[3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit.

A compound (L-655,708) has been identified which has at least 50-fold selectivity for the benzodiazepine site on GABAA receptors containing an alpha 5 subunit over those containing an alpha 1, alpha 2, alpha 3 or alpha 6 subunit in combination with beta 3 and gamma 2. The compound was radiolabelled with tritium and investigated as a novel radioligand which recognizes the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. [3H]L-655,708 labels one saturable and specific population of binding sites in rat hippocampus with a Kd of 2.4 +/- 0.7 nM and a Bmax of 256 +/- 42 fmol/mg protein. The pharmacology of the binding site labelled was consistent with that of receptors present in cells transfected with alpha 5, beta 2 and gamma 2 and with receptors immunoprecipitated from rat brain with an alpha 5-selective antiserum. It is concluded that [3H]L-655,708 is the first radioligand to date which is selective for any BZ2 subtype of the GABAA receptor and should provide a valuable tool for elucidating the structure and function of the alpha 5-containing GABAA receptor subtype.

Nonrandom chromosomal abnormalities in lymphocyte cultures of individuals with colorectal polyps and of asymptomatic relatives of patients with colorectal cancer or polyps.

We studied chromosomal alterations in the peripheral blood lymphocytes of 10 individuals with colorectal polyps and 10 asymptomatic first-degree relatives of patients with colon cancer or colorectal polyps. The analysis was performed on T-lymphocytes using short term blood cultures and on B-lymphocytes by establishing lymphoblastoid cell lines by Epstein-Barr virus transformation. Chromosomal changes were not common in T- and B-lymphocytes. Chromosomes 1 and 5 were most frequently involved in numerical or structural changes in the patients with polyps as well as in the asymptomatic relatives. These alterations were observed in either the T-lymphocytes or the B-lymphocytes but rarely in both, thus accentuating the importance of studying both the cultures concurrently. Chromosome 5, which is known to play an important role in the development of adenomatous polyps, was found to be involved in 6 (60%) of 10 patients with polyps and 4 (40%) of 10 asymptomatic relatives. These findings show that lymphocytic chromosomal analysis can aid in identifying individuals who are genetically susceptible and are at a higher risk of developing colorectal cancer. Because lymphocytic chromosomal analysis is relatively simple and inexpensive, we expect that it will be very useful in screening asymptomatic individuals who are at a higher risk due to inherited or environmental factors.