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P.2.07 Muscarinic transmission in the entorhinal cortex mediates inattention to irrelevant stimuli: relevance to schizophrenia
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Behavioural pharmacology
task, particularly in the late phase of training and during recall (5 days after the last training session), where all groups pre-treated with MDMA even at the lowest dose (1 mg/kg), showed a reduced ratio of conditioned changes when compared to the saline group. When MDMA was administrated after training no differences were evidenced during the recall test. A reduction of DAT binding sites in the striatum of mice treated with MDMA (40.46±3.83 fmol/mg) versus saline controls (80.74±7.71 fmol/mg) (p < 0.001) was observed 4 days after the last treatment. However, no differences in DAT binding sites were observed 23 days after last injection. Conclusions: In this study, we show for the first time the acute and enduring effects of different schedules of MDMA treatment on learning and recall of an active avoidance task in mice. MDMA modifies the acquisition and execution of active avoidance in mice and induces lasting effects on acquisition and recall tasks. Some of the deficits in learning and memory were produced at low doses, and were not related to changes in striatal DAT binding sites. Reference(s) [1] Kalechstein AD, De La Garza R, Mahoney JJ, Fantegrossi WE, Newton TF, 2007, MDMA use and neurocognition: a meta-analytic review. Psychopharmacology 189, 531–537. [2] Broening HW, Morford LL, Inman-Wood SL, Fukumura M, Vorhees CV, 2001, 3,4-methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development. J Neurosci 21, 3228–3235. [3] Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW, 1988, (±)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. J Am Med Assoc 260, 51−55. P.2.07 Muscarinic transmission in the entorhinal cortex mediates inattention to irrelevant stimuli: relevance to schizophrenia S. Barak1 ° , I. Weiner1 . 1 Tel-Aviv University, Department of Psychology, Tel-Aviv, Israel Background: Latent inhibition (LI) is a cross-species phenomenon manifested as the poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus. LI is considered to index the ability to ignore, or to in-attend to irrelevant stimuli, and treatment-induced disruption of LI has been used extensively as a model of schizophrenia. Lesion studies have indicated that the
entorhinal cortex (EC) plays a critical role in LI, in consistence with findings of EC abnormalities in schizophrenia patients. Moreover, temporal inactivation of EC confined to the pre-exposure stage of the LI procedure has been shown to disrupt LI (Jeanblanc et al. 2004; Seillier et al. 2007), suggesting that the EC specifically subserves the acquisition of inattention to the pre-exposed stimulus. Our recent finding that systemic administration of the muscarinic antagonist scopolamine also disrupted LI when injected in the pre-exposure but not in the conditioning stage (Barak and Weiner 2007), has led us to test the hypothesis that cholinergic transmission in the EC is responsible for the effects of EC manipulations on LI. Here, Experiment 1 tested the effects of intra-EC scopolamine infusion before the pre-exposure stage on LI, whereas Experiment 2 tested the effects of scopolamine infusion into the EC before the conditioning stage, or before both stages, on LI. Materials and Methods: Three months old male Wistar rats were implanted with guide cannulae aiming the EC. Following a recovery period, LI was measured in a thirst motivated conditioned emotional response (CER) procedure consisting of 3 stages: pre-exposure, in which rats received 40 tone pre-exposures (pre-exposed) or were confined to the cage without tone presentation (nonpre-exposed); conditioning, in which all rats received 2 tone-shock pairings; and test, in which LI was indexed by suppression of drinking in response to the tone. LI is manifested in lower suppression of the pre-exposed compared to the non-pre-exposed groups. Scopolamine (1 or 10 mg per hemisphere) was infused into the EC prior to the pre-exposure stage (Experiment 1), the conditioning stage, or both stages (Experiment 2). Results: We found that muscarinic blockade in the EC disrupted LI when introduced in pre-exposure (Experiment 1; p < 0.05) or in both pre-exposure and conditioning (Experiment 2; P < 0.05), but not if confined to conditioning (Experiment 2; P > 0.05). Conclusion: While cholinergic innervation of the EC has long been postulated to be involved in the attention to, and encoding of, novel stimuli, our results provide first evidence that it also plays a crucial role in the development of inattention to stimuli. Moreover, our results suggest that muscarinic receptors in the EC mediate acquisition of inattention. Thus, muscarinic dysfunction in the EC may underlie not only working memory deficits and impaired ability to maintain attention to significant stimuli, but also distractibility caused by impaired ability to in-attend irrelevant stimuli, seen in disorders such as schizophrenia. Reference(s) [1] Barak S, Weiner I, 2007, Scopolamine induces disruption of latent inhibition which is prevented
Behavioural pharmacology by antipsychotic drugs and an acetylcholinesterase inhibitor. Neuropsychopharmacology 32, 989−99. [2] Jeanblanc J, Peterschmitt Y, Hoeltzel A, Louilot A, 2004, Influence of the entorhinal cortex on accumbal and striatal dopaminergic responses in a latent inhibition paradigm. Neuroscience 128, 187–200. [3] Seillier A, Dieu Y, Herbeaux K, Di Scala G, Will B, Majchrzak M, 2007, Evidence for a critical role of entorhinal cortex at pre-exposure for latent inhibition disruption in rats. Hippocampus 17, 220−6.
