Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro04-6790

Rationale: Accumulating evidence suggests a potential role for the 5-HT6 receptor in cognitive function and the potential use of 5-HT6 receptor antagonists in the treatment of learning and memory disorders. Objectives: The aim of the current study was to investigate the effect of the selective 5-HT6 receptor antagonist, Ro04-6790, on both the performance of normal adult rats and restoration of a pharmacological disruption of memory function produced by the non-selective muscarinic receptor antagonist, scopolamine, or the dopamine D2 receptor antagonist, raclopride, in a rodent model of recognition memory. Methods: Passive, perceptually based, recognition memory was assessed using a novel object discrimination task. Following habituation to an arena, rats were presented with two identical objects during trial 1 (T1) and a novel and familiar object during trial 2 (T2). The time spent exploring the two objects in each trial was measured and novel object discrimination assessed in T2. Results: In the absence of drug all rats spent an equal time exploring the two identical objects in T1 but more time exploring the novel object in T2. Scopolamine (but not N-methylscopolamine) and raclopride both produced a dose-dependent reduction in novel object discrimination whilst the 5-HT6 receptor antagonist, Ro04-6790, had no effect on discrimination when given alone but completely reversed the scopolamine- but not the raclopride-induced deficit. Conclusion: This study demonstrates that acute administration of Ro04-6790 reverses a cholinergic but not a dopaminergic deficit in a rodent model of recognition memory and provides further support for a role of the 5-HT6 receptor in the regulation of cognitive functio

Geocoding routinely collected administrative data to measure access to alcohol outlets in Wales

ABSTRACT Objectives A substantial level of excess alcohol consumption results in a wide range of harm and the potential impact on health at the population level of a reduction in consumption is considerable. A proposed policy for reducing alcohol consumption is restricting the availability of alcohol through reducing the density of alcohol outlets. We set out to create a high spatial resolution alcohol outlet dataset suitable for evaluating longitudinal changes in chronic alcohol related conditions. Approach Requests were made for the names and location of all licensed alcohol outlets within each of the 22 Unitary Authorities in Wales, between Nov 2005 and Dec 2011. Data requested for each outlet consisted of: the date permission was granted or the licence became active, the licence expiry date or an indicated date of outlet closure, whether this premise is licensed for ON and/or OFF premise sales, the hours permissible to sell alcohol or general opening hours of the outlet and the type of premise as assigned by the LA if available. Our approach included collating, geocoding and manually matching alcohol outlet data received from each unitary authority for use in a longitudinal analysis of outlet density. Results All authorities were able to provide an actual or approximate license issue date, allowing us to summarise the number of outlets annually. Several authorities were unable to provide precise outlet closure dates, so the date of the last interaction with the outlet was used to generate an approximate end date. One-half of the unitary authorities were able to provide the On/Off sales status of outlets, and 9 were able to provide opening hours. From these data we were able to geocode 53% (range 28% to 72% by local authority) using GIS, the remaining 47% were matched using Google products to verify and extract a precise geographic location. Conclusions The collation and processing of retrospective alcohol outlet data was successfully completed to enable the building of a longitudinal exposure dataset. There was considerable variation between the unitary authorities in the quality of address data, and data related to the availability of alcohol, for example opening hours. The lack of address structure required us to devise a manual address matching process to capture the addresses that could not be geocoded. To aid future data linkage based evaluations to provide policy evidence in a timely manner, local government datasets should use standardised data fields, including addresses and Point-of-Capture address verification

Role of the anterior cingulate cortex in the retrieval of novel object recognition memory after a long delay

Previous in vivo electrophysiological studies suggest that the anterior cingulate cortex (ACgx) is an important substrate of novel object recognition (NOR) memory. However, intervention studies are needed to confirm this conclusion and permanent lesion studies cannot distinguish effects on encoding and retrieval. The interval between encoding and retrieval tests may also be a critical determinant of the role of the ACgx. The current series of experiments used micro-infusion of the GABAA receptor agonist, muscimol, into ACgx to reversibly inactivate the area and distinguish its role in encoding and retrieval. ACgx infusions of muscimol, before encoding did not alter NOR assessed after a delay of 20 min or 24 h. However, when infused into the ACgx before retrieval muscimol impaired NOR assessed after a delay of 24 h, but not after a 20 min retention test. Together these findings suggest that the ACgx plays a time-dependent role in the retrieval, but not the encoding, of NOR memory, neuronal activation being required for the retrieval of remote (24 h old), but not recent (20 min old) visual memory

Socioeconomic inequality in medication persistence in primary and secondary prevention of coronary heart disease - a population-wide electronic cohort study

