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CRF mediates conditioned anxiety to nicotine
$334
R3. Anxiety disorders and anxiolytics
[2] Manzaneque JM, Brain PE Navarro JF. (2002). Prog. NeuroPsychopharmacol. Biol. Psychiat., 26, 349-355. [3] File S. et al. (1998). Behav. Neurosci., 112, 142-149.
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potentiates anxiolytic effects Fof a lowdeprivation odose of onicotine d in deprived female rats
P.3~.3~.007~CRF mediates conditioned anxiety to nicotine S. Tucci, S. Cheeta, P. Seth, S.E. File. King's College London, P~ychopharmacology Research Unit, Centre for neuroscience, London, United Kingdom Although nicotine can have anxiolytic effects, depending on the dose and time of injection it has also been shown to have anxiogenic effects (Irvine et al., 1999). Furthermore, similar to cocaine, a high dose of nicotine (0.45 mg/kg) was shown to produce a conditioned anxiogenic effect in the social interaction (SI) test of anxiety in rats (File et al., 2001). This response was classically conditioned to contextual cues associated with the test environment. Five minutes after subcutaneous injection, a low dose of nicotine (0.1 mg/kg) also has an anxiogenic effect. The present experiment demonstrated that this low dose also produced a conditioned anxiogenic effect which was mediated by corticotrophin-releasing factor (CRF), as was previously found for cocaine (DeVries and Pert, 1998). On day 1 rats were exposed to the SI test after injection with nicotine (0.1 mg/kg) or vehicle. The following day half of each group was tested after i.c.v, injection with a CRF antagonist, a-helical CRF9_41, and the other half with artificial CSE The rats injected with the CRF antagonist did not show a conditioned anxiogenic response [F(1,33)=8.8, p<0.01], whereas those tested after artificial CSF showed a significant decrease in time spent in SI, indicating an anxiogenic response resulting from the previous day's experience with nicotine. In contrast to this role of CRF in anxiety conditioned to nicotine, or-helical CRF9.41 (5 ~tg i.c.v.) failed to antagonise the unconditioned anxiogenic response to the either dose of nicotine. These results are important in several ways. Firstly. they show that anxiety can be conditioned even to a low dose of nicotine suggesting a possible mechanism for persisting anxiogenic effects, which could contribute to the increased incidence of anxiety found in smokers. Secondly, the link with CRF suggests that this neuropeptide may play important roles in the aversive effects of nicotine, such as the increased depression and anxiety. Finally, they suggest that CRF receptor antagonists might be of some value in the treatment and prevention of stress-induced relapse to drug dependence long after detoxification. We are grateful to Dr Jean Rivier (Salk Institute) for providing the s-helical CRFg-41. This study was supported by CONICITULA, Venezuela.
References [1] DeVries AC, Pert A. Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin-releasing factor. Psychopharmacology 1998; 137:333~-0. [2] File SE, Irvine EE, Cheeta S, Akhtar M, Tucci S, Seth P. Nicotine and conditioned anxiety. Soc Neurosci Abst 200 1;222. 11. [3] lrvine EE, Cheeta S, File SE. Time-course of changes in the social interaction test of anxiety following acute and chronic administration of nicotine. Bebav Pharmacol 1999;10:691 7.
R.F. Genn, S. Tucci, J. Edwards, A. Thomas, S.E. File.
King's College London, Centre for Neuroscience Research, Psychopharmacology Research Unit, London, United Kingdom Nicotine has a well-established reputation as a modulator of anxiety in both animals and humans and recently there has been a gradual discovery of variables that may predetermine the biobehavioural responses to nicotine. Almost all the pre-clinical and clinical studies on nicotine have been conducted in males; potential effects on females have been largely ignored (Perkins et al., 1999). In adolescent rats there are sex differences in nicotine's effects on anxiety, with females showing greater sensitivity to anxiolytic effects (Cheeta et al., 2001). A similar sex difference was observed in the effects of nicotine on the mood of nonsmoking students (File et al., 2001). Today, the greatest increase in smoking initiation and maintenance is among young women and is often accompanied by dietary restriction. The purpose of the present study was to examine the consequences of 85% food deprivation in female rats in the elevated plus maze test of anxiety. Animals received a dose of nicotine sub-cutaneously (0, 0.05, 0.1, 0.25, 0.5 mg/kg) and were tested 30 min afterwards. On analysis, there was a significant interaction between deprivation state and drug dose (F4,70=4.4, p<0.01). The most striking consequence of food deprivation was seen in response to the lowest dose of nicotine (0.05 mg&g) where, in deprived females, it significantly increased the percentage of time spent on the open arms of the maze (F9,70=3.5, p<0.01) whereas it had the opposite effect in non-deprived animals. This close was without any effect on the number of closed entries in either group which precludes an effect on motor behaviour and points to a specific anxiolytic effect in the deprived females. Therefore, the modulatory effects of nicotine on anxiety are also vulnerable to the influence of deprivation state; a finding with great clinical relevance in terms of understanding women's motivation to smoke. Acknowledgements: These studies were supported in part by CONICIT/ULA, Venezuela.