P.2.08 Attention in adolescents recovered from major depression P. Wilkinson1 ° , I. Goodyer1 . 1 University of Cambridge, Department of Developmental Psychiatry, Cambridge, United Kingdom Introduction: Neurocognitive impairment has been proposed as a potential endophenotype (genetically-sensitive intermediate biological marker) for depression. Brainderived neurotrophic factor promoter genotype (Val66Met) is associated with attentional switching ability among adults with bipolar disorder1 . Depressed adolescents have impaired attentional switching and selective attention compared with healthy controls, as measured by the Test of Everyday Attention for Children (TEA-Ch)2 . A design using currently-depressed participants is not able to demonstrate whether the attentional impairments are due to the depressed state, or are a trait that is also present outside of depressive episodes, and so a potential endophenotype. Studies of adults recovered from depression have demonstrated recovered-control differences in attentional switching, sustained attention and selective attention. Results of these studies may have been confounded by current antidepressant use. The only study to exclude participants taking antidepressants demonstrated a recovered-control difference in sustained attention, but no difference in attentional switching3 . Method: 13 adolescents recovered from an episode of DSM-IV major depression (less than 2 symptoms for at least 8 weeks) were compared with 38 never depressed healthy controls. Attention was measured by the TEA-Ch. Age and gender-scaled standard scores were used, with 10 representing population mean, 3 population standard deviation, and higher scores representing better performance. Groups were compared on cognitive ability by Ravens Standard Progressive Matrices (RSPM, using age-scaled centile band) and the school standard attainment tests (SATS) at age 10/11. Selfrated depressive symptoms were measured using the Mood and Feelings Questionnaire (MFQ).
S43
Results: See the table. Controls (n = 38) Mean Gender, male:female Age (years) SATS RSPM band MFQ TEA-Ch latency Switching Selective TEA-Ch accuracy Switching Selective Sustained
s.d.
Recovered from depression (n = 13) Mean s.d.
11(29%):27(71%) 14.8 1.0 13.6 (n = 37) 1.6 4.6 1.7 5.1 4.2
3(23%):10(77%) 16.0 1.2 13.3 (n = 10) 2.3 5.0 1.6 5.4 4.4
9.4 10.5
1.8 1.9
7.8 9.6
3.9 4.5
10.7 9.9 9.4
2.7 3.1 3.1
8.7 10.4 6.2
4.3 2.6 3.7
There were no significant differences in measures of intelligence, gender nor current depressive symptoms (all p > 0.25). Recovered-depressed were significantly older than controls (p = 0.001). Age was added as covariate to MANCOVAs. MANCOVA for latency demonstrated no significant recovered-control differences (Main effect, Pillai’s F(df 2,47) = 0.45, p = 0.6; switching p = 0.9, selective p = 0.4). MANCOVA for accuracy demonstrated that recovered-depressed were significantly less accurate than controls, particularly for sustained attention (Main effect, Pillai’s F(df 3,46) = 2.8, p = 0.049; sustained p = 0.017, switching p = 0.088, selective, p = 0.8). Antidepressants may have confounded the results. Accuracy was lower on attentional tasks among the four participants not recently taking SSRIs compared with the eight currently taking them [mean (sd) sustained: 6.8 (3.6) vs 8.4 (2.9); switching: 7.5 (1.9) vs 9.9 (3.6)]. Conclusions: Adolescents recovered from an episode of unipolar major depression had significantly reduced accuracy on a test of sustained attention and a trend for reduced accuracy on a test of attentional switching compared with healthy controls. These results were not due to confounding effects of antidepressants. These medication-independent results on sustained attention replicate those of Weiland-Fiedler3 . If replicated in larger, medication-free samples, these neuropsychological variables may be worth investigating as endophenotypes of depression. Reference(s) [1] Rybakowski JK, Czerski PM, Skibinska M, Hauser J, 2003, Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 5(6), 468−72.
