The 5-hydroxytryptamine 5-HT1A receptor has been the focus of considerable research effort for ov... more The 5-hydroxytryptamine 5-HT1A receptor has been the focus of considerable research effort for over a decade. However, the definitive classification of this receptor and the full characterization of its pharmacology have awaited the development of highly selective 5-HT1A receptor ...
Preliminary findings suggest that Attention Deficit Hyperactivity Disorder (ADHD) may be associat... more Preliminary findings suggest that Attention Deficit Hyperactivity Disorder (ADHD) may be associated with disordered eating behaviour, but whether there is sufficient evidence to suggest an association between ADHD and specific types of disordered eating behaviour is unclear. Furthermore, it is uncertain whether specific features associated with ADHD are differentially associated with disordered eating behaviour. A systematic review of seventy-five studies was conducted to evaluate the potential association between ADHD symptomatology and disordered eating behaviour and to provide an estimate of the strength of evidence for any association. Overall, a moderate strength of evidence exists for a positive association between ADHD and disordered eating and with specific types of disordered-eating behaviour, in particular, overeating behaviour. There is consistent evidence that impulsivity symptoms of ADHD are positively associated with overeating and bulimia nervosa and more limited evid...
The effects of nine central 5-HT antagonists on food intake in free feeding male rats were examin... more The effects of nine central 5-HT antagonists on food intake in free feeding male rats were examined. The 5-HT2 antagonists ritanserin and ketanserin and the selective 5-HT3 antagonists ICS 205-930 and MDL 72222 had no effect on food intake. In contrast, the non-selective 5-HT antagonists metergoline, methiothepin, mesulergine, mianserin and methysergide (all of which have high affinity for various 5-HT1 receptor subtypes), dose-dependently increased food intake during a 4-h daytime test. Furthermore, metergoline dose dependently increased food intake over a 24-h period. Surprisingly, mesulergine decreased food intake over a 24-h period at the same doses that increased daytime food intake. This may indicate that the increase in daytime feeding produced by mesulergine is a non-specific response. Although the antagonists used have varying degrees of selectivity for 5-HT receptor subtypes, the pattern of results suggests that postsynaptic 5-HT1 receptors (possibly of the 5-HT1C type) play an important role in the control of feeding in rats.
Activation of 5-HT2C receptors is thought to enhance satiety and to mediate the action of the pro... more Activation of 5-HT2C receptors is thought to enhance satiety and to mediate the action of the prototypical anorectic drug d-fenfluramine. Four experiments investigated the role of the 5-HT2C receptor in the modulation of feeding by comparison of the effects of the putative selective 5-HT2C receptor agonist Ro 60-0175 and d-fenfluramine on feeding behaviour. Microstructural analyses of meal patterning and drinking of a palatable solution were made over a range of drug doses administered to male Lister hooded rats. Ro 60-0175 increased the latency to the first meal (3 mg/kg) and reduced meal size (1 mg/kg). d-Fenfluramine (1 mg/kg) produced a similar behavioural pattern, but 3 mg/kg produced a more profound hypophagia that persisted for 10-12 h. Ro 60-0175 (1, 3 mg/kg) and d-fenfluramine (1.5 mg/kg) reduced ingestion of a palatable glucose/saccharin solution, by a reduction in the number of bouts of licking, with little effect on the size of individual bouts. d-Fenfluramine-induced hypophagia (2.1 mg/kg) was challenged by the administration of the selective 5-HT2C receptor antagonist SB 242084 (1, 3 mg/kg) in the meal patterning paradigm. SB 242084 significantly attenuated the decrease in feeding rate and increase in latency to feed produced by d-fenfluramine, but had no effect on the fenfluramine-induced reduction in meal size. A similar pattern of results was obtained when Ro 60-0175-induced hypophagia (3 mg/kg) was challenged by SB 242084 (1, 3 mg/kg). These results demonstrate that Ro 60-0175 is a useful probe of the importance of 5-HT2C activation in the control of food intake and support the hypothesis that activation of 5-HT2C receptors is a critical aspect of the hypophagic action of d-fenfluramine. The 5-HT2C receptor may prove to be a useful target in the development of clinically effective drugs for the treatment of obesity.
