|
Abstract
The action of benzodiazepines on cell responses in the rat dorsal raphe nucleus (DR) were studied. Sprague-Dawley rats (22O-270 g) were anesthetized with chloral hydrate (400 mg/kg, i.p.) or paralyzed with gallamine iethiodide (Flaxedil, lb mg/kg, i.v.) and artificially respirated, then placed in a stereotaxic apparatus. Diazepam (Roche, up to 8 mg/kg, i.v.), chlordiazepoxide (Roche, up to 12 mg/kg, i.vA and flurazepam (Roche up to 30 mg/ kg, i.v.) did not affect DR firing while LSD (10 mcg/kg i.v.) totally inhibited it, in the anethetized rat. Diazepam sometimes reduced firing in the paralyzed rat when carbon dioxide levels were below 3.0%. Serotonin (5HT, Sigma, 10-16 nA), GABA (Calbiochem, 1-5 mA) and glycine (Sigma, 1-5 mA) when administered microiontophoretically specifically inhibited firing. Diazepam (i mg/kg, i.vA increased the inhibition with GABA from 50% to i 00%, without affecting subsequent responses to 5HT. This effect was blocked by simultaneous microiontophoretic administration of picrotoxin (K+K 10 mA). 5HT and glycine responses were unaffected by diazepam. Strychnine (Sigma, 0.6 mg/kg, i.v.) blocked the effects of glycine but not those of 5HT and GABA, or GABA with diazepam. The benzodiazopines when administered microiontophoretically did not affect DR spontaneous firing, but when flurazepam or chlordiazepoxide were given microintophoretically with GABA its inhibition was incrased. The benzodiazepines did not affect 5HT and glycine responses. Simultaneous microiontophoresis of nepecotic acid (Abbott, 5 nA) maximally increased the GABA effect, while 10 nA had no effect on spontaneous DR activity. Simultaneous administration of nipecotic acid and flurazepam produced an additive potentiation of the GABA effect. After pretreatment of the anesthetized rat with amino-oxyacetic acid (Sigma, 60 mg/kg, i.p.), diazepam partially or totally blocked spontaneous DR activity. Picrotoxin (0.6 mg/kg, i.v.) reversed this effect and partially blocked the GABA effects in the presence or absence of benzodiazepines. Amino oxyacetic acid did not affect responses to 5HT or LSD. Diazepam (20 mg/kg, i.v.) did not inhibit cell firing in the locus coeruleus in the anethetized rat while clonidine (Boehr Ingelheim, 7.5+1.5 mcg/kg) did. GABA potentiation by benzodiazepines is mediated postsynaptically and benzodiazopine effects on spontaneous DR activity are only possible when GABA activity is high.
|