Behavioural pharmacology
task, particularly in the late phase of training and during recall (5 days after the last training session), where all groups pre-treated with MDMA even at the lowest dose (1 mg/kg), showed a reduced ratio of conditioned changes when compared to the saline group. When MDMA was administrated after training no differences were evidenced during the recall test. A reduction of DAT binding sites in the striatum of mice treated with MDMA (40.46±3.83 fmol/mg) versus saline controls (80.74±7.71 fmol/mg) (p < 0.001) was observed 4 days after the last treatment. However, no differences in DAT binding sites were observed 23 days after last injection. Conclusions: In this study, we show for the first time the acute and enduring effects of different schedules of MDMA treatment on learning and recall of an active avoidance task in mice. MDMA modifies the acquisition and execution of active avoidance in mice and induces lasting effects on acquisition and recall tasks. Some of the deficits in learning and memory were produced at low doses, and were not related to changes in striatal DAT binding sites. Reference(s) [1] Kalechstein AD, De La Garza R, Mahoney JJ, Fantegrossi WE, Newton TF, 2007, MDMA use and neurocognition: a meta-analytic review. Psychopharmacology 189, 531–537. [2] Broening HW, Morford LL, Inman-Wood SL, Fukumura M, Vorhees CV, 2001, 3,4-methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development. J Neurosci 21, 3228–3235. [3] Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW, 1988, (±)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. J Am Med Assoc 260, 51−55. P.2.07 Muscarinic transmission in the entorhinal cortex mediates inattention to irrelevant stimuli: relevance to schizophrenia S. Barak1 ° , I. Weiner1 . 1 Tel-Aviv University, Department of Psychology, Tel-Aviv, Israel Background: Latent inhibition (LI) is a cross-species phenomenon manifested as the poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus. LI is considered to index the ability to ignore, or to in-attend to irrelevant stimuli, and treatment-induced disruption of LI has been used extensively as a model of schizophrenia. Lesion studies have indicated that the
entorhinal cortex (EC) plays a critical role in LI, in consistence with findings of EC abnormalities in schizophrenia patients. Moreover, temporal inactivation of EC confined to the pre-exposure stage of the LI procedure has been shown to disrupt LI (Jeanblanc et al. 2004; Seillier et al. 2007), suggesting that the EC specifically subserves the acquisition of inattention to the pre-exposed stimulus. Our recent finding that systemic administration of the muscarinic antagonist scopolamine also disrupted LI when injected in the pre-exposure but not in the conditioning stage (Barak and Weiner 2007), has led us to test the hypothesis that cholinergic transmission in the EC is responsible for the effects of EC manipulations on LI. Here, Experiment 1 tested the effects of intra-EC scopolamine infusion before the pre-exposure stage on LI, whereas Experiment 2 tested the effects of scopolamine infusion into the EC before the conditioning stage, or before both stages, on LI. Materials and Methods: Three months old male Wistar rats were implanted with guide cannulae aiming the EC. Following a recovery period, LI was measured in a thirst motivated conditioned emotional response (CER) procedure consisting of 3 stages: pre-exposure, in which rats received 40 tone pre-exposures (pre-exposed) or were confined to the cage without tone presentation (nonpre-exposed); conditioning, in which all rats received 2 tone-shock pairings; and test, in which LI was indexed by suppression of drinking in response to the tone. LI is manifested in lower suppression of the pre-exposed compared to the non-pre-exposed groups. Scopolamine (1 or 10 mg per hemisphere) was infused into the EC prior to the pre-exposure stage (Experiment 1), the conditioning stage, or both stages (Experiment 2). Results: We found that muscarinic blockade in the EC disrupted LI when introduced in pre-exposure (Experiment 1; p < 0.05) or in both pre-exposure and conditioning (Experiment 2; P < 0.05), but not if confined to conditioning (Experiment 2; P > 0.05). Conclusion: While cholinergic innervation of the EC has long been postulated to be involved in the attention to, and encoding of, novel stimuli, our results provide first evidence that it also plays a crucial role in the development of inattention to stimuli. Moreover, our results suggest that muscarinic receptors in the EC mediate acquisition of inattention. Thus, muscarinic dysfunction in the EC may underlie not only working memory deficits and impaired ability to maintain attention to significant stimuli, but also distractibility caused by impaired ability to in-attend irrelevant stimuli, seen in disorders such as schizophrenia. Reference(s) [1] Barak S, Weiner I, 2007, Scopolamine induces disruption of latent inhibition which is prevented
Behavioural pharmacology by antipsychotic drugs and an acetylcholinesterase inhibitor. Neuropsychopharmacology 32, 989−99. [2] Jeanblanc J, Peterschmitt Y, Hoeltzel A, Louilot A, 2004, Influence of the entorhinal cortex on accumbal and striatal dopaminergic responses in a latent inhibition paradigm. Neuroscience 128, 187–200. [3] Seillier A, Dieu Y, Herbeaux K, Di Scala G, Will B, Majchrzak M, 2007, Evidence for a critical role of entorhinal cortex at pre-exposure for latent inhibition disruption in rats. Hippocampus 17, 220−6.
