Normal male human subjects ingested amino acid mixtures which were tryptophan-free, balanced or contained excess tryptophan. The tryptophan-free mixture causes a marked depletion of plasma tryptophan by 5 h. At this time the subjects in the tryptophan-free group had significantly elevated scores on the depression scale of the Multiple Affect Adjective Checklist. The tryptophan-free group also performed worse than the other two groups in a proofreading task carried out while listening to a tape with themes of hopelessness and helplessness (dysphoric distractor). Cognitive theories of depression predict greater distractability of depressed individuals by dysphoric themes. Thus, both measures indicate a rapid mood lowering effect of tryptophan depletion in normal males. This effect is probably mediated by a lowering of brain 5-hydroxytryptamine. Although the mood-lowering effect was not as great as that seen in depressed patients, our results suggest that low brain 5HT might be one factor precipitating depression in some patients.

HARVARD MEDICAL SCHOOL AND NEUROSURGICAL SERVICE, MASSACHUSETTS GENERAL HOSPITALGustatory aversions, induced in rats by conditionally pairinfl a distinctive flavor with a noxious drug, were readily established wen when injections were delayed an hour or more. The optimal interstimulus interval and effectiveness of cues for learning appear to be a function of the specific effects of the reinforcer on the organism.It is considered axiomatic in theory and practice that no learning will occur without immediate reinforcement. For example, a hungry rat will not learn to press a lever for food unless the response is immediately followed by food (primary reinforcement) or by a signal which has been associated with food in the past (secondary reinforcement). Food can be described as rewarding, but the same general rule has been applied to punishing agents also. Delays of the order of 3 to 45 sec. have a deleterious effect upon learning in a wide variety of experimental situations. The significance of these findings for reinforcement theory was discussed by Spence (1947) and a recent review (Renner, 1964) reveals there has been no major modification of the temporal contiguity aspect. However, our data indicates that immediate reinforcement is not a general requirement for all learning. MethodYoung adult male rats (Sprague-Dawley, 300 to 400 gm)were maintained in individual cages with Purina Laboratory Chow ad lib. Drinking was restricted to a 10-min, period each day. After one week of habituation to this schedule, treatment began. In Experiment A, five groups (N = 8 each) were treated. One experimental group (Sac-Apo:inj) was given a gustatory cue in its drinking water (1 gm saccharine per liter) and after a delay was injected with a drug which produced gastriC disturbances (7mg/kg apomorphine hydrochloride I.P.). The animals were injected in serial order at I-min. intervals with the first animal injected at 5 min. and the last one at 12 min. after the saccharin water bottle was removed from the home cage. One control group (Sac-Sal:inj) drank saccharinwater and was injected with saline, while another control (Wat-Apo:inj) drank water and was injected with apomorphine. An additional experimental group (SacApo:inj) received delayed injections in serial order from 15 to 22 min. post-drinking. Other rats (Sac-Shock), immediately after drinking saccharin -water, were taken from their cages and placed in a box with an electric grid floor and three shocks (0.5 sec. pulses at 3 mal were delivered within 1 min. to the paws.All groups received four treatments, one every third day and then three extinction tests (Le. no injections or shock) on the same schedule. Between treatment days, the animals were given water for 10 min.

Amyloid beta (Abeta) protein immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Abeta plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Abeta peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Abeta antibodies that labeled Abeta plaques in human, AD transgenic mouse and vervet brains; bound Abeta1-7; and recognized monomeric and oligomeric Abeta but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Abeta titers were detected in CSF. Abetax-40 levels were elevated approximately 2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Abetax-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Abeta42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Abeta deposition in the vervet monkey as well as the lowering of cerebral Abeta by Abeta vaccination in a non-human primate. The findings further support Abeta immunotherapy as a potential prevention and treatment of AD.