References [1] Cheeta, $., lrvine, E.E., Tucci, S., Sandhu, L, File, S.E., 2001. In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats. Neuropsychopharm. 25, 601-607. [2] File, S.E., Fluck, E., Leahy, A., 2001. Nicotine has calming effects on stress-induced mood changes in females, but enhances aggressive mood in males. Int. J. Neuropsychopharm. 4, 371-376. [3] Perkins, K.A., Donny, E., Caggiula, R., 1999. Sex differences in nicotine effects and self administration: Review of animal and human evidence. Nic. Tob. Res. 1,301-315.
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Mirtazapine in posttraumatic stress disorder: Results of a placebo-controlled trial
K.M. Connor 1, J.R.T. Davidson 1, R.H. Weisle~ ,1, M.I. Butterfield3'1, C.D. Casat 4'1 . 1Department of Psychiatry
and Behauioral Sciences, Duke University Medical Center, Box 3812 2, Durham, NC 27710, US.A," 2priuate Practice, Raleigh, NC, US.A; 3 Veterans Administration Medical Center, Durham, NC, US.A, 4Carolinas Medical Center, Charlotte, NC, U.S.A. Objective: Posttraumatic stress disorder (PTSD) is a chronic, disabling, and widely prevalent disorder, with lifetime prevalence
R3. Anxiety disorders and anxiolytics
[2] Manzaneque JM, Brain PE Navarro JF. (2002). Prog. NeuroPsychopharmacol. Biol. Psychiat., 26, 349-355. [3] File S. et al. (1998). Behav. Neurosci., 112, 142-149.
•
potentiates anxiolytic effects Fof a lowdeprivation odose of onicotine d in deprived female rats
P.3~.3~.007~CRF mediates conditioned anxiety to nicotine S. Tucci, S. Cheeta, P. Seth, S.E. File. King's College London, P~ychopharmacology Research Unit, Centre for neuroscience, London, United Kingdom Although nicotine can have anxiolytic effects, depending on the dose and time of injection it has also been shown to have anxiogenic effects (Irvine et al., 1999). Furthermore, similar to cocaine, a high dose of nicotine (0.45 mg/kg) was shown to produce a conditioned anxiogenic effect in the social interaction (SI) test of anxiety in rats (File et al., 2001). This response was classically conditioned to contextual cues associated with the test environment. Five minutes after subcutaneous injection, a low dose of nicotine (0.1 mg/kg) also has an anxiogenic effect. The present experiment demonstrated that this low dose also produced a conditioned anxiogenic effect which was mediated by corticotrophin-releasing factor (CRF), as was previously found for cocaine (DeVries and Pert, 1998). On day 1 rats were exposed to the SI test after injection with nicotine (0.1 mg/kg) or vehicle. The following day half of each group was tested after i.c.v, injection with a CRF antagonist, a-helical CRF9_41, and the other half with artificial CSE The rats injected with the CRF antagonist did not show a conditioned anxiogenic response [F(1,33)=8.8, p<0.01], whereas those tested after artificial CSF showed a significant decrease in time spent in SI, indicating an anxiogenic response resulting from the previous day's experience with nicotine. In contrast to this role of CRF in anxiety conditioned to nicotine, or-helical CRF9.41 (5 ~tg i.c.v.) failed to antagonise the unconditioned anxiogenic response to the either dose of nicotine. These results are important in several ways. Firstly. they show that anxiety can be conditioned even to a low dose of nicotine suggesting a possible mechanism for persisting anxiogenic effects, which could contribute to the increased incidence of anxiety found in smokers. Secondly, the link with CRF suggests that this neuropeptide may play important roles in the aversive effects of nicotine, such as the increased depression and anxiety. Finally, they suggest that CRF receptor antagonists might be of some value in the treatment and prevention of stress-induced relapse to drug dependence long after detoxification. We are grateful to Dr Jean Rivier (Salk Institute) for providing the s-helical CRFg-41. This study was supported by CONICITULA, Venezuela.