P.2.08 Attention in adolescents recovered from major depression P. Wilkinson1 ° , I. Goodyer1 . 1 University of Cambridge, Department of Developmental Psychiatry, Cambridge, United Kingdom Introduction: Neurocognitive impairment has been proposed as a potential endophenotype (genetically-sensitive intermediate biological marker) for depression. Brainderived neurotrophic factor promoter genotype (Val66Met) is associated with attentional switching ability among adults with bipolar disorder1 . Depressed adolescents have impaired attentional switching and selective attention compared with healthy controls, as measured by the Test of Everyday Attention for Children (TEA-Ch)2 . A design using currently-depressed participants is not able to demonstrate whether the attentional impairments are due to the depressed state, or are a trait that is also present outside of depressive episodes, and so a potential endophenotype. Studies of adults recovered from depression have demonstrated recovered-control differences in attentional switching, sustained attention and selective attention. Results of these studies may have been confounded by current antidepressant use. The only study to exclude participants taking antidepressants demonstrated a recovered-control difference in sustained attention, but no difference in attentional switching3 . Method: 13 adolescents recovered from an episode of DSM-IV major depression (less than 2 symptoms for at least 8 weeks) were compared with 38 never depressed healthy controls. Attention was measured by the TEA-Ch. Age and gender-scaled standard scores were used, with 10 representing population mean, 3 population standard deviation, and higher scores representing better performance. Groups were compared on cognitive ability by Ravens Standard Progressive Matrices (RSPM, using age-scaled centile band) and the school standard attainment tests (SATS) at age 10/11. Selfrated depressive symptoms were measured using the Mood and Feelings Questionnaire (MFQ).
S43
Results: See the table. Controls (n = 38) Mean Gender, male:female Age (years) SATS RSPM band MFQ TEA-Ch latency Switching Selective TEA-Ch accuracy Switching Selective Sustained
s.d.
Recovered from depression (n = 13) Mean s.d.
11(29%):27(71%) 14.8 1.0 13.6 (n = 37) 1.6 4.6 1.7 5.1 4.2
3(23%):10(77%) 16.0 1.2 13.3 (n = 10) 2.3 5.0 1.6 5.4 4.4
9.4 10.5
1.8 1.9
7.8 9.6
3.9 4.5
10.7 9.9 9.4
2.7 3.1 3.1
8.7 10.4 6.2
4.3 2.6 3.7
There were no significant differences in measures of intelligence, gender nor current depressive symptoms (all p > 0.25). Recovered-depressed were significantly older than controls (p = 0.001). Age was added as covariate to MANCOVAs. MANCOVA for latency demonstrated no significant recovered-control differences (Main effect, Pillai’s F(df 2,47) = 0.45, p = 0.6; switching p = 0.9, selective p = 0.4). MANCOVA for accuracy demonstrated that recovered-depressed were significantly less accurate than controls, particularly for sustained attention (Main effect, Pillai’s F(df 3,46) = 2.8, p = 0.049; sustained p = 0.017, switching p = 0.088, selective, p = 0.8). Antidepressants may have confounded the results. Accuracy was lower on attentional tasks among the four participants not recently taking SSRIs compared with the eight currently taking them [mean (sd) sustained: 6.8 (3.6) vs 8.4 (2.9); switching: 7.5 (1.9) vs 9.9 (3.6)]. Conclusions: Adolescents recovered from an episode of unipolar major depression had significantly reduced accuracy on a test of sustained attention and a trend for reduced accuracy on a test of attentional switching compared with healthy controls. These results were not due to confounding effects of antidepressants. These medication-independent results on sustained attention replicate those of Weiland-Fiedler3 . If replicated in larger, medication-free samples, these neuropsychological variables may be worth investigating as endophenotypes of depression. Reference(s) [1] Rybakowski JK, Czerski PM, Skibinska M, Hauser J, 2003, Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 5(6), 468−72.