In a companion paper the alpha 2-adrenoceptor antagonist yohimbine was found to produce a dose-dependent anticonflict effect in a modified Vogel's conflict test. The behavioral data further indicated that noradrenergic and serotonergic neurons as well as the benzodiazepine (BDZ) receptor may be involved in the anticonflict effect of yohimbine. In the present study the effects on rat brain monoamine neurochemistry and GABAA/BDZ receptor function (36Cl-uptake in corticohippocampal synaptoneurosomes) of a maximally anticonflict producing dose of yohimbine (4.0 mg/kg, i.p.) were studied. The levels of rat brain catecholamines and indoleamines were measured ex vivo using high performance liquid chromatography with electrochemical detection (HPLC-ED). Yohimbine decreased noradrenaline levels both in the hippocampus and the hemispheres but instead increased DOPAC levels in these brain regions as well as in the limbic forebrain. Yohimbine also markedly enhanced DOPA accumulation in the hippocampus and the hemispheres after inhibition of 1-aromatic amino acid decarboxylase by means of NSD 1015, whereas in the limbic system only a modest increase was obtained. The yohimbine-induced effects on the catecholamine synthesis rate were largely abolished in animals severely depleted of NA by means of 6-hydroxy-dopamine (6-OH-DA) pretreatment. Yohimbine decreased both the 5-HIAA/5-HT quotient (an indicator of 5-HT turnover) and 5-HTP accumulation after NSD 1015 in the hemispheres, whereas in the hippocampus and the limbic system only 5-HTP accumulation was decreased. The yohimbine-induced effect on the indoleamine synthesis rate was not influenced by 6-OH-DA pretreatment, whereas this effect and that on the catecholamine synthesis rate were both abolished by reserpine pretreatment. Neither in vivo nor in vitro administration of yohimbine significantly altered baseline or GABA-induced accumulation of 36Cl- in corticohippocampal synaptoneurosomes. In conclusion, the present study provides neurochemical support for the suggestion that yohimbine may exert its anticonflict effect in a modified Vogel's conflict test by increasing and decreasing NA and 5-HT neurotransmission, respectively, whereas no evidence was obtained for a direct interaction of yohimbine with GABAA/BDZ receptor function.
The effects of sustained exposure to ethylene glycol dinitrate (EGDN; 50 mg.kg-1.2, 10 days) on heart rate (HR) and mean arterial blood pressure (MAP), isolated strips from aorta and vena cava, catecholamine (CA) and DOPAC levels in brain, heart, adrenals and plasma, and synaptosomal uptake of noradrenaline (NA) have been investigated in rats. Aortic strips showed a decreased responsiveness to EGDN and were more sensitive to NA than were control strips 2, 24 and 96 hrs after cessation of EGDN. Acute cumulative doses of EGDN induced a decrease in MAP at all time intervals but 2 hrs after cessation of chronic EGDN-treatment, while NA induced a dose-dependent increase in MAP. MAP was lower 2 hrs after cessation of EGDN, than in the control rats, while HR was higher. After 24 hrs, MAP was slightly higher than in the controls and HR was still elevated. EGDN induced a decrease in the accumulation of L-DOPA and DOPAC in all brain structures measured, which was especially prominent 2 hrs after cessation of EGDN. The levels of CA's and DOPAC in peripheral tissues did generally not change significantly, although there was a tendency to a decrease. L-DOPA, NA and adrenaline (A) in plasma decreased significantly, while DOPAC and dopamine (DA) increased. No consistent effects on uptake of NA into synaptosomes could be distinguished. However, the amount of protein was generally lower at all times after cessation of EGDN. It is suggested that prolonged exposure to EGDN not only induces tolerance at the cellular level, but also interferes with arterial smooth muscle sensitivity to NA and with resetting of MAP and HR. The decrease in the synthesis and turnover of CA's and DOPAC in the brain indicated a decrease in nervous activity, which is reflected by a corresponding decrease of NA and A levels in plasma.
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