Behavioural profile of exendin-4/naltrexone dose combinations in male rats during tests of palatable food consumption.

RATIONALE: The glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 potently suppresses food intake in animals and humans. However, little is known about the behavioural specificity of this effect either when administered alone or when co-administered with another anorectic agent. OBJECTIVES: The present study characterises the effects of exendin-4, both alone and in combination with naltrexone, on behaviours displayed by male rats during tests with palatable mash. METHODS: Experiment 1 examined the dose-response effects of exendin-4 (0.025-2.5 µg/kg, IP), while experiment 2 profiled the effects of low-dose combinations of the peptide (0.025 and 0.25 µg/kg) and naltrexone (0.1 mg/kg). RESULTS: In experiment 1, exendin-4 dose dependently suppressed food intake as well as the frequency and rate of eating. However, these effects were accompanied by dose-dependent reductions in all active behaviours and, at 2.5 µg/kg, a large increase in resting and disruption of the behavioural satiety sequence (BSS). In experiment 2, while exendin-4 (0.25 µg/kg) and naltrexone each produced a significant reduction in intake and feeding behaviour (plus an acceleration in the BSS), co-treatment failed to produce stronger effects than those seen in response to either compound alone. CONCLUSION: Similarities between the behavioural signature of exendin-4 and that previously reported for the emetic agent lithium chloride would suggest that exendin-4 anorexia is related to the aversive effects of the peptide. Furthermore, as low-dose combinations of the peptide with naltrexone failed to produce an additive/synergistic anorectic effect, this particular co-treatment strategy would not appear to have therapeutic significance.

On the behavioural specificity of hypophagia induced in male rats by mCPP, naltrexone, and their combination.

RATIONALE: Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation. OBJECTIVES: In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT2C/1B receptor agonist mCPP and their combination. METHODS: Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose-response profile of mCPP (0.1-3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg). RESULTS: Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone. CONCLUSIONS: In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT2C/1B receptor mechanisms.

Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash.

RATIONALE: In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioural analysis). Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behaviour during feeding tests have not been thoroughly investigated. OBJECTIVES: This study aimed to assess the behavioural specificity of anorectic responses to bupropion, naltrexone and their combination. METHODS: Video analysis was employed to characterise the behavioural effects of acute systemic treatment with bupropion (10.0-40.0 mg/kg), naltrexone (0.1-3.0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0.1-1.0 mg/kg) in non-deprived male rats exposed for 1 h to palatable mash. Particular attention was paid to the behavioural satiety sequence (BSS). RESULTS: In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS. In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS. In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant. CONCLUSIONS: Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion.

Orexin-1 receptor antagonism fails to reduce anxiety-like behaviour in either plus-maze-naïve or plus-maze-experienced mice.

Although several lines of evidence have recently implicated orexins and their receptors in fear and anxiety, there is also a growing number of apparently inconsistent and/or negative findings. In the present study, we have used ethological methods to comprehensively profile the behavioural effects of the orexin-1 receptor antagonist SB-334867 (3-30 mg/kg) in mice exposed to the elevated plus-maze. Two experiments were performed, the first involving test-naïve animals and the second using prior undrugged experience of the maze to induce a qualitatively different emotional response to that seen on first exposure. In Experiment 1, a reference benzodiazepine (chlordiazepoxide, CDP, 15 mg/kg) produced a robust anxioselective profile comprising substantial increases in open arm exploration and reduced risk assessment without any signiifcant change in general activity levels. In contrast, SB-334867 failed to produce any behavioural effects over the dose range tested. In Experiment 2, 5 min undrugged experience of the maze 24h prior to testing increased open arm avoidance and abolished the anxiolytic efficacy of CDP. Despite this altered baseline, SB-334867 again failed to alter plus-maze behaviour. These findings agree with several recent reports that orexin receptor antagonists, such as SB-334867 and almorexant, do not alter basal anxiety levels in rats but markedly contrast with the anxiolytic-like effects of the same agents when anxiety levels have been exacerbated by fear conditioning, drug challenge or hypercapnia. This unique pattern of activity suggests that orexin receptor antagonists may have therapeutic value in those clinical anxiety disorders characterised by intense emotional arousal.

Low dose naloxone attenuates the pruritic but not anorectic response to rimonabant in male rats.

RATIONALE: Previous research suggests that the acute anorectic effect of cannabinoid CB1 receptor antagonist/inverse agonists may be secondary to response competition from the compulsive scratching and grooming syndrome characteristic of these agents. OBJECTIVES: As the pruritic effect of rimonabant can be attenuated by the opioid receptor antagonist naloxone, these studies test the prediction that naloxone co-treatment should prevent acute rimonabant anorexia. METHODS: Two experiments comprehensively profiled the behavioural effects of an anorectic dose of rimonabant (1.5 mg/kg) in the absence or presence of naloxone (experiment 1: 0.01 or 0.1 mg/kg; experiment 2: 0.05 mg/kg). RESULTS: In both experiments, rimonabant not only significantly suppressed food intake and time spent eating but also induced compulsive scratching and grooming. In experiment 1, although the lower dose of naloxone seemed to weakly attenuate the effects of rimonabant both on ingestive and compulsive behaviours, the higher dose more strongly suppressed the compulsive elements but did not significantly affect the anorectic response. The results of experiment 2 showed that naloxone at a dose which markedly attenuated rimonabant-induced grooming and scratching did not alter the effects of the compound on food intake or time spent feeding. The apparent independence of the ingestive and compulsive effects of rimonabant was confirmed by the observation that despite a 'normalising' effect of naloxone co-treatment on behavioural structure (BSS), the opioid antagonist did not impact the suppressant effect of rimonabant on peak feeding. CONCLUSION: The acute anorectic response to rimonabant would not appear to be secondary to compulsive scratching and grooming.

Patients' and practice nurses' perceptions of secondary preventive care for established ischaemic heart disease: a qualitative study.

A significant proportion of patients with established ischaemic heart disease remain unrecognized in general practice and those who are receiving treatment are experiencing sub-optimal care. The provision of coronary prevention by practice nurses may be an important strategy to improve the quality of this care, and this is feasible and effective. This study explored what occurred during patients' initial assessment for secondary prevention of ischaemic heart disease with a practice nurse and investigated patients' and practice nurses' views ofnurse-led clinics in primary care. Nurses were effective in history taking and offering reassurance and dietary advice, yet were less confident in discussing patients' understandings of heart disease and related medication. Practice nurse-led coronary preventive care is acceptable to both nurses and patients. Further practice nurse education is required in heart disease, cardiac medications and skills necessary for exploring and challenging patients' understandings of these issues.