Noradrenergic denervation facilitates the release of acetylcholine and serotonin in the hippocampus: towards a mechanism underlying upregulations described in MCI patients?

Patients with mild cognitive impairment (MCI), who are at risk for Alzheimer's disease (AD), or those with early AD, exhibit noradrenergic degeneration in the locus coeruleus. In MCI patients, upregulations of cholinergic and serotonergic functions were described in the hippocampus. To investigate the effects of selective noradrenergic denervation on hippocampal neurotransmitter functions, rats were treated with 50 mg/kg (i.p.) of N-2-chlorethyl-N-ethyl-2-bromobenzylamin (DSP-4). DSP-4 treatment reduced hippocampal noradrenaline (NA) by more than 90% (vs. controls), whereas dopamine and 5-HT levels were unaffected. The accumulation and electrically-evoked release (in nCi) of [(3)H]-NA in hippocampal slices were strongly reduced. Accumulation of [(3)H]-5-HT was reduced in DSP-4 rats, whereas spontaneous and electrically-evoked release of [(3)H]-5-HT was significantly enhanced, probably due to a weaker effect of endogenous NA via alpha(2)-adrenoceptors on serotonergic terminals. Accordingly, the alpha(2)-agonist UK-14,304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] more potently inhibited the evoked 5-HT release in DSP-4 rats, whereas the alpha(2)-antagonist idazoxan failed to exert facilitatory effects. Most surprisingly, the accumulation of [(3)H]-choline, and both the basal and electrically-evoked overflow of [(3)H] from hippocampal slices preincubated with [(3)H]-choline, were also significantly increased in DSP-4 rats. These observations suggest that noradrenergic damage in the locus coeruleus may facilitate cholinergic and serotonergic functions in the hippocampus. Although the current lesion model does not mimic the protracted evolution of neurodegenerative processes in MCI and AD, our data could point to an explanation for the upregulations of cholinergic and serotonergic functions described in the hippocampus of MCI patients.