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EFFECTS OF SYSTEMIC PHENCYCLIDINE ON NEURONAL ACTIVITY OF VENTRAL TEGMENTAL AREA IN A CLASSICAL CONDITIONING PARADIGM
Abstracts
hydrocannabinol (THC) and the potentially anti-psychotic-like cannabidiol (CBD). Thus, we investigated the behavioural effects of chronic adolescent THC exposure and chronic adult cannabidiol treatment in heterozygous transmembrane domain neuregulin 1 mutant mice (Nrg1 HET). NRG1 is a susceptibility gene for schizophrenia. Methods: Adolescent male Nrg1 HET mice and their wild type-like (WT) littermates received vehicle or THC (10 mg/kg i.p.) for 21 days whereas an adult cohort was treated with vehicle or CBD (1, 50, 100 mg/kg). On the first day of treatment and throughout chronic treatment, behavioural tests were performed to assess locomotion, anxiety, prepulse inhibition, cognition and memory as well as social interaction. Results: Nrg1 HET and WT mice were equally sensitive to the locomotor suppressant effects of adolescent THC. THC decreased the startle response, but there were no main effects of treatment or genotype on prepulse inhibition. THC had cognition-impairing and social interaction-suppressing effects only in WT mice. Chronic exposure to high dose CBD attenuated the hyperlocomotor activity and prepulse inhibition deficit observed in vehicle-treated Nrg1 HET mice. Discussion: Male Nrg1 HET mice exposed to THC during early adolescence appear to be less sensitive to some of its behavioural effects than WT mice. Importantly, chronic treatment with CBD could partially rescue some of the behavioural abnormalities observed in this mouse model for Nrg1.
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one of the two tones (CS+) was followed by the unconditioned stimulus. Intracranial stimulation to the medial forebrain bundle was given as an unconditioned stimulus immediately after cessation of the target tone. The CS+ tone was presented with probability 30% of all trials. The total number of tone presentation (trials) was 400 in one conditioning session. Recording sessions were performed on the next day after conditioning sessions. After the first recording session, animals received an intraperitoneal injection of a subanesthetic dose of 10 mg/kg PCP or 1 ml/kg physiological saline. The second and third session was started 15 and 180 min after injection of PCP or saline. The total number of tone presentation (trials) was 200 in one recording session. To analyze the firing activity of recorded neurons for conditioned auditory stimuli, we generated cumulative peristimulus time histograms (PSTHs, 10 msec bin width) for each neuron sampled from 2 sec before to 3 sec after each tone presentation. The baseline period was defined as the 2 sec period preceding the tone presentation. Results: Most of VTA neurons exhibited clear phasic excitation to CS+. Systemic PCP considerably reduced such phasic responses to both conditioned stimuli (CS+, CS-), regardless of whether the spontaneous activity of neurons was affected by PCP or not. The responsiveness of neurons to CS+ recovered 180 min after PCP injection. Discussion: Our present results indicate that PCP may affect firing activity of VTA neurons, which are involved in motivation and learning. Therefore, repeated-alteration of VTA activity by repeated administration of PCP may induce long-lasting changes in neural circuits to induce disturbed motivation.