Background Coronary heart disease (CHD) mortality in England fell by 36% between 2000 and 2007 and it is estimated that approximately 50% of the fall was due to improved treatment uptake. Marked socio-economic inequalities in CHD mortality in the United Kingdom (UK) remain, with higher age-adjusted rates in more deprived groups. Inequalities in the persistence of medication for primary and secondary prevention of CHD may contribute to the observed social gradient and we investigated this possibility in the population of Wales (UK). Methods and findings An electronic cohort of individuals aged over 20 (n = 1,199,342) in Wales (UK) was formed using linked data from primary and secondary care and followed for six years (2004–2010). We identified indications for medication (statins, aspirin, ACE inhibitors, clopidogrel) recommended in UK National Institute for Clinical Excellence (NICE) guidance for CHD (high risk, stable angina, stable angina plus diabetes, unstable angina, and myocardial infarction) and measured the persistence of indicated medication (time from initiation to discontinuation) across quintiles of the Welsh Index of Multiple Deprivation, an area-based measure of socio-economic inequality, using Cox regression frailty models. In models adjusted for demographic factors, CHD risk and comorbidities across 15 comparisons for persistence of the medications, none favoured the least deprived quintile, two favoured the most deprived quintile and 13 showed no significant differences. Conclusions During our study period (2004–2010) we found no significant evidence of socio-economic inequality in the persistence of recommended medication for primary and secondary prevention of CHD

Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone

The psychoactive effects of mephedrone are commonly compared to those of 3,4-methylenedioxymethamphetamine, but because of a shorter duration of action users often employ repeated administration to maintain its psychoactive actions. This study examined the effects of repeated mephedrone administration on locomotor activity, body temperature and striatal dopamine and 5-hydroxytryptamine (5-HT) levels, and the role of dopaminergic and serotonergic neurons in these responses. Adult male Lister hooded rats received three injections of vehicle (1ml/kg, i.p.) or mephedrone HCl (10mg/kg) at 2h intervals for radiotelemetry (temperature and activity) or microdialysis (dopamine and 5-HT) measurements. Intracerebroventricular pre-treatment (21 to 28 days earlier) with 5,7-dihydroxytryptamine (5,7-DHT, 150μg) or 6-hydroxydopamine (6-OHDA, 300μg) was used to examine the impact of 5-HT or dopamine depletion on mephedrone-induced changes in temperature and activity. A final study examined the influence of i.p. pre-treatment (-30min) with the 5-HT1A receptor antagonist WAY-100635 (0.5mg/kg), 5-HT1B receptor antagonist GR 127935 (3mg/kg) or the 5-HT7 receptor antagonist SB-258719 (10mg/kg) on mephedrone-induced changes in locomotor activity and rectal temperature. Mephedrone caused rapid-onset hyperactivity, hypothermia (attenuated on repeat dosing), and increased striatal dopamine and 5-HT release following each injection. Mephedrone-induced hyperactivity was attenuated by 5-HT depletion and 5-HT1B receptor antagonism, whereas the hypothermia was completely abolished by 5-HT depletion and lessened by 5-HT1A receptor antagonism. These findings suggest that stimulation of central 5-HT release and/or inhibition of 5-HT reuptake play a pivotal role in both the hyperlocomotor and hypothermic effects of mephedrone, which are mediated in part via 5-HT1B and 5-HT1A receptors

Caffeine alters the behavioural and body temperature responses to mephedrone without causing long-term neurotoxicity in rats

Administration of caffeine with 3,4-methylenedioxymethamphetamine (MDMA) alters the pharmacological properties of MDMA in rats. The current study examined whether caffeine alters the behavioural and neurochemical effects of mephedrone, which has similar psychoactive effects to MDMA. Rats received either i.p. saline, mephedrone (10mg/kg), caffeine (10mg/kg) or combined caffeine and mephedrone twice weekly on consecutive days for three weeks. Locomotor activity (days 1 and 16), novel object discrimination (NOD, day two), elevated plus maze (EPM, day eight) exploration, rectal temperature changes (day nine) and prepulse inhibition of acoustic startle (PPI, day 15) response were assessed. Seven days after the final injection, brain regions were collected for measurement of 5-hydroxytryptamine (5-HT), dopamine and their metabolites. Combined caffeine and mephedrone further enhanced the locomotor response observed following either drug administered alone, and converted mephedrone-induced hypothermia to hyperthermia. Co-administration also abolished mephedrone-induced anxiogenic response on the EPM but had no effect on NOD or PPI. Importantly, no long-term neurotoxicity was detected following repeated mephedrone alone or when co-administered with caffeine. In conclusion, the study suggests a potentially dangerous effect of concomitant caffeine and mephedrone, and highlights the importance of taking polydrug use into consideration when investigating the acute adverse effect profile of popular recreational drugs