Acute tolerance to noradrenaline ("noradrenaline escape")]

The decline in arterial systemic blood pressure which follows the initial rise during i.v. perfusion of L-noradrenaline in normal rats has been compared with the same type of decline induced by metaraminol or phenylephrine, both alpha-sympathomimetic drugs (acute tolerance or escape). Vasoconstrictor activity of noradrenaline in shot i.v. injection is regularly decreased when acute tolerance develops. This hyposensitivity to NA indicates that a change in alpha-receptor affinity for circulating NA may explain the acute tolerance as well as the noradrenaline escape.     

Forebrain noradrenaline and metrazol-induced seizures

The role of forebrain noradrenaline in seizures induced by the convulsant drug Metrazol was examined in animals pretreated with injections of 6-hydroxydopamine into the fibers of the ascending noradrenergic bundles. A consistent potentiation of the duration and intensity of the seizures was found in the noradrenaline-depleted animals.     

Functional coupling of serotonin and noradrenaline transporters

Re-uptake of the neurotransmitters serotonin and noradrenaline out of the synaptic cleft is mediated by selective transporter proteins, the serotonin transporter and the noradrenaline transporter respectively. Both are integral membrane proteins that are have a high degree of homology and represent members of a larger neurotransmitter transporter superfamily. Several studies have indicated that the serotonin transporter has an an oligomeric structure. To determine whether monoamine transporters can also function in oligomeric structures in situ, we constructed a concatenate consisting of one molecule of serotonin transporter covalently linked to one molecule of noradrenaline transporter. Heterologous expression of this hybrid construct allowed us to analyse the function, i.e. transport activity, and the structure, i.e. the molecular weight of the total construct and of its single components, at the same time. We showed that serotonin-noradrenaline transporter fusion proteins are fully active and exhibit the pharmacological profile of both their individual components. These findings support the hypothesis that monoamine transporters are expressed and may function as oligomeric proteins composed of non-interacting monomers.     

Differential alpha-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade

Parietal and occipital cortices, while densely innervated by noradrenalin 2 (NA) projections, possess a comparatively sparse dopamine 2 (DA) innervation, even sparser than the prefrontal cortex. We previously reported that reboxetine and desipramine, two selective norepinephrine transporter (NET) blockers, at doses that maximally increase DA in the prefrontal cortex, do not increase DA in the parietal and occipital cortices. In the present study, we performed a full dose-response study of the effect of systemic reboxetine and desipramine on DA and NA in dialysates from the parietal and occipital cortices. Seven doses of reboxetine (0.1, 0.25, 0.5, 1.0, 2.5, 5.0 and 10 mg/kg) and four doses of desipramine (0.25, 1.0, 2.5 and 5.0 mg/kg) were tested. Reboxetine and desipramine differentially affected dialysate DA as compared with NA. Reboxetine increased DA maximally by about 100% after doses of 0.25-0.5 mg/kg and showed a bell-shaped dose-response function in both areas; desipramine did not affect DA in the parietal cortex and increased it in the occipital cortex only at 2.5 mg/kg. NA was maximally increased by 275% by 0.5-2.5 mg/kg reboxetine and by about 300% by 5.0 mg/kg desipramine with a more linear dose-response curve. The mechanism of peculiar dose-response function of dialysate DA after reboxetine and desipramine was further investigated by testing the effect of drugs on dialysate DA and NA under alpha(2) receptor blockade. Under local perfusion of the occipital cortex with idazoxan, an otherwise ineffective dose of reboxetine and desipramine (5 mg/kg) became effective in raising extracellular DA. In contrast, the effect of reboxetine on NA was potentiated, while that of desipramine was not affected. These results suggest that, in the parietal and occipital cortices, extracellular NA, raised by NET blockade, exerts a preferential inhibitory influence on DA release by acting on local alpha(2) receptors, thus accounting for the bell-shaped feature of the dose-response function of drugs on dialysate DA in these areas.     

