title: 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.
abstract: 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.
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Weinstein
authors.forename: D
authors.initials: D
authors.lastname: Magnuson
authors.forename: J
authors.initials: J
authors.lastname: Lee
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism* / Q000493:pharmacokinetics; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006165:Guanylyl Imidodiphosphate / Q000378:metabolism; D006801:Humans; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism* / Q000493:pharmacokinetics; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D006165:Guanylyl Imidodiphosphate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D019204:GTP-Binding Proteins