Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function.

Variability in expression of the 5-HT transporter (5-HTT) gene in the human population has been associated with a range of behavioural phenotypes. The underlying mechanisms are unclear but may involve changes in 5-HT receptor levels and/or signalling. The present study used a novel 5-HTT overexpressing transgenic mouse to test the hypothesis that variability in 5-HTT expression may alter 5-HT(2A) receptor function. In wildtype mice, the 5-HT(2) receptor agonist DOI increased regional brain mRNA expression of two immediate early genes (c-fos and Arc), and induced head twitches, and both effects were abolished by pre-treatment with the 5-HT(2A) receptor antagonist MDL 100907. In 5-HTT overexpressing mice, DOI induced a greater increase in both c-fos and Arc mRNA expression in cortical brain regions, and more head twitches, compared to wildtype mice. Autoradiographic and in situ hybridisation experiments showed that 5-HT(2A) receptor binding sites and 5-HT(2A) receptor mRNA did not differ between transgenic and wildtype mice. Finally, the transgenic mice had lower regional brain 5-HT levels compared to wildtype mice. This depletion of 5-HT may underpin the increase in 5-HT(2A) receptor function because in wildtype mice 5-HT depletion using the 5-HT synthesis inhibitor, p-chlorophenylalanine, enhanced the head twitch response to DOI. These data demonstrate that elevated 5-HTT expression is accompanied by increased 5-HT(2A) receptor function, an effect possibly mediated by decreased availability of synaptic 5-HT. Variation in levels of 5-HTT expression may therefore be a source of variability in 5-HT(2A) receptor function, which may be an important modifier of 5-HTT-linked phenotypes.

Mice overexpressing the 5-hydroxytryptamine transporter show no alterations in feeding behaviour and increased non-feeding responses to fenfluramine.

RATIONALE: The 5-HT transporter (5-HTT) is implicated in the regulation of appetite. Expression of the 5-HTT varies in the human population, and this variation may determine both individual differences in feeding and abnormal feeding behaviours such as eating disorders. OBJECTIVES: The effects of 5-HTT expression on feeding and satiety were examined in a transgenic mouse model of 5-HTT overexpression. MATERIALS AND METHODS: We measured free-feeding food intake and observed the behavioural satiety sequence (BSS) after food deprivation in mice at baseline and after administration of the anorectic drug fenfluramine. RESULTS: 5-HTT overexpressing mice were both lighter and shorter than their wildtype littermates. Despite this size difference, food intake by transgenic and wildtype mice did not differ. There was no effect of genotype on the BSS or on food intake during the test at baseline. Increasing doses of fenfluramine reduced food intake in a similar manner in both transgenic and wildtype mice. After 0.3 and 1 mg/kg fenfluramine, the temporal pattern of the BSS was the same for both groups, whereas 3 and 10 mg/kg fenfluramine disrupted the BSS. In transgenic mice, this disruption was evident at the 3 mg/kg dose, while in wildtypes, it emerged only at the 10-mg/kg dose. CONCLUSION: These data suggest that overexpression of the 5-HTT does not lead to alterations in feeding or satiety in food-deprived mice but does increase the occurrence of other non-feeding behaviours in response to the 5-HT releasing agent fenfluramine.

Differential involvement of serotonin and dopamine systems in cost-benefit decisions about delay or effort.

RATIONALE: Although tasks assessing the role of dopamine in effort-reward decisions are similar to those concerned with the role of serotonin in impulsive choice in that both require analysis of the costs and benefits of possible actions, they have never been directly compared. OBJECTIVES: This study investigated the involvement of serotonin and dopamine in two cost-benefit paradigms, one in which the cost was delay and the other in which it was physical effort. METHODS: Sixteen rats were trained on a T-maze task in which they chose between high and low reward arms. In one version, the high reward arm was obstructed by a barrier, in the other, delivery of the high reward was delayed by 15 s. Serotonin and dopamine function were manipulated using systemic pCPA and haloperidol injections, respectively. RESULTS: Haloperidol-treated rats were less inclined either to exert more effort or to countenance a delay for a higher reward. pCPA had no effect on the performance of the rats on the effortful task, but significantly increased the rats' preference for an immediate but smaller reward. All animals (drug treated and controls) chose the high reward arm on the majority of trials when the delay or effort costs were matched in both high and low reward arms. CONCLUSION: A dissociation was found between the neurotransmitter systems involved in different types of cost-benefit decision making. While dopaminergic systems were required for decisions about both effort and delay, serotonergic systems were only needed for the latter.

Human exposure to fipronil from dogs treated with frontline.

This investigation determined fipronil residues on gloves worn while petting dogs after Frontline application. Frontline contains 9.8% fipronil, which controls fleas and ticks on dogs for at least 30 d. Frontline (1.34 ml) was applied topically on adult household dogs and gloves worn for 5 min during pettingwere collected 24 hr and 1, 2, 3, 4 and 5 w post-Frontline application for fipronil residue determinations using GC/MS. The highest concentration of fipronil (589.3 +/- 205.7ppm) was detected 24 h after Frontline application and was undetectable in the gloves collected at 5w. Repeated exposure to such contamination can pose human health risks.