The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (... more The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (L-364, 718) on analgesia induced by morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for pain when given alone, whereas morphine (2-16 mg/kg) induced dose-dependent analgesia. Cholecystokinin (4-16 micrograms/kg) abolished the analgesia induced by 8 mg/kg morphine. In contrast, doses of 1 and 2 mg/kg MK-329 enhanced the analgesia induced by 8 and 4 mg/kg morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance, opiate-induced analgesia in response to thermal pain stimuli. In addition, the results show that CCK/opiate interactions extend to mechanical pain stimuli. Recent ligand binding studies have shown that CCK receptors in the spinal cord of the rat (where CCK/opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The drug MK-329 has a relatively weak (micromolar) affinity for CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of MK-329 are required to enhance opiate-induced analgesia in the paw pressure test and tail flick test in rats it appears that CCK/opiate interactions in this species involve CCK-B receptors.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jun 28, 2016
Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-as... more Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was n...
The effects of the putative, selective dopamine autoreceptor antagonist (+)-AJ 76 on yawning, pen... more The effects of the putative, selective dopamine autoreceptor antagonist (+)-AJ 76 on yawning, penile grooming and mouth movements induced by small doses of apomorphine in male rats were examined. Yawning induced by 0.05mg/kg apomorphine was dose dependently blocked by (+)-AJ-76, significant decreases being observed at 0.86 and 3.5mg/kg of the drug. A dose of 0.86mg/kg (+)-AJ 76 caused a two fold shift to the right of the apomorphine dose response curve for yawning. In contrast, (+)-AJ 76 had no effect on penile grooming and vacuous mouth movements induced by small doses of apomorphine. This pattern of results is similar to that observed after bilateral 6-hydroxydopamine-induced lesions of the substantia nigra which also blocked apomorphine-induced yawning but spared penile grooming and mouth movements. Previous studies have suggested that (+)-AJ 76 is a selective dopamine autoreceptor antagonist that has little or no effect on behaviour mediated by post-synaptic dopamine receptors. Therefore, these data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors.
The 5-hydroxytryptamine 5-HT1A receptor has been the focus of considerable research effort for ov... more The 5-hydroxytryptamine 5-HT1A receptor has been the focus of considerable research effort for over a decade. However, the definitive classification of this receptor and the full characterization of its pharmacology have awaited the development of highly selective 5-HT1A receptor ...
Preliminary findings suggest that Attention Deficit Hyperactivity Disorder (ADHD) may be associat... more Preliminary findings suggest that Attention Deficit Hyperactivity Disorder (ADHD) may be associated with disordered eating behaviour, but whether there is sufficient evidence to suggest an association between ADHD and specific types of disordered eating behaviour is unclear. Furthermore, it is uncertain whether specific features associated with ADHD are differentially associated with disordered eating behaviour. A systematic review of seventy-five studies was conducted to evaluate the potential association between ADHD symptomatology and disordered eating behaviour and to provide an estimate of the strength of evidence for any association. Overall, a moderate strength of evidence exists for a positive association between ADHD and disordered eating and with specific types of disordered-eating behaviour, in particular, overeating behaviour. There is consistent evidence that impulsivity symptoms of ADHD are positively associated with overeating and bulimia nervosa and more limited evid...
The effects of nine central 5-HT antagonists on food intake in free feeding male rats were examin... more The effects of nine central 5-HT antagonists on food intake in free feeding male rats were examined. The 5-HT2 antagonists ritanserin and ketanserin and the selective 5-HT3 antagonists ICS 205-930 and MDL 72222 had no effect on food intake. In contrast, the non-selective 5-HT antagonists metergoline, methiothepin, mesulergine, mianserin and methysergide (all of which have high affinity for various 5-HT1 receptor subtypes), dose-dependently increased food intake during a 4-h daytime test. Furthermore, metergoline dose dependently increased food intake over a 24-h period. Surprisingly, mesulergine decreased food intake over a 24-h period at the same doses that increased daytime food intake. This may indicate that the increase in daytime feeding produced by mesulergine is a non-specific response. Although the antagonists used have varying degrees of selectivity for 5-HT receptor subtypes, the pattern of results suggests that postsynaptic 5-HT1 receptors (possibly of the 5-HT1C type) play an important role in the control of feeding in rats.