The potentiation of cortical neuron responses to noradrenaline by 2-phenylethylamine is independent of endogenous noradrenaline

2-Phenylethylamine (PE) is an endogenous brain amine which produces sympathomimetic responses and potentiates cortical neuron responses to noradrenaline (NA). In order to examine further the mechanism of action of PE, extracellular recordings were made of the activity of single neurones in the cerebral cortex in urethane-anesthetized rats. Sympathomimetic responses to PE were blocked by pretreatment with reserpine, reserpine plus -methyl-p-tyrosine and desipramine. It is concluded that the sympathomimetic responses to PE are indirect. 2-Phenylethylamine potentiated cortical neuron responses to electrical stimulation of the locus coeruleus in a dose-dependent manner. This was seen when PE was given systemically (with as little as 1 g/kg) and iontophoretically. The effects of PE were not reproduced by its metabolite phenylacetic acid or its putative metabolite phenylethanolamine. Iontophoretic applications of PE (0–6 nA, 2–5 minutes) potentiated cortical neuron responses to iontophoretically applied NA, without affecting the spontaneous firing rate, or the responses to iontophoretically applied GABA or acetylcholine. This effect of PE was not blocked by pretreatment with -methyl-p-tyrosine or desipramine, and was potentiated by pretreatment with reserpine and reserpine plus -methyl-p-tyrosine. It is probable that the ability of PE to modulate neuronal responses to NA does not involve the presynaptic NA terminal or endogenous NA and it is likely that PE acts directly to increase the efficacy of NA. These findings are consistent with the hypothesis that the physiological role of PE is to modulate catecholaminergic transmission within the central nervous system.     

Age related changes in noradrenaline,noradrenaline turnover and adrenaline in brainstem nuclei of wistar kyoto and spontaneously hypertensive rats

Noradrenaline and noradrenaline turnover were determined in regions enriched in catecholamine nuclei of the brainstem (A1, A2, C1, C2 and C3), in the locus coeruleus (A6) and in the nucleus tractus spinalis n. trigemini (Sp5C) of Wistar Kyoto and spontaneously hypertensive rats at four ages from 6 to 40 weeks. Adrenaline levels were also determined but were only consistently detected in the C1 and C2 regions. There was an age-related decline in noradrenaline concentrations in both strains of rats in all brainstem catecholamine nuclei however noradrenaline turnover decreased only in the A2 and C3 regions and this may contribute to the progressive rise in blood pressure with age in spontaneously hypertensive and Wistar Kyoto rats. Adrenaline levels did not alter with age providing evidence of a functional disassociation between adrenaline and noradrenaline neuronal systems. There were several strain-related differences in noradrenaline and adrenaline concentrations in the regions studied, however noradrenaline turnover was reduced only in the A2 and C2 regions (nucleus tractus solitarius) of spontaneously hypertensive rats which is consistent with the sympathoinhibitory role of this nucleus in central blood pressure regulation.     

Involvement of D1 dopamine receptors in the nicotine-induced noradrenaline release from hypothalamic and preoptic noradrenaline nerve terminal systems

Nicotine (4 × 2 mg/kg, i.p.) was given every 30 min for 2 h to male rats. Some rats were pretreated with the D1 dopamine (DA) receptor antagonist SCH 23390 (1 mg/kg, i.p.) or with the D2 DA receptor antagonist raclopride (1 mg/kg, i.p.), 5 min before nicotine treatment. Hypothalamic and preoptic catecholamine levels were measured by quantitative histofluorimetry in discrete DA and noradrenaline nerve terminal systems.Nicotine treatment produced a depletion of catecholamine stores in noradrenaline and DA nerve terminals of the hypothalamus, the preoptic area and the median eminence, an action which was counteracted by SCH 23390 but not by raclopride.The results indicate that hypothalamic D1 DA receptors may regulate the sensitivity of the nicotinic cholinoceptors and increase their ability to release hypothalamic noradrenaline. A possible role of D1 DA receptor antagonists to reduce the ability of nicotine treatment to produce rapid increases in LH, prolactin and corticosterone secretion and tonic arousal is implicated.