References [1] DeVries AC, Pert A. Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin-releasing factor. Psychopharmacology 1998; 137:333~-0. [2] File SE, Irvine EE, Cheeta S, Akhtar M, Tucci S, Seth P. Nicotine and conditioned anxiety. Soc Neurosci Abst 200 1;222. 11. [3] lrvine EE, Cheeta S, File SE. Time-course of changes in the social interaction test of anxiety following acute and chronic administration of nicotine. Bebav Pharmacol 1999;10:691 7.
R.F. Genn, S. Tucci, J. Edwards, A. Thomas, S.E. File.
King's College London, Centre for Neuroscience Research, Psychopharmacology Research Unit, London, United Kingdom Nicotine has a well-established reputation as a modulator of anxiety in both animals and humans and recently there has been a gradual discovery of variables that may predetermine the biobehavioural responses to nicotine. Almost all the pre-clinical and clinical studies on nicotine have been conducted in males; potential effects on females have been largely ignored (Perkins et al., 1999). In adolescent rats there are sex differences in nicotine's effects on anxiety, with females showing greater sensitivity to anxiolytic effects (Cheeta et al., 2001). A similar sex difference was observed in the effects of nicotine on the mood of nonsmoking students (File et al., 2001). Today, the greatest increase in smoking initiation and maintenance is among young women and is often accompanied by dietary restriction. The purpose of the present study was to examine the consequences of 85% food deprivation in female rats in the elevated plus maze test of anxiety. Animals received a dose of nicotine sub-cutaneously (0, 0.05, 0.1, 0.25, 0.5 mg/kg) and were tested 30 min afterwards. On analysis, there was a significant interaction between deprivation state and drug dose (F4,70=4.4, p<0.01). The most striking consequence of food deprivation was seen in response to the lowest dose of nicotine (0.05 mg&g) where, in deprived females, it significantly increased the percentage of time spent on the open arms of the maze (F9,70=3.5, p<0.01) whereas it had the opposite effect in non-deprived animals. This close was without any effect on the number of closed entries in either group which precludes an effect on motor behaviour and points to a specific anxiolytic effect in the deprived females. Therefore, the modulatory effects of nicotine on anxiety are also vulnerable to the influence of deprivation state; a finding with great clinical relevance in terms of understanding women's motivation to smoke. Acknowledgements: These studies were supported in part by CONICIT/ULA, Venezuela.
References [1] Cheeta, $., lrvine, E.E., Tucci, S., Sandhu, L, File, S.E., 2001. In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats. Neuropsychopharm. 25, 601-607. [2] File, S.E., Fluck, E., Leahy, A., 2001. Nicotine has calming effects on stress-induced mood changes in females, but enhances aggressive mood in males. Int. J. Neuropsychopharm. 4, 371-376. [3] Perkins, K.A., Donny, E., Caggiula, R., 1999. Sex differences in nicotine effects and self administration: Review of animal and human evidence. Nic. Tob. Res. 1,301-315.
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Mirtazapine in posttraumatic stress disorder: Results of a placebo-controlled trial
K.M. Connor 1, J.R.T. Davidson 1, R.H. Weisle~ ,1, M.I. Butterfield3'1, C.D. Casat 4'1 . 1Department of Psychiatry
and Behauioral Sciences, Duke University Medical Center, Box 3812 2, Durham, NC 27710, US.A," 2priuate Practice, Raleigh, NC, US.A; 3 Veterans Administration Medical Center, Durham, NC, US.A, 4Carolinas Medical Center, Charlotte, NC, U.S.A. Objective: Posttraumatic stress disorder (PTSD) is a chronic, disabling, and widely prevalent disorder, with lifetime prevalence