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P.2.27 Effects of nicotine and ethanol on social play behaviour in adolescent rats
Behavioural pharmacology Reference(s) [1] Palucha, A., Pilc, A., 2007, Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther 115: 116–147. [2] Galici, R., Echemendia, N.G., Rodriguez, A.L., Conn, P.J., 2005, A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models. J Pharmacol Exp Ther 315: 1181– 1187.
P.2.26 Effect of MK-801 on sustained attention in rats I. Sukhanov1 ° , O.A. Dravolina1 , E.E. Zvartau1 , A.Y. Bespalov1 . 1 Pavlov Medical University, pharmacology, St. Petersburg, Russia Background: Schizophrenia encompasses cognitive impairment in areas of memory, attention and executive function. This cognitive impairment may be explained by sensory gating defect seen in studies of schizophrenic patients [1]. Psychotic patients appear to be flooded by stimuli whose intensity they cannot regulate through sensory gating mechanisms. The inability to filter out irrelevant information from the environment can induce information overloading of the brain and eventually results in cognitive deficits. Operant signal detection task is used for analysis sustained attention in animal research. The present study aimed to characterize the temporal dynamics of performance in operant signal detection task impaired by prototypic psychotomimetic agent, MK-801. Methods: Male Wistar rats were tested in standard two-lever operant boxes. The experimental procedure was adapted from previous studies [2]. After initial shaping, subjects were trained to learn an operant signal detection rule. The detection task is predicated on the idea of detecting the presence or absence of a target stimulus. The animals were trained to discriminate between “signal” − presentation of compound target stimulus that varied in length (10, 30, or 500 ms) and consisted of a signal lights illumination and 3 kHz tone (70 dB) − and “blank” types of trials presented in a pseudo-random order. Both signal and non-signal events were followed by 4-sec response window during which two levers were extended into the box and were remained active until a lever press occurred. Presses on one lever were reinforced following presentation of a signal (termed as a hit) whereas presses on the other lever were reinforced following a non-signal event. Daily sessions were divided into four blocks of 25 trials. Prior
S55
to the tests, rats were pretreated with MK-801 (0, 0.03, 0.1, 0.18 and 0.3 mg/kg, i.p.). Result: Under no-drug conditions, sustained attention performance was characterized by signal-length dependence of the hit rate (F(2,93) = 59.23, P < 0.001). Rats easily discriminated between “signal” and “blank” trials when duration of stimulus was 500 ms (percent of hits reached 100%). At 30-ms stimulus duration level, the percent of hits approached the 50% chance level. The animals did not recognize 10-ms signals, the percent of hits was about 30%. Pretreatment with MK-801 did not affect rats’ performance at shorter signal duration values (10 and 30 ms). In contrast, the ability of rats to detect long signals was highly sensitive to MK-801 pretreatment (F(3,31) = 4.18, P < 0.05). MK-801 (0.18 mg/kg) produced a decline in sustained attention performance that increased over the session and reached significance only in the final stages of the test (cognitive fatigue). Conclusion: The results of the present study suggest that MK-801 induced time-dependent impairment of sustained attention. These results further support earlier proposed view that sustained attention deficits induced by NMDA receptor blockade are caused by information overloading. Reference(s) [1] Quednow, B.B., Frommann, I., Berning, J., K¨uhn, K.U., Maier, W., Wagner, M., 2008, Impaired sensorimotor gating of the acoustic startle response in the prodrome of schizophrenia. Biol Psychiatry 64(9): 766–773. [2] McGaughy, J., Sarter, M., 1995, Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology 117(3): 340–357. P.2.27 Effects of nicotine and ethanol on social play behaviour in adolescent rats V. Trezza1 ° , P.J.J. Baarendse1 , L.J.M.L. Vanderschuren1 . 1 Rudolf Magnus Institute of Neuroscience, Dept of Neuroscience and Pharmacology, Utrecht, The Netherlands Nicotine and ethanol, alone or in combination, are widely abused by adolescents. The initial motivation to use these drugs is closely linked to social factors, such as peer pressure and the common belief that these drugs facilitate interactions with peers and group cohesion. Indeed, studies in rodents have shown that low doses of nicotine and ethanol increase social behavior in adolescent and young adult rats (Cheeta
S56
Behavioural pharmacology
