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

Abstract

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-b-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. The nucleus accumbens (NACS) is, in the human, a small area of the basal forebrain adjacent to the caudate nucleus, putamen and ventral septum that is considered to play an important role in rewarding and motivational function, likely mediated by the neurotransmitter dopamine (Wise 2004;Roitman et al. 2005;Epstein et al. 2006). In extension of the original observation of Farley and Hornykiewicz (1977), reporting, inter alia, high amount of noradrenaline in the human NACS, we recently reported that in the human NACS the distribution of noradrenaline is highly heterogeneous, with the caudomedial portion of the nucleus having a strikingly high concentration of the neurotransmitter; thus, this NACS subdivision represents the only area in human brain having equally high levels of both noradrenaline and dopamine (Tong et al. 2006). In view of the existing data in the human, it is somewhat surprising that the mammalian NACS is still assumed to contain little or no noradrenaline (see McKittrick and Abercrombie 2007). Although the biological significance of noradrenaline in the NACS is hypothetical, the high level of the neurotransmitter (similar to that in other noradrenaline-rich areas of human brain, see below) implies a role for noradrenaline in accumbens function in the human. In this regard, experimental animal studies have disclosed higher levels of the a 2A noradrenergic receptor in NACS than in the caudate/putamen (Talley et al. 1996). Similarly, intra-accumbens rather than caudate/putamen injection of an a 1 -noradrenergic antagonist produces behavioural inhibition (Stone et al. 2004).Received January...

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