doi:10.1016/j.schres.2010.02.705 doi:10.1016/j.schres.2010.02.706
Poster 211 EFFECTS OF SYSTEMIC PHENCYCLIDINE ON NEURONAL ACTIVITY OF VENTRAL TEGMENTAL AREA IN A CLASSICAL CONDITIONING PARADIGM Tadahiro Katayama, Eiichi Jodo, Masahiro Okamoto, Yoshiaki Suzuki, Ken-Yo Hoshino, Yukihiko Kayama Dept. of Neurophysiology, Neuropsychiatry, Fukushima Medical University School of Medicine Fukushima, Fukushima, Japan Background: Patients with schizophrenia exhibit deficits in motivation and learning, which suggests impairment in the reward system. Many studies have reported that phencyclidine (PCP) also induces schizophrenia-like negative symptoms, such as reduced motivation, blunted affect and social withdrawal in both human and animals. PCP-administered animals are therefore considered to be a reliable pharmacological model of schizophrenia. The pathophysiology of PCP-induced disturbances in motivation and learning, however, remains still unknown. Previous studies indicated that the dopaminergic neurons in the ventral tegmental area (VTA) play a pivotal role in the development of reward-associated learning and motivation. However, there is no study so far that examines the effects of PCP on firing activity of VTA neurons in a classical conditioning paradigm. In the present study we recorded for the first time the unit activity of VTA neurons in freely-moving rats before and after systemic administration of PCP in a classical conditioning paradigm. Methods: Adult male Sprague–Dawley rats were used as subjects. A commercial micromanipulator with a tungsten microelectrode was used to record single-unit activity in the VTA. The recording electrode was lowered unilaterally into the right VTA, and the micromanipulator was then fixed onto the cranium using dental cement. Conditioning sessions were started at least 2 weeks after surgery. Two tones (1000 Hz, 2000 Hz) were sequentially presented, in which
Poster 212 THE EFFECTS OF THE CANNABINOID CB2 RECEPTOR ANTAGONIST, AM630, ON ISOLATION REARING-INDUCED BEHAVIOURAL DEFICITS IN RATS Asma Khan, David A. Kendall, Kevin C.F. Fone School of Biomedical Sciences, Institute of Neuroscience, Queen's Medical Centre, University of Nottingham Nottingham, Nottinghamshire, United Kingdom Background: Exposure to early-life adversity is thought to be a risk factor for the development of schizophrenia. In the last decade much attention has also focused on the potential role of endocannabinoids (ECs) in the pathogenesis of schizophrenia. The present study examined whether the CB2 receptor selective antagonist AM630 (6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]1H-indol-3-y l](4-methoxyphenyl)methanone; CB2 antagonist) can reverse the behavioural defects elicited by rearing rats in social isolation (a developmental model of schizophrenia). Methods: Male Lister-hooded rats were weaned on postnatal day (PND) 22-24 and half of each litter either group housed (3-4/ cage; n = 9) or socially isolated (SI; n = 9) for 5 weeks, during which they received minimal handling but had visual, auditory and olfactory interaction with each other. Rats were injected with either AM630 (1 mg/kg; i.p; n = 10) or saline once daily for 7 consecutive days in the first week of isolation. On PND 61 novel cage-induced locomotor activity (LMA) was recorded in automated infrared activity boxes. On PND 66 all rats were habituated to individual test arenas for 1 hr and on day 67 two trial novel object recognition (NOR) was assessed in same arena using a 2 h intra trial interval (ITI). On PND 81 the conditioned emotional response (CER) was monitored by placing individual
hydrocannabinol (THC) and the potentially anti-psychotic-like cannabidiol (CBD). Thus, we investigated the behavioural effects of chronic adolescent THC exposure and chronic adult cannabidiol treatment in heterozygous transmembrane domain neuregulin 1 mutant mice (Nrg1 HET). NRG1 is a susceptibility gene for schizophrenia. Methods: Adolescent male Nrg1 HET mice and their wild type-like (WT) littermates received vehicle or THC (10 mg/kg i.p.) for 21 days whereas an adult cohort was treated with vehicle or CBD (1, 50, 100 mg/kg). On the first day of treatment and throughout chronic treatment, behavioural tests were performed to assess locomotion, anxiety, prepulse inhibition, cognition and memory as well as social interaction. Results: Nrg1 HET and WT mice were equally sensitive to the locomotor suppressant effects of adolescent THC. THC decreased the startle response, but there were no main effects of treatment or genotype on prepulse inhibition. THC had cognition-impairing and social interaction-suppressing effects only in WT mice. Chronic exposure to high dose CBD attenuated the hyperlocomotor activity and prepulse inhibition deficit observed in vehicle-treated Nrg1 HET mice. Discussion: Male Nrg1 HET mice exposed to THC during early adolescence appear to be less sensitive to some of its behavioural effects than WT mice. Importantly, chronic treatment with CBD could partially rescue some of the behavioural abnormalities observed in this mouse model for Nrg1.