et al., 2001; Varlinskaya and Spear, 2006). However, the neurobehavioral mechanisms underlying nicotineand ethanol-induced social facilitation are incompletely understood. To address this issue, we investigated the effect of nicotine and ethanol on social play behavior in adolescent rats. Social play is the most vigorous form of social interaction displayed by adolescent mammals, and it is of major importance for social and cognitive development. Consistent with its importance for development and survival, social play is rewarding for adolescent rats, and it is modulated through neural systems that also mediate the reinforcing properties of drugs of abuse. For example, we have recently shown that interacting opioid, cannabinoid and dopamine systems modulate the performance of social play (Trezza and Vanderschuren, 2008). Since opioid, cannabinoid and dopaminergic neurotransmission have been implicated in the reinforcing effects of nicotine and ethanol, we hypothesized that these neurotransmitter systems were also involved in the effects of nicotine and ethanol on social play. Four-week old, male Wistar rats were briefly socially isolated before testing, injected with drugs or vehicle, and tested in either a familiar or an unfamiliar test cage, with either a same drug- or vehicle-treated social partner. The results showed that both nicotine and ethanol increased social play behavior, at doses of 0.1 mg/kg and 0.25 g/kg, respectively. The increase in social play induced by nicotine and ethanol was dependent on the level of social activity of the social partner. Thus, nicotine and ethanol increased play solicitation. In addition, nicotineand ethanol-treated rats were more responsive to play solicitation, but only when reciprocated by an equally motivated partner, such as another drug-treated animal. While the effects of nicotine were similar in a familiar and an unfamiliar test cage, the effects of ethanol were more pronounced in an unfamiliar environment. Interestingly, at the doses that increased social play, nicotine and ethanol did not change locomotor activity and failed to alter behavior in the elevated plus-maze test. The effects of nicotine on social play were blocked by the opioid receptor antagonist naloxone, the CB1 cannabinoid receptor antagonist SR141716A, and the dopamine receptor antagonist alpha-flupenthixol. The effects of ethanol on social play were blocked by SR141716A, alphaflupenthixol, but not by naloxone. These results shed light on the neurobiological mechanisms underlying the social facilitatory effects of nicotine and ethanol: both drugs increased the rewarding and motivational properties of social play through dopamine- and cannabinoid-dependent mechanisms. However, opioid neurotransmission was differently involved in the effects of nicotine and ethanol on social play. Furthermore, our results reveal
a dissociation between the effects of these drugs on social behavior and their anxiolytic-like properties. Reference(s) [1] Cheeta, S., Irvine, E., File, S.E., 2001, Social isolation modifies nicotine’s effects in animal tests of anxiety. Br. J. Pharmacol. 132, 1389–1395. [2] Trezza, V., Vanderschuren, L.J.M.J., 2008, Bidirectional cannabinoid modulation of social behavior in adolescent rats. Psychopharmacology 197: 217–227. [3] Varlinskaya, E.I., Spear, L.P., 2006, Differences in the social consequences of ethanol emerge during the course of adolescence in rats: social facilitation, social inhibition, and anxiolysis. Dev. Psychobiol. 48: 146– 161. P.2.28 Lack of leptin signalling in the ventral tegmental area accelerates starvationinduced hyperactivity L.A.W. Verhagen1 ° , M.C.M. Luijendijk1 , M.W.A. de Backer1 , M. Koppers1 , K.M. Garner1 , R.J. DiLeone2 , R.A.H. Adan1 . 1 Rudolf Magnus Institute of Neuroscience, Dept of Neuroscience & Pharmacology, Utrecht, The Netherlands; 2 Yale University, Dept of Psychiatry Division of Molecular Psychiatry, New Haven, USA The discovery of leptin and its receptors unravelled the relation between adipose energy stores and neural circuits involved in energy balance. Leptin suppresses food intake and increases energy expenditure by stimulating thermogenesis and locomotor activity. Most research has focused on leptin receptor function within the hypothalamus. Recent data identified leptin receptors on dopaminergic neurons of the ventral tegmental area (VTA) in the mesolimbic midbrain, a brain area known to be involved in locomotion. DiLeone and researchers showed that leptin signaling directly to VTA neurons inhibited feeding behavior and that lack of leptin signaling in the VTA stimulated locomotor activity [1], which contrasts with the stimulatory effect on locomotor activity by peripheral and central administered leptin. Anorectic patients display high levels of physical activity which has been associated with low plasma leptin levels. Activity-based anorexia (ABA) is an animal model mimicking important characteristics of anorexia nervosa, in particular excessive exercise and reduced food consumption. Exposure to the ABA model leads to a chronic catabolic state caused by reduced food intake and increased running wheel activity (RWA). A study using the ABA model showed that chronic leptin treatment prevented ABA rats to develop hyperactivity
