Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder.

RATIONALE: The psychomotor stimulant methylphenidate is used in the treatment of attention deficit hyperactivity disorder (ADHD). Whereas the mechanism is not fully understood it is suggested to involve restoration of impaired dopamine function found in ADHD. OBJECTIVES: The aim of this study was to determine the effects of methylphenidate on brain region activation in vivo using pharmacological magnetic resonance imaging (phMRI) in a potential rat model of ADHD. METHODS: Rats were treated bi-daily [from postnatal day (PND) 24] for 4 days with the dopamine re-uptake inhibitor GBR 12909 (30 mg/kg i.p) or vehicle (control). On PND 57 rats were administered methylphenidate (4 mg/kg i.p) and locomotor activity measured. In a separate group of animals, blood oxygen level dependent (BOLD) response was measured using phMRI to determine changes in brain region activation produced by methylphenidate (4 mg/kg i.p.) in GBR 12909-pretreated or control rats. RESULTS: Methylphenidate produced a greater locomotor-stimulant response in controls compared with GBR 12909 rats. Pretreatment with GBR 12909 reduced the BOLD response produced by methylphenidate compared with that in control animals. The main effects of methylphenidate on the BOLD response were seen in the caudate, frontal cortex, hippocampus and hypothalamus. CONCLUSIONS: Short-term treatment with GBR 12909 in young rats causes long-term changes in dopaminergic systems, altering the methylphenidate-induced behavioural response and brain region activation compared with that in vehicle-pretreated rats. The results further support the view that altered dopaminergic function may be an important factor in ADHD and the value of animal models with this functional neurochemical deficit.

Serotonin 2C receptor agonists and the behavioural satiety sequence in mice.

The studies reported here examined the role of the 5-hydroxytryptamine (5-HT)(2C) receptor subtype in the control of ingestive behaviour in mice. Behavioural satiety sequence (BSS) and food intake measurements were taken, comparing the selective 5-HT(2C) receptor agonist (S)-2-(6-chloro-5-fluoro-indol-l-yl)-l-methylethylamine hydrochloride (Ro 60-0175; 1.0, 3.0 and 10.0 mg/kg) and D-fenfluramine (3.0 mg/kg). Ro 60-0175 produced a dose-dependent decrease in food intake. The effects of Ro 60-0175 (3.0 mg/kg) on the BSS were similar to the hypophagic effects of D-fenfluramine (3.0 mg/kg). In a second experiment, the specific effects on feeding produced by Ro 60-0175 (5.6 mg/kg) were attenuated by pretreatment with the selective 5-HT(2C) receptor antagonist 6-chloro-5-methyl-1-[2(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline (SB 242084; 0.5 mg/kg). The 5-HT(1B/2C) receptor agonist 1-(m-chlorophenyl)piperazine (mCPP; 3 mg/kg) also produced a substantial decrease in food intake, which was attenuated by SB 242084 (0.5 mg/kg). A dose of the selective 5-HT(1B/1D) antagonist 2'-methyl-4'(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-(5-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935; 3.0 mg/kg) that successfully attenuated the action of the 5-HT(1B) agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969; 5.0 mg/kg) failed to attenuate mCPP-induced hypophagia. These data suggest that Ro 60-0175- and mCPP-induced hypophagia in mice are mediated via activation of 5-HT(2C) receptors and that stimulation of 5-HT(1B) receptors plays only a minor role in mCPP-induced hypophagia.

Corticotropin-releasing factor receptor 1 activation during exposure to novelty stress protects against Alzheimer's disease-like cognitive decline in AßPP/PS1 mice.

A lifestyle rich in physical and mental activities protects against Alzheimer's disease (AD) but the underlying mechanisms are unclear. We have proposed that this is mediated by a stress response and have shown that repeated exposure to novelty stress, which induces physical and exploratory activities, delays the progression of AD-like pathology in the TASTPM mouse model. Here, we aimed to establish the role played by corticotrophin-releasing factor receptor 1 (CRFR1), a major component of the stress axis, in TASTPM's behavioral and neuroendocrine responses to novelty and related protective effects. We show that the stress response of TASTPM mice is altered with reduced CRFR1-mediated neuroendocrine and behavioral responses to novelty and a distinct profile of behavioral responses. Repeated novelty-induced CRFR1 activation, however, mediated the improved contextual fear memory and extinction performance of TASTPM mice and increased hippocampal and fronto-cortical levels of synaptophysin, a marker of synaptic density, and fronto-cortical levels of the post-synaptic marker PSD95. The N-methyl-D-aspartate receptor (NMDAR) is the major receptor for synaptic plasticity underlying learning and memory. Although novelty-induced NMDAR activation contributed to enhancement of fear memory and synaptophysin levels, antagonism of CRFR1 and NMDAR prevented the novelty-induced increase in hippocampal synaptophysin levels but reversed the other effects of CRFR1 inactivation, i.e., the enhancement of contextual fear extinction and fronto-cortical synaptophysin and PSD95 levels. These findings suggest a novel mechanism whereby a stimulating environment can delay AD symptoms through CRFR1 activation, facilitating NMDAR-mediated synaptic plasticity and synaptogenesis in a region-dependent manner, either directly, or indirectly, by modulating PSD95.

A comparison of InVivoStat with other statistical software packages for analysis of data generated from animal experiments.

InVivoStat is a free-to-use statistical software package for analysis of data generated from animal experiments. The package is designed specifically for researchers in the behavioural sciences, where exploiting the experimental design is crucial for reliable statistical analyses. This paper compares the analysis of three experiments conducted using InVivoStat with other widely used statistical packages: SPSS (V19), PRISM (V5), UniStat (V5.6) and Statistica (V9). We show that InVivoStat provides results that are similar to those from the other packages and, in some cases, are more advanced. This investigation provides evidence of further validation of InVivoStat and should strengthen users' confidence in this new software package.

Behavioural characterisation of the effects of acute and repeated administration of GBR 12909 in rats: further evaluation of a potential model of ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterised by excessive levels of hyperactivity, inattentiveness and impulsivity. Stimulant drugs which increase dopamine neurotransmission are treatments for ADHD. Hypodopaminergic fronto-striatal function with associated overactivity of the dopamine transporter (DAT) represents one possible neurobiological mechanism underlying ADHD. Few, if any, of the existing animal models of ADHD mimic the underlying neurobiology of the disorder. In this study we have further characterised the behavioural profile of a model of a hyperactive inattentive animal through manipulation of the DAT. The behavioural effects of acute treatment and following withdrawal from sub-chronic treatment with GBR 12909 (30 mg/kg i.p.), a potent and highly selective DAT inhibitor, were examined in juvenile rats. GBR 12909 treatment was used to produce a compensatory up regulation following withdrawal. Acute treatment with GBR 12909 (30 mg/kg i.p.) resulted in a marked increase in locomotor and rearing behaviours on the first and fourth days during a 4 consecutive bi-daily drug treatment regime in postnatal weaned rats. Adolescent rats after 10, 20 and 30 days withdrawal from GBR 12909 pre-treatment maintained mild increases in locomotor activity and failed to discriminate a familiar over a novel object in the novel object discrimination task (using both 1 min and 3 h inter-trial intervals) indicating impaired learning and memory. Prepulse inhibition of acoustic startle was unaltered following withdrawal from GBR 12909 treatment. These data reinforce the potential role of the DAT in the underlying neurobiology of ADHD. They also add further evidence to suggest that postnatal changes in the DAT following withdrawal from treatment with the DAT inhibitor, GBR 12909, may prove to be a useful animal model of ADHD with potential for examining the effectiveness of novel ADHD treatments.