ABSTRACT
The sensitivity of insect nervous systems to anoxia can be modulated genetically and pharmacologically, but the cellular mechanisms responsible are poorly understood. We examined the effect of a heat shock pretreatment (HS) on the sensitivity of the locust (Locusta migratoria) nervous system to anoxia induced by water immersion. Prior HS made locusts more resistant to anoxia by increasing the time taken to enter a coma and by reducing the time taken to recover the ability to stand. Anoxic comas were accompanied by surges of extracellular potassium ions in the neuropile of the metathoracic ganglion, and HS reduced the time taken for clearance of excess extracellular potassium ions. This could not be attributed to a decrease in the activity of protein kinase G, which was increased by HS. In homogenates of the metathoracic ganglion, HS had only a mild effect on the activity of Na(+)-K(+)-ATPase. However, we demonstrated that HS caused a threefold increase in the immunofluorescent localization of the α-subunit of Na(+)-K(+)-ATPase in metathoracic neuronal plasma membranes relative to background labeling of the nucleus. We conclude that HS induced trafficking of Na(+)-K(+)-ATPase into neuronal plasma membranes and suggest that this was at least partially responsible for the increased resistance to anoxia and the increased rate of recovery of neural function after a disturbance of K(+) homeostasis.
Subject(s)
Heat-Shock Response , Hypoxia/metabolism , Insect Proteins/metabolism , Neurons/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Animals , Cell Membrane/metabolism , Ganglia, Invertebrate/cytology , Ganglia, Invertebrate/metabolism , Grasshoppers , Neuropil/metabolism , Protein Subunits , Protein TransportABSTRACT
Effects of varenicline (Champix), a nicotinic partial agonist, were evaluated on subjective effects of nicotine (drug discrimination), motivation for nicotine taking (progressive-ratio schedule of intravenous nicotine self-administration) and reinstatement (cue-induced reinstatement of previously extinguished nicotine-seeking behaviour). Effects on motor performance were assessed in rats trained to discriminate nicotine (0.4 mg/kg) from saline under a fixed-ratio (FR 10) schedule of food delivery and in rats trained to respond for food under a progressive-ratio schedule. At short pretreatment times (5-40 min), varenicline produced full or high levels of partial generalization to nicotine's discriminative-stimulus effects and disrupted responding for food, while there were low levels of partial generalization and no disruption of responding for food at 2- or 4-h pretreatment times. Varenicline (1 and 3 mg/kg, 2-h pretreatment time) enhanced discrimination of low doses of nicotine and to a small extent decreased discrimination of the training dose of nicotine. It also dose-dependently decreased nicotine-taking behaviour, but had no effect on food-taking behaviour under progressive-ratio schedules. Finally, varenicline significantly reduced the ability of a nicotine-associated cue to reinstate extinguished nicotine-seeking behaviour. The ability of varenicline to reduce both nicotine-taking and nicotine-seeking behaviour can contribute to its relatively high efficacy in treating human smokers.
Subject(s)
Benzazepines/pharmacology , Cues , Drug-Seeking Behavior/drug effects , Quinoxalines/pharmacology , Tobacco Use Disorder/drug therapy , Animals , Conditioning, Operant/drug effects , Data Interpretation, Statistical , Discrimination, Psychological/drug effects , Dose-Response Relationship, Drug , Feeding Behavior/drug effects , Male , Motivation/drug effects , Nicotine/pharmacology , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Reinforcement Schedule , Self Administration , Tobacco Use Disorder/psychology , VareniclineABSTRACT
Normotensive female rats exhibit age-related decreases in estrous cyclicity and increases in blood pressure. In spontaneously hypertensive rats, estrogens, including dietary phytoestrogens, prevent or attenuate the increased blood pressure associated with estrogen depletion. The present studies examine the effects of ovariectomy (OVX) at either 3 or 10 mo of age. Although blood pressure increases from 3 to 9 mo, OVX at 3 mo of age has no added effect--despite the fact that OVX (compared to ovary-intact) rats weighed significantly more. In contrast, aging from 10 to 16 mo is associated with a further increase in blood pressure, which is potentiated by estrogen depletion. Removal of dietary phytoestrogens exacerbated the hypertensive effects of OVX in these middle-aged rats. As in younger rats, estrogen depletion at 10 mo of age was associated with greater weight gain. Whereas estrogen depletion at 3 mo of age was without effect on fluid intake over the next 6 mo, OVX at 10 mo of age was associated with decreased fluid intake. In a final study, rats were OVX at 3 mo of age with estradiol (E2) treatment initiated at 10 mo of age. Long-term OVX ( >10 mo) was associated with increased blood pressure and mortality at 14-16 mo of age. Circulating levels of E2 were decreased by OVX. Plasma aldosterone was increased by OVX, an effect which was prevented by either E2 or phytoestrogens. Neither E2 nor aldosterone was affected by age. These data indicate that (a) the physiological effects of estrogen depletion vary with age; (b) phytoestrogens in the diet exert some protective effects; and (c) long-term OVX in the absence of hormone re-placement is associated with premature mortality. We suggest that chronic increases in aldosterone and sympathetic tone underlie the hypertensive effects of estrogen depletion.