P.2.26 Effect of MK-801 on sustained attention in rats I. Sukhanov1 ° , O.A. Dravolina1 , E.E. Zvartau1 , A.Y. Bespalov1 . 1 Pavlov Medical University, pharmacology, St. Petersburg, Russia Background: Schizophrenia encompasses cognitive impairment in areas of memory, attention and executive function. This cognitive impairment may be explained by sensory gating defect seen in studies of schizophrenic patients [1]. Psychotic patients appear to be flooded by stimuli whose intensity they cannot regulate through sensory gating mechanisms. The inability to filter out irrelevant information from the environment can induce information overloading of the brain and eventually results in cognitive deficits. Operant signal detection task is used for analysis sustained attention in animal research. The present study aimed to characterize the temporal dynamics of performance in operant signal detection task impaired by prototypic psychotomimetic agent, MK-801. Methods: Male Wistar rats were tested in standard two-lever operant boxes. The experimental procedure was adapted from previous studies [2]. After initial shaping, subjects were trained to learn an operant signal detection rule. The detection task is predicated on the idea of detecting the presence or absence of a target stimulus. The animals were trained to discriminate between “signal” − presentation of compound target stimulus that varied in length (10, 30, or 500 ms) and consisted of a signal lights illumination and 3 kHz tone (70 dB) − and “blank” types of trials presented in a pseudo-random order. Both signal and non-signal events were followed by 4-sec response window during which two levers were extended into the box and were remained active until a lever press occurred. Presses on one lever were reinforced following presentation of a signal (termed as a hit) whereas presses on the other lever were reinforced following a non-signal event. Daily sessions were divided into four blocks of 25 trials. Prior
S55
to the tests, rats were pretreated with MK-801 (0, 0.03, 0.1, 0.18 and 0.3 mg/kg, i.p.). Result: Under no-drug conditions, sustained attention performance was characterized by signal-length dependence of the hit rate (F(2,93) = 59.23, P < 0.001). Rats easily discriminated between “signal” and “blank” trials when duration of stimulus was 500 ms (percent of hits reached 100%). At 30-ms stimulus duration level, the percent of hits approached the 50% chance level. The animals did not recognize 10-ms signals, the percent of hits was about 30%. Pretreatment with MK-801 did not affect rats’ performance at shorter signal duration values (10 and 30 ms). In contrast, the ability of rats to detect long signals was highly sensitive to MK-801 pretreatment (F(3,31) = 4.18, P < 0.05). MK-801 (0.18 mg/kg) produced a decline in sustained attention performance that increased over the session and reached significance only in the final stages of the test (cognitive fatigue). Conclusion: The results of the present study suggest that MK-801 induced time-dependent impairment of sustained attention. These results further support earlier proposed view that sustained attention deficits induced by NMDA receptor blockade are caused by information overloading. Reference(s) [1] Quednow, B.B., Frommann, I., Berning, J., K¨uhn, K.U., Maier, W., Wagner, M., 2008, Impaired sensorimotor gating of the acoustic startle response in the prodrome of schizophrenia. Biol Psychiatry 64(9): 766–773. [2] McGaughy, J., Sarter, M., 1995, Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology 117(3): 340–357. P.2.27 Effects of nicotine and ethanol on social play behaviour in adolescent rats V. Trezza1 ° , P.J.J. Baarendse1 , L.J.M.L. Vanderschuren1 . 1 Rudolf Magnus Institute of Neuroscience, Dept of Neuroscience and Pharmacology, Utrecht, The Netherlands Nicotine and ethanol, alone or in combination, are widely abused by adolescents. The initial motivation to use these drugs is closely linked to social factors, such as peer pressure and the common belief that these drugs facilitate interactions with peers and group cohesion. Indeed, studies in rodents have shown that low doses of nicotine and ethanol increase social behavior in adolescent and young adult rats (Cheeta
S56
Behavioural pharmacology
