Noradrenergic mechanisms in the prefrontal cortex

Abstract

There is growing evidence that noradrenergic inputs to the prefrontal cortex (PFC) play an important role in regulating its function. This paper reviews the pharmacological control of noradrenaline (NA) release in this region, with particular reference to our studies using brain microdialysis, and also describes how NA levels are modulated by antidepressant and antipsychotic drugs. The suggestion that atypical antipsychotics such as clozapine and risperidone may produce clinical benefits by their ability to increase NA release is discussed. Finally, a new class of drugs, which show selectivity for imidazoline receptors is described. These compounds are shown to similarly increase extracellular NA in the PFC. Their potential utility as clinical treatments is discussed.

Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test

“…As discussed above for the 5-HT data, differences between the nature, duration and intensity of the stress or FST paradigm used as well as species differences could account for these discrepancies. Selective I 2 receptor ligands, including BU224, have been shown to elevate extracellular levels of norepinephrine by increasing neuronal release in a number of regions including the frontal cortex and hippocampus Nutt et al 1995Nutt et al , 1997Hudson et al 1999) as well as in the hypothalamic PVN (Finn et al 2002). An I 2 receptor ligand-or FSTmediated increase in norepinephrine synthesis or increased re-uptake following release combined with inhibition of the metabolising enzyme monoamine oxidase is a possible explanation for the reduction in turnover observed although conclusions to this effect cannot be drawn based solely on the present data.…”

“…There are currently three known imidazoline receptor subtypes (I 1 , I 2 and I 3 ) and the I 2 subtype has been shown to be present in a number of brain regions important in mediating the stress response in animals (Lione et al 1998;Finn et al 2000). Acute administration of selective imidazoline 2 (I 2 ) receptor ligands elevates extracellular levels of norepinephrine in the frontal cortex and hippocampus Nutt et al 1995Nutt et al , 1997Hudson et al 1999) and 5-HT in the dorsal raphe nucleus (Ugedo et al 1999). Recent studies in our laboratory have demonstrated that the selective I 2 receptor ligand 2-(4,5-dihydroimidaz-2-yl)-quinoline (BU224) increases extracellular levels of norepinephrine in the rat PVN and increases levels of plasma corticosterone (Finn et al 1999a(Finn et al , 2002.…”

Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic

“…Since clozapine has considerable affinity for a 2 -adrenoceptors (Bymaster et al 1996) and blockade of these receptors localized on noradrenergic neurons results in increased NA output, clozapine-induced increase in extracellular NA has been attributed to its ability to block a 2 -adrenoceptors (Nutt et al 1997;Hertel et al 1999a). On the other hand, the concomitant increase in DA and NA might be the consequence of increased synaptic concentration of NA, since it has been suggested that the NA transporter contributes to the clearance of DA from extracellular compartments within the cortex (Carboni et al 1990;Gresch et al 1995;Moron et al 2002).…”

Differential region-specific regulation of central ?1-adrenoceptor binding following chronic haloperidol and clozapine administration in the rat

“…Whereas NA impairs working memory through actions at a 1 -ARs, it has beneficial effects via its interactions with a 2 -ARs (Arnsten et al 1996(Arnsten et al , 1999. It has been demonstrated that clozapine increases NA release in the frontal cortex, predominantly by presynaptic a 2 -AR blockade (Westerink et al 1998) and that this is hypothesised to improve negative symptoms (Nutt et al 1997). Therefore, at relatively low doses, clozapine's concurrent NA release and cortical a 1 -AR blockade may facilitate cognitive enhancing effects of NA at postsynaptic a 2 -ARs whilst preventing detrimental a 1 -AR activation.…”