Noradrenaline Stanford

Figure 8.7 Schematic diagram of the proposed structure of the noradrenaline neuronal transporter showing the 12 transmembrane, hydrophobic domains with the N- and C-termini projecting towards the cell cytoplasm. Binding domains for specific ligands are thought to be within regions indicated by the solid bars. (From Stanford 1999, reproduced with permission)...

Figure 8.11 Noradrenaline efflux, measured by microdialysis, in the rat frontal cortex and hypothalamus, (a) Repeated exposure to a tone, alone, has no effect on noradrenaline efflux in either brain region, (b) After repeated pairing of the tone with transfer of the rat to a brightly lit (aversive) arena, the sound of the tone alone triggers a significant ( P<0.05, cf last basal sample) increase in noradrenaline efflux in the frontal cortex, but not the hypothalamus. (Based on a figure from McQuade and Stanford 2000)...

Dailey, JW, Mason, K and Stanford, SC (1996) Increased levels of extracellular noradrenaline in the frontal cortex of rats exposed to naturalistic environmental stimuli modulation by acute systemic administration of diazepam or buspirone. Psychopharmacology 127 47-54. 

All these animal models express behavioural deficits that are paralleled by some abnormality in noradrenaline and/or 5-HT function but it is unlikely that the monoamines are the only neurotransmitters to influence these complex behaviours. Nevertheless, the behavioural deficits all respond, with varying degrees of specificity, to established antidepressants and central monoamines appear to have a crucial role in the therapeutic effects of these drugs. For a more detailed review of this subject see Stanford (1995). 

Paroxetine is the most potent inhibitor of 5-HT reuptake but, in terms of distinguishing one compound from another, their preferential selectivity for inhibition of 5-HT rather than noradrenaline reuptake is the key criterion. Citalopram is by far the most selective in vitro (1500-3000-fold) and fluoxetine, the most frequently prescribed SSRI in the UK, is the least selective of all these agents (see Stanford 1999). In fact, it is worth questioning whether fluoxetine is a true SSRI at all. 

Fillenz, M and Stanford, SC (1981) Vesicular noradrenaline stores in peripheral nerves of the rat and their modification by tranylcypromine. Brit. J. Pharmacol. 73 401-404. 

Geranton SM, Heal DJ, Stanford SC. 2004. 5-HT has contrasting effects in the frontal cortex, but not the hypothalamus, on changes in noradrenaline efflux induced by the monoamine releasing-agent, D-amphetamine, and the reuptake inhibitor, bts 54 354. Neuropharmacology 46(4) 511-518. 

Kamimori et al. (129) tested the effects of approximately 150, 300, and 600 mg caffeine on noradrenaline and adrenaline levels, sleep latency, Stanford Sleepiness Scale ratings, and choice reaction time in volunteers who were dosed after 49 hr of continuous wakefulness (and kept awake for an additional 12 hr). 

Smith BN, Davis SF, van den Pol AN et al (2002) Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Neuroscience 115 707-14 Smith-White MA, Herzog H, Potter EK (2002) Role of neuropeptide Y Y2 receptors in modulation of cardiac parasympathetic neurotransmission. Regul Peptides 103 105-11 Stanford IM, Cooper Al (1999) Presynaptic mu and delta opioid receptor modulation of GABAa IPSCs in the rat globus pallidus in vitro. 1 Neurosci 19 4796 4803 Starke K (1977) Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 77 1-124... 

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