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.     

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.     

Marked dissociation between high noradrenaline versus low noradrenaline transporter levels in human nucleus accumbens

We recently identified a noradrenaline-rich caudomedial subdivision of the human nucleus accumbens (NACS), implying a special function for noradrenaline in this basal forebrain area involved in motivation and reward. To establish whether the NACS, as would be expected, contains similarly high levels of other noradrenergic markers, we measured dopamine-beta-hydroxylase (DBH) and noradrenaline transporter in the accumbens and, for comparison, in 23 other brain regions in autopsied human brains by immunoblotting. Although the caudomedial NACS had high DBH levels similar to those in other noradrenaline-rich areas, the noradrenaline transporter concentration was low (only 11% of that in hypothalamus). Within the accumbens, transporter concentration in the caudal portion was only slightly (by 30%) higher than that in the rostral subdivisions despite sharply increasing rostrocaudal gradients of noradrenaline (15-fold) and DBH. In contrast, the rostrocaudal gradient in the accumbens for the serotonin transporter and serotonin were similar (2-fold increase). The caudomedial NACS thus appears to represent the only instance in human brain having a striking mismatch in high levels of a monoamine neurotransmitter versus low levels of its uptake transporter. This suggests that noradrenaline signalling is much less spatially and temporally restricted in the caudomedial accumbens than in other noradrenaline-rich brain areas.     

Inhibition of noradrenaline deamination by antidepressants

Anti-norepinephrine deaminative activity of some antidepressants of different structure was studied. Pyrazidol (10(-5) M) reduced considerably the rate of norepinephrine deamination in bovine brain (80% inhibition), the inhibitory effects of inkazan and imipramine were also apparent (50-60%). Zimelidine, viloxazine and norzimelidine were found to be less active: at 10(-4) M, they caused a not more than 50% inhibition of oxidative norepinephrine deamination. The difference was revealed between the influence of some drugs on deamination of two monoamine oxidase A substrates: norepinephrine and serotonin. Thus, pyrazidol, viloxazine, zimelidine and norzimelidine were more active in suppressing norepinephrine, than serotonin deamination. Inhibition of norepinephrine deamination in the brain seems to be an important component of the neurochemical spectrum of pyrazidol and imipramine.     

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.     

Effects of insulin on rat brain noradrenaline

A single intracardial injection of streptozotocin produced a significant increase in rat hypothalamic noradrenaline while no changes were observed in the olfactory tubercles. The parenteral administration of a single dose of insulin decreased rat hypothalamic noradrenaline; the effect had a rapid onset and lasted for at least six hours. Similar noradrenaline reductions were observed in the olfactory tubercles but in this tissue the depletion started later and recovered earlier. In addition, in olfactory tubercles after insulin injection, tyrosine level and dopamine metabolism were increased. The results show that the increases in hypothalamic NA observed in streptozotocin diabetic rats are counteracted by insulin administration and possibly the consequence of changes in noradrenaline turnover.