391
one of the two tones (CS+) was followed by the unconditioned stimulus. Intracranial stimulation to the medial forebrain bundle was given as an unconditioned stimulus immediately after cessation of the target tone. The CS+ tone was presented with probability 30% of all trials. The total number of tone presentation (trials) was 400 in one conditioning session. Recording sessions were performed on the next day after conditioning sessions. After the first recording session, animals received an intraperitoneal injection of a subanesthetic dose of 10 mg/kg PCP or 1 ml/kg physiological saline. The second and third session was started 15 and 180 min after injection of PCP or saline. The total number of tone presentation (trials) was 200 in one recording session. To analyze the firing activity of recorded neurons for conditioned auditory stimuli, we generated cumulative peristimulus time histograms (PSTHs, 10 msec bin width) for each neuron sampled from 2 sec before to 3 sec after each tone presentation. The baseline period was defined as the 2 sec period preceding the tone presentation. Results: Most of VTA neurons exhibited clear phasic excitation to CS+. Systemic PCP considerably reduced such phasic responses to both conditioned stimuli (CS+, CS-), regardless of whether the spontaneous activity of neurons was affected by PCP or not. The responsiveness of neurons to CS+ recovered 180 min after PCP injection. Discussion: Our present results indicate that PCP may affect firing activity of VTA neurons, which are involved in motivation and learning. Therefore, repeated-alteration of VTA activity by repeated administration of PCP may induce long-lasting changes in neural circuits to induce disturbed motivation.
doi:10.1016/j.schres.2010.02.705 doi:10.1016/j.schres.2010.02.706
Poster 211 EFFECTS OF SYSTEMIC PHENCYCLIDINE ON NEURONAL ACTIVITY OF VENTRAL TEGMENTAL AREA IN A CLASSICAL CONDITIONING PARADIGM Tadahiro Katayama, Eiichi Jodo, Masahiro Okamoto, Yoshiaki Suzuki, Ken-Yo Hoshino, Yukihiko Kayama Dept. of Neurophysiology, Neuropsychiatry, Fukushima Medical University School of Medicine Fukushima, Fukushima, Japan Background: Patients with schizophrenia exhibit deficits in motivation and learning, which suggests impairment in the reward system. Many studies have reported that phencyclidine (PCP) also induces schizophrenia-like negative symptoms, such as reduced motivation, blunted affect and social withdrawal in both human and animals. PCP-administered animals are therefore considered to be a reliable pharmacological model of schizophrenia. The pathophysiology of PCP-induced disturbances in motivation and learning, however, remains still unknown. Previous studies indicated that the dopaminergic neurons in the ventral tegmental area (VTA) play a pivotal role in the development of reward-associated learning and motivation. However, there is no study so far that examines the effects of PCP on firing activity of VTA neurons in a classical conditioning paradigm. In the present study we recorded for the first time the unit activity of VTA neurons in freely-moving rats before and after systemic administration of PCP in a classical conditioning paradigm. Methods: Adult male Sprague–Dawley rats were used as subjects. A commercial micromanipulator with a tungsten microelectrode was used to record single-unit activity in the VTA. The recording electrode was lowered unilaterally into the right VTA, and the micromanipulator was then fixed onto the cranium using dental cement. Conditioning sessions were started at least 2 weeks after surgery. Two tones (1000 Hz, 2000 Hz) were sequentially presented, in which
Poster 212 THE EFFECTS OF THE CANNABINOID CB2 RECEPTOR ANTAGONIST, AM630, ON ISOLATION REARING-INDUCED BEHAVIOURAL DEFICITS IN RATS Asma Khan, David A. Kendall, Kevin C.F. Fone School of Biomedical Sciences, Institute of Neuroscience, Queen's Medical Centre, University of Nottingham Nottingham, Nottinghamshire, United Kingdom Background: Exposure to early-life adversity is thought to be a risk factor for the development of schizophrenia. In the last decade much attention has also focused on the potential role of endocannabinoids (ECs) in the pathogenesis of schizophrenia. The present study examined whether the CB2 receptor selective antagonist AM630 (6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]1H-indol-3-y l](4-methoxyphenyl)methanone; CB2 antagonist) can reverse the behavioural defects elicited by rearing rats in social isolation (a developmental model of schizophrenia). Methods: Male Lister-hooded rats were weaned on postnatal day (PND) 22-24 and half of each litter either group housed (3-4/ cage; n = 9) or socially isolated (SI; n = 9) for 5 weeks, during which they received minimal handling but had visual, auditory and olfactory interaction with each other. Rats were injected with either AM630 (1 mg/kg; i.p; n = 10) or saline once daily for 7 consecutive days in the first week of isolation. On PND 61 novel cage-induced locomotor activity (LMA) was recorded in automated infrared activity boxes. On PND 66 all rats were habituated to individual test arenas for 1 hr and on day 67 two trial novel object recognition (NOR) was assessed in same arena using a 2 h intra trial interval (ITI). On PND 81 the conditioned emotional response (CER) was monitored by placing individual