Altered G-protein coupling of a frontal cortical low affinity [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin serotonergic binding site in Alzheimer's disease.

In Alzheimer's disease (AD), there are marked deficits in the function of both the cholinergic and serotonergic systems. We and others have shown altered muscarinic M1 receptor/G-protein coupling in the superior frontal cortex (Brodmann areas 8 and 9) from AD patients. In the present study, we investigated whether similar receptor/G-protein alterations would occur at the 5-HT1A receptor in the same brain area. Using [3H]8-OH-DPAT as a radioligand, two binding sites with high and low affinity were found. The high affinity site (Kd = 1 nM), which is consistent with the classical 5-HT1A receptor, was not affected in AD either in the absence or presence of the non-hydrolyzable guanine nucleotide analog, GppNHp (100 microM). On the other hand, although there was no change in the affinity of [3H]8-OH-DPAT at the low affinity site (Kd = 8-10 nM), agonist binding was less sensitive to inhibition by GppNHp in AD (-29%) compared to age-matched controls (-51%). Based on these findings, alterations in receptor/G-protein coupling of both cholinergic and serotonergic receptors may be one explanation why neurotransmitter replacement drug therapies have been unsuccessful thus far in the treatment of AD.