Rapid tryptophan depletion improves decision-making cognition in healthy humans without affecting reversal learning or set shifting

Rapid tryptophan (Trp) depletion (RTD) has been reported to cause deterioration in the quality of decision making and impaired reversal learning, while leaving attentional set shifting relatively unimpaired. These findings have been attributed to a more powerful neuromodulatory effect of reduced 5-HT on ventral prefrontal cortex (PFC) than on dorsolateral PFC. In view of the limited number of reports, the aim of this study was to independently replicate these findings using the same test paradigms. Healthy human subjects without a personal or family history of affective disorder were assessed using a computerized decision making/gambling task and the CANTAB ID/ED attentional set-shifting task under Trp-depleted (n=17; nine males and eight females) or control (n=15; seven males and eight females) conditions, in a double-blind, randomized, parallel-group design. There was no significant effect of RTD on set shifting, reversal learning, risk taking, impulsivity, or subjective mood. However, RTD significantly altered decision making such that depleted subjects chose the more likely of two possible outcomes significantly more often than controls. This is in direct contrast to the previous report that subjects chose the more likely outcome significantly less often following RTD. In the terminology of that report, our result may be interpreted as improvement in the quality of decision making following RTD. This contrast between studies highlights the variability in the cognitive effects of RTD between apparently similar groups of healthy subjects, and suggests the need for future RTD studies to control for a range of personality, family history, and genetic factors that may be associated with 5-HT function.

Facile synthesis of two diastereomeric indolizidines corresponding to the postulated structure of alkaloid 5,9E-259B from a Bufonid toad (Melanophryniscus)

A short synthesis of the postulated structure for indolizidine alkaloid 259B with the hydrogens at C5 and C9 entgegen has been achieved with complete control of stereochemistry at C5. Both diastereoisomers at C8 were obtained, but neither proved to be the natural product. The comparison of the mass and FTIR spectral properties of the synthetic compounds to those of the natural material strongly suggest that the gross structure is correct and that the difference may be a branch in the C5 alkyl side-chain. The GC-retention times of the two synthetic compounds were markedly longer than that of the natural 5,9E-259B.

Synthesis of the alkaloid homaline in ( ) and natural (S,S)-(-) forms, using amination and transamidative ring expansion in liquid ammonia.

Crombie, Leslie; Haigh, David; Jones, Raymond C. F.; Mat-Zin, A.Rasid. Dep. Chem., Univ. Nottingham, Nottingham, UK. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1993), (17), 2047-54. CODEN: JCPRB4 ISSN: 0300-922X. Journal written in English. CAN 120:164608 AN 1994:164608 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract The alkaloid homaline I was prepd. in (?) and natural (S,S)-(-) forms. Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes is examd. (?)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2'-dithiodipyridine/triphenylphosphine-mediated cyclization, and then by amination and transamidative ring expansion from N-(3-chloropropyl)-4-phenylazetidin-2-one in liq. ammonia, followed by N-methylation. Coupling through a 1,4-dihalogenobutane of either the N-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in (?) and meso forms. (R)-(-)-phenylglycine was converted via (S)-?-phenyl-?-alanine into an (S)-?-lactam which was then alkylated with 1-bromo-3-chloropropane, and aminated and ring expanded in liq. ammonia. Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, gave (S,S)-(-)-homaline identical with the natural material.

A revised structure for alkaloid 235C isolated from skin extracts of mantellid (Mantella) frogs of Madagascar

Madagascan frogs of the mantellid genus Mantella have been a rich source of alkaloids derived from dietary arthropods. Two species of frogs, inhabiting swamp forest, contain a unique set of alkaloids, previously proposed, based only on GC-MS and GC-FTIR data, to represent dehydro analogues of the homopumiliotoxins. The major alkaloid of this set, alkaloid 235C (2), now has been isolated in sufficient quantities (ca. 0.3 mg) to allow determination of the structure by NMR analysis. The structure of alkaloid 235C proved to be a 7,8-dehydro-8-desmethylpumiliotoxin. A comparison is presented between the mass, infrared, and H-1 NMR spectra of 235C (2) and a synthetic dehydrohomopumiliotoxin (1), initially proposed incorrectly as the structure for 235C.

Allelic variation at the A218C tryptophan hydroxylase polymorphism influences agitation and aggression in Alzheimer's disease

The behavioural and psychological symptoms of dementia are common, distressing to carers, and directly linked to the requirement for institutional care. Symptoms of aggression and agitation are particularly difficult for carers to tolerate. The origin of these features is unclear although genetic and environmental modification of pre-frontal serotonergic circuitry which regulates the control of negative emotions is proposed. Following the suggestion that the A218C intronic polymorphism of the tryptophan hydroxylase gene influences aggression and anger in non-demented individuals, we tested the influence of A218C on symptoms of agitation/aggression in 396 Alzheimer's disease patients using the Neuropsychiatric Inventory. Overall, 50% of participants experienced agitation/aggression in the month prior to interview. It was observed that male patients with a history of agitation/aggression were more likely to possess C-containing genotypes (P = 0.044, OR = 1.65, CI = 0.98-2.76). We conclude that aggression in male subjects with Alzheimer's disease may be genetically linked to polymorphic variation at the tryptophan hydroxylase gene.