et al., 2001; Varlinskaya and Spear, 2006). However, the neurobehavioral mechanisms underlying nicotineand ethanol-induced social facilitation are incompletely understood. To address this issue, we investigated the effect of nicotine and ethanol on social play behavior in adolescent rats. Social play is the most vigorous form of social interaction displayed by adolescent mammals, and it is of major importance for social and cognitive development. Consistent with its importance for development and survival, social play is rewarding for adolescent rats, and it is modulated through neural systems that also mediate the reinforcing properties of drugs of abuse. For example, we have recently shown that interacting opioid, cannabinoid and dopamine systems modulate the performance of social play (Trezza and Vanderschuren, 2008). Since opioid, cannabinoid and dopaminergic neurotransmission have been implicated in the reinforcing effects of nicotine and ethanol, we hypothesized that these neurotransmitter systems were also involved in the effects of nicotine and ethanol on social play. Four-week old, male Wistar rats were briefly socially isolated before testing, injected with drugs or vehicle, and tested in either a familiar or an unfamiliar test cage, with either a same drug- or vehicle-treated social partner. The results showed that both nicotine and ethanol increased social play behavior, at doses of 0.1 mg/kg and 0.25 g/kg, respectively. The increase in social play induced by nicotine and ethanol was dependent on the level of social activity of the social partner. Thus, nicotine and ethanol increased play solicitation. In addition, nicotineand ethanol-treated rats were more responsive to play solicitation, but only when reciprocated by an equally motivated partner, such as another drug-treated animal. While the effects of nicotine were similar in a familiar and an unfamiliar test cage, the effects of ethanol were more pronounced in an unfamiliar environment. Interestingly, at the doses that increased social play, nicotine and ethanol did not change locomotor activity and failed to alter behavior in the elevated plus-maze test. The effects of nicotine on social play were blocked by the opioid receptor antagonist naloxone, the CB1 cannabinoid receptor antagonist SR141716A, and the dopamine receptor antagonist alpha-flupenthixol. The effects of ethanol on social play were blocked by SR141716A, alphaflupenthixol, but not by naloxone. These results shed light on the neurobiological mechanisms underlying the social facilitatory effects of nicotine and ethanol: both drugs increased the rewarding and motivational properties of social play through dopamine- and cannabinoid-dependent mechanisms. However, opioid neurotransmission was differently involved in the effects of nicotine and ethanol on social play. Furthermore, our results reveal
a dissociation between the effects of these drugs on social behavior and their anxiolytic-like properties. Reference(s) [1] Cheeta, S., Irvine, E., File, S.E., 2001, Social isolation modifies nicotine’s effects in animal tests of anxiety. Br. J. Pharmacol. 132, 1389–1395. [2] Trezza, V., Vanderschuren, L.J.M.J., 2008, Bidirectional cannabinoid modulation of social behavior in adolescent rats. Psychopharmacology 197: 217–227. [3] Varlinskaya, E.I., Spear, L.P., 2006, Differences in the social consequences of ethanol emerge during the course of adolescence in rats: social facilitation, social inhibition, and anxiolysis. Dev. Psychobiol. 48: 146– 161. P.2.28 Lack of leptin signalling in the ventral tegmental area accelerates starvationinduced hyperactivity L.A.W. Verhagen1 ° , M.C.M. Luijendijk1 , M.W.A. de Backer1 , M. Koppers1 , K.M. Garner1 , R.J. DiLeone2 , R.A.H. Adan1 . 1 Rudolf Magnus Institute of Neuroscience, Dept of Neuroscience & Pharmacology, Utrecht, The Netherlands; 2 Yale University, Dept of Psychiatry Division of Molecular Psychiatry, New Haven, USA The discovery of leptin and its receptors unravelled the relation between adipose energy stores and neural circuits involved in energy balance. Leptin suppresses food intake and increases energy expenditure by stimulating thermogenesis and locomotor activity. Most research has focused on leptin receptor function within the hypothalamus. Recent data identified leptin receptors on dopaminergic neurons of the ventral tegmental area (VTA) in the mesolimbic midbrain, a brain area known to be involved in locomotion. DiLeone and researchers showed that leptin signaling directly to VTA neurons inhibited feeding behavior and that lack of leptin signaling in the VTA stimulated locomotor activity [1], which contrasts with the stimulatory effect on locomotor activity by peripheral and central administered leptin. Anorectic patients display high levels of physical activity which has been associated with low plasma leptin levels. Activity-based anorexia (ABA) is an animal model mimicking important characteristics of anorexia nervosa, in particular excessive exercise and reduced food consumption. Exposure to the ABA model leads to a chronic catabolic state caused by reduced food intake and increased running wheel activity (RWA). A study using the ABA model showed that chronic leptin treatment prevented ABA rats to develop hyperactivity