Cholinergic denervation and sympathetic ingrowth result in persistent changes in hippocampal muscarinic receptors

Abstract

Our laboratory has been utilizing the model of hippocampal sympathetic ingrowth, which has been suggested to occur in Alzheimer's disease, to investigate the effects of cholinergic denervation and hippocampal rearrangements. After cholinergic denervation by medial septal lesions, peripheral sympathetic fibres originating from the superior cervical ganglia grow into the rat hippocampus. This hippocampal sympathetic ingrowth can be prevented by superior cervical ganglionectomy. We examined the long-term effects of these treatments on muscarinic receptors by comparing [ 3H]quinuclidinyl benzilate binding in rat dorsal hippocampus four and 12 weeks post lesion. Four groups of animals were employed, including controls (sham lesion + sham ganglionectomy), animals with ingrowth (medial septal lesion + sham ganglionectomy), animals with cholinergic denervation alone (medial septal lesion + ganglionectomy), and ganglionectomy alone (sham lesion + ganglionectomy) animals. In dorsal hippocampus four weeks post lesion, binding affinity was similar among all groups, while muscarinic receptor number was increased in ingrowth animals as compared to both the control ( P<0.0002) and ganglionectomy animals ( P<0.01). By 12 weeks, receptor affinity was significantly decreased in ingrowth ( P<0.0001) and cholinergic denervation ( P<0.0003) groups, and receptor number remained significantly elevated in ingrowth animals as compared to control ( P<0.01), ganglionectomy ( P<0.02) and cholinergic denervation ( P<0.01) groups. The decrease in muscarinic receptor affinity may provide some insight into the ineffectiveness of cholinomimetic therapies in Alzheimer's disease, in that agonist efficacy would be reduced at the receptor.