiride

As part of a continuing effort to assess the role of monoaminergic neuronal systems in the subjective effects of CNS stimulants, 10 rats trained to discriminate 1.0 mg/kg d-amphetamine from saline were treated with compounds that act through different dopaminergic mechanisms. In substitution (generalization) tests, 20 mg/kg of the dopamine (DA) uptake inhibitor GBR 12909 mimicked the training drug completely; at a dose of 15 mg/kg, GBR 12909 substituted for d-amphetamine incompletely. Neither the D1 agonist SK&F 38393 (1, 10 mg/kg) nor the D2 agonist quinpirole (LY 171555; 0.05-0.2 mg/kg) had amphetamine-like effects. When given in combination with the training drug, the D1 antagonist SCH 23390 blocked the amphetamine cue completely at a dose of 0.05 mg/kg but did not have significant effects at higher or lower doses; the D2 antagonist metoclopramide did not block d-amphetamine at any dose tested (1-5 mg/kg). These data indicate that: a) The discriminable effects of d-amphetamine are due, at least in part, to inhibition of DA uptake; b) direct stimulation of either D1 or D2 receptor sites is not sufficient to evoke d-amphetamine-like responding; and c) blockade of D1 receptors attenuates the subjective effects of d-amphetamine to a greater extent than blockade of D2 receptors.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dextroamphetamine; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Generalization, Stimulus; Male; Metoclopramide; Neurotransmitter Uptake Inhibitors; Piperazines; Quinpirole; Rats; Rats, Sprague-Dawley

The behavioral effects of cocaine and GBR 12909, a highly selective dopamine uptake inhibitor, were compared in squirrel monkeys trained to respond under a fixed-interval schedule of stimulus termination and a second-order schedule of drug self-administration. Both drugs exhibited similar pharmacological profiles; intermediate doses increased response rates markedly and higher doses decreased response rates below control values. The magnitude of the rate-increasing effect was similar for cocaine and GBR 12909, although cocaine was approximately 3 times more potent. In contrast, the direct-acting dopamine agonists, SKF 38393 and quinpirole, produced only decreases in response rates. When cocaine and GBR 12909 were studied in combination with dopamine antagonists, the effects of either on fixed-interval performance were attenuated in a similar manner by a D1-selective antagonist (SCH 23390) and a D2-selective antagonist (spiperone), indicating the involvement of both D1 and D2 receptor subtypes. In contrast, an alpha 1-selective antagonist (prazosin) did not alter the dose-effect curve for cocaine or GBR 12909 in a manner that indicated a pharmacological antagonism. When doses of cocaine were administered in combination with GBR 12909, the effects on behavior were additive. However, the combined effects of cocaine and SKF 38393 or cocaine and quinpirole were more complex and did not appear to be additive. When the cocaine or GBR 12909 was self-administered under a second-order, fixed-interval schedule of drug injection, schedule-appropriate responding was maintained and the potency difference between the two drugs was comparable to that observed under the stimulus-termination schedule.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Cocaine; Dopamine Agents; Drug Interactions; Ergolines; Injections, Intravenous; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Quinpirole; Saimiri; Self Administration

The present study has employed the technique of fast cyclic voltammetry to measure electrically-evoked dopamine release within the central amygdaloid complex in a rat brain slice. Local electrical stimulation caused the release of an electroactive substance which was identified, biochemically and pharmacologically, as being neuronal dopamine. Dopamine release could be inhibited by the dopamine D2 receptor agonist, quinpirole, but not by the D1 receptor agonist, SKF38393. Quinpirole-induced inhibitions were antagonized by sulpiride, metoclopramide and clozapine but not by SCH23390. It is concluded that dopamine release in the amygdala can be modulated by presynaptic D2 receptors which appear to be the same type as those found in striatum and nucleus accumbens.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; Amygdala; Animals; Antipsychotic Agents; Benzazepines; Clozapine; Dopamine; Electric Stimulation; Ergolines; Male; Metoclopramide; Neurotransmitter Uptake Inhibitors; Nialamide; Piperazines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Secretory Rate; Sulpiride

Electrochemically modified carbon-fiber electrodes were used to assess the effects of indirect (amphetamine and GBR-12909) as well as direct D1 (SKF-38393) and D2 (quinpirole) dopamine agonists on extracellular ascorbate in the neostriatum of awake, behaving rats. Relative to controls, 2.5 mg/kg d-amphetamine and 20.0 mg/kg GBR-12909 produced marked behavioral activation concomitant with a significant increase in ascorbate. Comparable effects were observed following the combined administration of 10.0 mg/kg SKF-38393 and 1.0 mg/kg quinpirole, but not after either of these drugs alone. Thus, behavioral activation and release of neostriatal ascorbate were closely related to the concurrent stimulation of both D1 and D2 dopamine receptors.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamine; Animals; Ascorbic Acid; Behavior, Animal; Corpus Striatum; Dopamine Agents; Electrochemistry; Electrodes; Ergolines; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotaxic Techniques; Stimulation, Chemical