These studies have been conducted on 40 dogs, twenty each of a genetically nervous strain and of a normal strain of short-haired pointers. The nervous strain after about age 3 months displays extreme hypervigilance, timidity, human avoidance, and often shows catatonic-like muscle rigidity when in the presence of humans or novel stimuli. Measurements of probenecid-induced accumulation of acid metabolites in cisternal cerebrospinal fluid (CSF) have been carried out. Among the compounds measured at from 1.5 hr to 6.0 hr after probenecid treatment, homovanillic acid (HVA) was similar for the two strains, 5-hydroxy-indoleacetic acid (5-HIAA) was lower, but cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) were higher for the nervous strain when compared with age- and sex-matched behaviorally normal dogs. Probenecid levels in CSF were similar at all points in time from 1.5 to 6.0 hr after its intravenous administration in a dose of 50 mg/kg body weight. These findings coupled with previously observed differences in the two strains suggest that hyperresponsiveness of the central nervous system (CNS) noradrenergic and cholinergic systems and a hyporesponsiveness of the serotoninergic system are related to the genetically expressed aberrant behavior.