Activation of 5-HT2C receptors is thought to enhance satiety and to mediate the action of the pro... more Activation of 5-HT2C receptors is thought to enhance satiety and to mediate the action of the prototypical anorectic drug d-fenfluramine. Four experiments investigated the role of the 5-HT2C receptor in the modulation of feeding by comparison of the effects of the putative selective 5-HT2C receptor agonist Ro 60-0175 and d-fenfluramine on feeding behaviour. Microstructural analyses of meal patterning and drinking of a palatable solution were made over a range of drug doses administered to male Lister hooded rats. Ro 60-0175 increased the latency to the first meal (3 mg/kg) and reduced meal size (1 mg/kg). d-Fenfluramine (1 mg/kg) produced a similar behavioural pattern, but 3 mg/kg produced a more profound hypophagia that persisted for 10-12 h. Ro 60-0175 (1, 3 mg/kg) and d-fenfluramine (1.5 mg/kg) reduced ingestion of a palatable glucose/saccharin solution, by a reduction in the number of bouts of licking, with little effect on the size of individual bouts. d-Fenfluramine-induced hypophagia (2.1 mg/kg) was challenged by the administration of the selective 5-HT2C receptor antagonist SB 242084 (1, 3 mg/kg) in the meal patterning paradigm. SB 242084 significantly attenuated the decrease in feeding rate and increase in latency to feed produced by d-fenfluramine, but had no effect on the fenfluramine-induced reduction in meal size. A similar pattern of results was obtained when Ro 60-0175-induced hypophagia (3 mg/kg) was challenged by SB 242084 (1, 3 mg/kg). These results demonstrate that Ro 60-0175 is a useful probe of the importance of 5-HT2C activation in the control of food intake and support the hypothesis that activation of 5-HT2C receptors is a critical aspect of the hypophagic action of d-fenfluramine. The 5-HT2C receptor may prove to be a useful target in the development of clinically effective drugs for the treatment of obesity.
The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (... more The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (L-364, 718) on analgesia induced by morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for pain when given alone, whereas morphine (2-16 mg/kg) induced dose-dependent analgesia. Cholecystokinin (4-16 micrograms/kg) abolished the analgesia induced by 8 mg/kg morphine. In contrast, doses of 1 and 2 mg/kg MK-329 enhanced the analgesia induced by 8 and 4 mg/kg morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance, opiate-induced analgesia in response to thermal pain stimuli. In addition, the results show that CCK/opiate interactions extend to mechanical pain stimuli. Recent ligand binding studies have shown that CCK receptors in the spinal cord of the rat (where CCK/opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The drug MK-329 has a relatively weak (micromolar) affinity for CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of MK-329 are required to enhance opiate-induced analgesia in the paw pressure test and tail flick test in rats it appears that CCK/opiate interactions in this species involve CCK-B receptors.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jun 28, 2016
Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-as... more Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was n...
The effects of the putative, selective dopamine autoreceptor antagonist (+)-AJ 76 on yawning, pen... more The effects of the putative, selective dopamine autoreceptor antagonist (+)-AJ 76 on yawning, penile grooming and mouth movements induced by small doses of apomorphine in male rats were examined. Yawning induced by 0.05mg/kg apomorphine was dose dependently blocked by (+)-AJ-76, significant decreases being observed at 0.86 and 3.5mg/kg of the drug. A dose of 0.86mg/kg (+)-AJ 76 caused a two fold shift to the right of the apomorphine dose response curve for yawning. In contrast, (+)-AJ 76 had no effect on penile grooming and vacuous mouth movements induced by small doses of apomorphine. This pattern of results is similar to that observed after bilateral 6-hydroxydopamine-induced lesions of the substantia nigra which also blocked apomorphine-induced yawning but spared penile grooming and mouth movements. Previous studies have suggested that (+)-AJ 76 is a selective dopamine autoreceptor antagonist that has little or no effect on behaviour mediated by post-synaptic dopamine receptors. Therefore, these data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors.
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Papers by Colin T Dourish