dizocilpine-maleate and talipexole

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

Chronic treatment with the dopamine (DA) agonist B-HT 920 (0.25-1 mg/kg) or bromocriptine (1 mg/kg) followed by morphine (10 mg/kg) on days 1-9 prevented the development of tolerance to the antinociceptive effect of morphine as measured by the tail-flick test in mice, but failed to suppress the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of testing. Repeated administration of SKF 38393 (5 mg/kg) followed by morphine for 9 days significantly reduced naloxone-precipitated jumps on day 10 but failed to produce any significant change in tail-flick latency from the saline-pretreated group of mice on days 9 and 10 of testing. Repeated administration of B-HT 920 or bromocriptine enhanced the ability of MK-801 to attenuate the development of morphine tolerance and dependence while SKF 38393 failed to do so. The above data suggest a preferential role of D2 DA receptors in morphine tolerance and D1 receptors in the development of morphine dependence. D2 DA receptor stimulation may also play an important role in enhancing the effectiveness of MK-801 in the treatment of opiate tolerance and dependence.

Topics: Animals; Apomorphine; Azepines; Bromocriptine; Dizocilpine Maleate; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Tolerance; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate