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P.2.15 Aripiprazole and risperidone improve working memory in healthy volunteers; an fMRI study
Behavioural pharmacology P.2.14 Effects of acute abstinence and nicotine administration on taste perception in cigarette smokers E. Mullings1 ° , L.F. Donaldson2 , J.K. Melichar3 , M.R. Munaf`o1 . 1 University of Bristol, Experimental Psychology, Bristol, United Kingdom; 2 University of Bristol, Physiology & Pharmacology, Bristol, United Kingdom; 3 University of Bristol, Pharmacology, Bristol, United Kingdom Smoking cessation is associated with marked increase in body weight [2], and this contributes to relapse [1]. We investigated the effects of acute abstinence from smoking and nicotine administration on taste, since modulation of taste is a likely mechanism by which eating behaviours may be altered in abstinent smokers helping to identify novel treatments for post cessation weight gain. Cigarette smokers (n = 48) who reported smoking within 1 hour of waking were aged on average, 27 years (SD = 9, range 18–55), smoked 15 cigarettes per day (SD = 5, range 5–28), and had smoked for 10 years (SD = 8, range 1–44). Participants were randomised to abstain for 12 hours or smoke as normal prior to testing, confirmed by exhaled carbon monoxide monitoring. At the session, participants completed subjective ratings of mood, and ratings of intensity and pleasantness of supra-threshold salt and sucrose solutions, followed by a measurement of the threshold at which these solutions could be detected on the tongue. Participants were then randomised to smoking either a nicotine-containing or denicotinised cigarette, after which further subjective ratings were completed. A mixed model ANOVA with abstinence, cigarette and sex as between-subject factors, and time as a withinsubject factor were conducted for taste pleasantness, intensity and threshold data. Pleasantness indicated significant main effects of taste (F[1,40] = 42.76, p < 0.001), reflecting higher ratings of pleasantness for sucrose compared with salt solutions, and abstinence (F[1,40] = 4.51, p = 0.040), reflecting higher ratings of pleasantness in the non-abstinent conditions compared with the abstinent condition. For taste intensity a significant time x taste interaction (F[1,40] = 4.28, p = 0.045), reflecting greater increase in ratings of salt compared with sucrose solutions over time. Threshold data indicated a significant sex x cigarette x time interaction (F[1,38] = 4.99, p = 0.031), reflecting relatively higher taste thresholds for both salt and sucrose solutions among female participants who had smoked a nicotine-containing cigarette compared with those who had smoked a denicotinised (F[1,22] = 6.20, p = 0.021). The effect of cigarette was not significant among males (p = 0.20). There were no significant main
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effects or interaction terms involving the abstinence factor (ps > 0.15). Our data suggest among non-abstinent smokers, females have lower taste thresholds (i.e., greater sensitivity) than males, but that this sex difference is not present among abstinent smokers. This suggests that acute abstinence causes a relative increase in taste threshold among females (i.e., reduced sensitivity). In addition females had lower taste thresholds for sucrose solutions following denicotinised cigarette smoking compared with nicotinised cigarette smoking. This effect was not observed among males, and did not differ as a function of abstinence condition. Taken together, theses data support a relationship between cigarette smoking and taste, which may contribute to the known effects of cigarette smoking on appetite and eating behaviour, and suggest possible sex differences in the nature of this relationship. Reference(s) [1] Knobf, M.K., Morra, M.E., 1983, Smokers, former smokers, and non-smokers: a correlational study of nurses in Connecticut. Oncol Nurses Forum 10: 40−45. [2] Klesges, R.G., Meyers, A.W., Klesges, L.M., LaVasque, M.E., 1989, Smoking, body weight, and their effects on smoking behavior: A comprehensive review of the literature. Psychol Bull 106: 204–230. P.2.15 Aripiprazole and risperidone improve working memory in healthy volunteers; an fMRI study A. Murphy1 ° , J.F.W. Deakin1 . 1 University of Manchester, Neuroscience & Psychiatry Unit, Manchester, United Kingdom Background: Dopamine plays an important role in modulating prefrontal cortex activity during working memory (Egan et al 2001). Reduced prefrontal dopamine concentrations have been implicated in the deficits in working memory and disrupted prefrontal cortex activation in schizophrenia. Studies have suggested that atypical antipsychotic drugs improve cognitive impairments, possibly due to an ability to increase prefrontal dopamine release via actions at 5-HT receptors or through partial agonism at dopamine D2 receptors in the case of aripiprazole. We aimed to investigate the role of D2 partial agonism on brain activity and performance of a working memory task by comparing the effects of aripiprazole with risperidone, an atypical antipsychotic drug with high affinity for the D2 receptor and 5HT2a antagonist properties.
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Behavioural pharmacology
Method: 34 participants were randomised to receive a single oral dose of either 5 mg aripiprazole (n = 12), 1 mg risperidone (n = 11), or placebo (n = 11) following a double blind study design. Particpants were instructed in the the N-Back task of working memory to ensure they fully understood task. 3.5 hours after drug administration participants underwent functional magnetic resonance imaging whilst performing the N-back task. Initial analysis focused on the 2-back condition. Images were acquired on a Philips Achiva 3Telsa scanner. Imaging data were preprocessed and analysed using SPM5. Reaction time and errors of omission and commission were recorded but behavioural data from 3 subjects were lost due to technical breakdown. Behavioural data were analysed with SPSS. Results: The 2-back task resulted in expected activations in dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, frontal pole, anterior cingulate and parietal cortices, irrespective of treatment group. Increased activation of the DLPFC and parietal cortex was seen in the aripiprazole group as compared with the placebo group. This was associated with a significantly faster reaction time for correct responses than the placebo group. Similarly, compared to the risperidone group, aripiprazole increased activation of the DLPFC and also the superior and inferior parietal lobe and the anterior cingulate. There were no significant behavioural differences between the aripiprazole and risperidone groups in number of errors or reaction times. Risperidone resulted in an increased activation of the bilateral frontal pole region as compared with both the placebo and aripiprazole group. The risperidone group produced less commission errors as compared with the placebo group. Conclusion: Both drugs improved performance on the working memory task but in different ways. Aripiprazole speeded reaction times and enhanced activation in DLPFC compared to placebo and in more widespread areas of the working memory network than risperidone. However risperidone decreased errors of commission suggesting reduced impulsivity and this was associated with increased frontal pole activation. The contrasting effects of two drugs may reflect the partial D2 agonist effects of aripiprazole and the more potent actions of risperidone on the 5-HT2A receptor. However, contrasting actions at the D2 receptor in the striatum cannot be excluded although no fMRI differences were observed in this region. Reference(s) [1] Egan MF et al. (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98: 6917– 6922.
P.2.16 Altered expression of hippocampal mGLUR7 mRNA in a model of depression C. O’Mahony1 ° , T.G. Dinan2 , J.F. Cryan3 . 1 University College Cork, Dept. of Pharmacology & TherapeuticsCavanagh Pharmacy Building, Cork, Ireland; 2 University College Cork, Dept. of Psychiatry, Cork, Ireland; 3 University College Cork, School of Pharmacy, Cork, Ireland Two of the major contributing factors to the onset of major depression include life stress and genetic predisposition [1]. However, a clear aetiology and understanding of the mechanisms underlying the genetic basis of the disorder have remained elusive. Glutamate is the principal excitatory neurotransmitter in the brain and is abundant within the central nervous system. Glutamatergic neurotransmission has been strongly implicated in the pathophysiology of emotional disorders such as anxiety and major depression. mGlu receptors are involved in modulating the activity of this neurotransmission in the CNS. mGluR7 is known to be expressed in the hippocampus, a region critically involved in the modulation of anxiety, depression-related behaviour, memory and learning processes. Mice deficient in mGluR7 have an antidepressant-like behaviour and altered stress response suggesting a key role of this receptor in depression [2]. Furthermore, studies have indicated an important role of brain-derived neurotrophic factor (BDNF) in relation to depression in both human and animal studies. Moreover, an increase in BDNF in the hippocampus of mGluR7 KO has also been shown [3]. The Wistar Kyoto (WKY) rat model is a genetically selected strain that has been showed to have marked elevation in anxiety and elicit behavioural and hormonal responses suggestive of a depressive phenotype compared to normoanxious Sprague Dawley (SD) rats. The aim of the present study was to examine and compare the expression of hippocampal mGluR7 and to investigate whether there is differential expression between the stress sensitive strain and the “normal” strain. The open field and the forced swim test were used to examine anxiety behaviour and depressive-like behaviours in the Sprague Dawley and Wistar Kyoto rat strains. In this study, mGluR7 was localised in the hippocampus using in situ hybridisation. The hippocampal regions analysed for the presence of mGluR7 mRNA were the CA1, CA3 and the dentate gyrus. These regions were chosen as dysfunction of the hippocampus has previously been implicated in depression. Using this procedure we have compared mGluR7 expression in SD and WKY rats. Our data demonstrate distinct expression patterns of
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effects or interaction terms involving the abstinence factor (ps > 0.15). Our data suggest among non-abstinent smokers, females have lower taste thresholds (i.e., greater sensitivity) than males, but that this sex difference is not present among abstinent smokers. This suggests that acute abstinence causes a relative increase in taste threshold among females (i.e., reduced sensitivity). In addition females had lower taste thresholds for sucrose solutions following denicotinised cigarette smoking compared with nicotinised cigarette smoking. This effect was not observed among males, and did not differ as a function of abstinence condition. Taken together, theses data support a relationship between cigarette smoking and taste, which may contribute to the known effects of cigarette smoking on appetite and eating behaviour, and suggest possible sex differences in the nature of this relationship. Reference(s) [1] Knobf, M.K., Morra, M.E., 1983, Smokers, former smokers, and non-smokers: a correlational study of nurses in Connecticut. Oncol Nurses Forum 10: 40−45. [2] Klesges, R.G., Meyers, A.W., Klesges, L.M., LaVasque, M.E., 1989, Smoking, body weight, and their effects on smoking behavior: A comprehensive review of the literature. Psychol Bull 106: 204–230. P.2.15 Aripiprazole and risperidone improve working memory in healthy volunteers; an fMRI study A. Murphy1 ° , J.F.W. Deakin1 . 1 University of Manchester, Neuroscience & Psychiatry Unit, Manchester, United Kingdom Background: Dopamine plays an important role in modulating prefrontal cortex activity during working memory (Egan et al 2001). Reduced prefrontal dopamine concentrations have been implicated in the deficits in working memory and disrupted prefrontal cortex activation in schizophrenia. Studies have suggested that atypical antipsychotic drugs improve cognitive impairments, possibly due to an ability to increase prefrontal dopamine release via actions at 5-HT receptors or through partial agonism at dopamine D2 receptors in the case of aripiprazole. We aimed to investigate the role of D2 partial agonism on brain activity and performance of a working memory task by comparing the effects of aripiprazole with risperidone, an atypical antipsychotic drug with high affinity for the D2 receptor and 5HT2a antagonist properties.
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Behavioural pharmacology
Method: 34 participants were randomised to receive a single oral dose of either 5 mg aripiprazole (n = 12), 1 mg risperidone (n = 11), or placebo (n = 11) following a double blind study design. Particpants were instructed in the the N-Back task of working memory to ensure they fully understood task. 3.5 hours after drug administration participants underwent functional magnetic resonance imaging whilst performing the N-back task. Initial analysis focused on the 2-back condition. Images were acquired on a Philips Achiva 3Telsa scanner. Imaging data were preprocessed and analysed using SPM5. Reaction time and errors of omission and commission were recorded but behavioural data from 3 subjects were lost due to technical breakdown. Behavioural data were analysed with SPSS. Results: The 2-back task resulted in expected activations in dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, frontal pole, anterior cingulate and parietal cortices, irrespective of treatment group. Increased activation of the DLPFC and parietal cortex was seen in the aripiprazole group as compared with the placebo group. This was associated with a significantly faster reaction time for correct responses than the placebo group. Similarly, compared to the risperidone group, aripiprazole increased activation of the DLPFC and also the superior and inferior parietal lobe and the anterior cingulate. There were no significant behavioural differences between the aripiprazole and risperidone groups in number of errors or reaction times. Risperidone resulted in an increased activation of the bilateral frontal pole region as compared with both the placebo and aripiprazole group. The risperidone group produced less commission errors as compared with the placebo group. Conclusion: Both drugs improved performance on the working memory task but in different ways. Aripiprazole speeded reaction times and enhanced activation in DLPFC compared to placebo and in more widespread areas of the working memory network than risperidone. However risperidone decreased errors of commission suggesting reduced impulsivity and this was associated with increased frontal pole activation. The contrasting effects of two drugs may reflect the partial D2 agonist effects of aripiprazole and the more potent actions of risperidone on the 5-HT2A receptor. However, contrasting actions at the D2 receptor in the striatum cannot be excluded although no fMRI differences were observed in this region. Reference(s) [1] Egan MF et al. (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98: 6917– 6922.
P.2.16 Altered expression of hippocampal mGLUR7 mRNA in a model of depression C. O’Mahony1 ° , T.G. Dinan2 , J.F. Cryan3 . 1 University College Cork, Dept. of Pharmacology & TherapeuticsCavanagh Pharmacy Building, Cork, Ireland; 2 University College Cork, Dept. of Psychiatry, Cork, Ireland; 3 University College Cork, School of Pharmacy, Cork, Ireland Two of the major contributing factors to the onset of major depression include life stress and genetic predisposition [1]. However, a clear aetiology and understanding of the mechanisms underlying the genetic basis of the disorder have remained elusive. Glutamate is the principal excitatory neurotransmitter in the brain and is abundant within the central nervous system. Glutamatergic neurotransmission has been strongly implicated in the pathophysiology of emotional disorders such as anxiety and major depression. mGlu receptors are involved in modulating the activity of this neurotransmission in the CNS. mGluR7 is known to be expressed in the hippocampus, a region critically involved in the modulation of anxiety, depression-related behaviour, memory and learning processes. Mice deficient in mGluR7 have an antidepressant-like behaviour and altered stress response suggesting a key role of this receptor in depression [2]. Furthermore, studies have indicated an important role of brain-derived neurotrophic factor (BDNF) in relation to depression in both human and animal studies. Moreover, an increase in BDNF in the hippocampus of mGluR7 KO has also been shown [3]. The Wistar Kyoto (WKY) rat model is a genetically selected strain that has been showed to have marked elevation in anxiety and elicit behavioural and hormonal responses suggestive of a depressive phenotype compared to normoanxious Sprague Dawley (SD) rats. The aim of the present study was to examine and compare the expression of hippocampal mGluR7 and to investigate whether there is differential expression between the stress sensitive strain and the “normal” strain. The open field and the forced swim test were used to examine anxiety behaviour and depressive-like behaviours in the Sprague Dawley and Wistar Kyoto rat strains. In this study, mGluR7 was localised in the hippocampus using in situ hybridisation. The hippocampal regions analysed for the presence of mGluR7 mRNA were the CA1, CA3 and the dentate gyrus. These regions were chosen as dysfunction of the hippocampus has previously been implicated in depression. Using this procedure we have compared mGluR7 expression in SD and WKY rats. Our data demonstrate distinct expression patterns of