Frank Sams-Dodd

Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood.

Abstract The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 μmol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.

Effects of Continuous D-Amphetamine and Phencyclidine Administration on Social Behaviour, Stereotyped Behaviour, and Locomotor Activity in Rats

D-amphetamine (AMPH) and phencyclidine (PCP) can induce a model psychosis that mimic the positive symptoms of schizophrenia, but only PCP also mimics the negative symptoms. Recent studies in the rat social interaction test have shown that PCP, and not AMPH, induce social withdrawal following single and repeated injections, and this effect may, therefore, be used to model negative symptoms. However, an AMPH psychosis is usually only seen after a prolonged period of repeated injections or continuous administration for 3–5 days of high doses of AMPH. It is, therefore, possible that in these studies, AMPH was administered at insufficient levels in rats, and this may explain its lack of effect. The present study has determined the effects of continuous administration of AMPH (23 to 94 μmol/kg/day; 4.2 to 17 mg/kg/day) and PCP (18 to 107 μmol/kg/day; 5.0 to 30 mg/kg/day) in rats after five days of infusion in the social interaction test and after 6–7 days in standard activity cages. The study found that AMPH and PCP dose-dependently induced stereotyped behaviour and locomotor hyperactivity, behaviours believed to be related to positive symptoms, and that only PCP induced social withdrawal. These findings confirm previous studies that only PCP and not AMPH induce deficits in the social behaviour of rats.

Automation of the social interaction test by a video-tracking system: behavioural effects of repeated phencyclidine treatment

The social interaction test is a valuable behavioural model for testing anxiolytic and neuroleptic drugs. The test quantifies the level of social behaviour between pairs of rats and it is usually based on manual analysis of behaviour. Advances in computer technology have made it possible to track the movements of pairs of rats in an arena, and the present paper describes the automation of the social interaction test by the commercial video-tracking programme, the EthoVision system. The ability of the automated system to correctly measure the social behaviour of rats is demonstrated by determining a dose-response relationship in the social interaction test for phencyclidine, a psychotomimetic drug that reduces social behaviour between pairs of rats. These data are subsequently analysed by the manual and automated data-acquisition methods and the results are compared. The study shows that the automated data-acquisition method best describes the behavioural effects of phencyclidine in the social interaction test by the locomotor activity of the rats, how much time the rats spend in different sections of the testing arena, and the level of social behaviour. Correlation analysis of the results from the manual and automated data-acquisition methods shows that the social behaviour measured by the automated system corresponds correctly to the social behaviour measured by the manual analysis. The present study has shown that the automated data-acquisition method can quantify locomotor activity, how rats use a testing arena and the level of social behaviour between rats in the social interaction test. The system cannot distinguish between social and aggressive behaviours, and therefore the rats should be tested in an unfamiliar arena to reduce territorial behaviour. Taking this limitation into consideration, the social interaction test can be automated by this computer-based video-tracking system and can be used as a routine test for quantifying the effects of drugs on the social behaviour of rats.

A Test of the Predictive Validity of Animal Models of Schizophrenia Based on Phencyclidine and D-Amphetamine

Antipsychotic drugs can inhibit the effects of phencyclidine (PCP) and d-amphetamine (AMPH) in many rodent tests, but the effects are usually seen at doses that also affect vehicle-treated control rats, suggesting that the inhibition may be nonspecific. This study will attempt to test the predictive validity of these models based on the clinical observations that antipsychotics are not fully effective until after 2–3 weeks of administration in patients and that patients do not relapse immediately following abrupt withdrawal of medication. Haloperidol and clozapine were tested in rats after daily administration for 3 and 21 days in combination with vehicle or PCP (2.0 mg/kg) in the social interaction test, and with vehicle or AMPH (0.5 mg/kg) in standard activity cages. To separate acute from more long-lasting effects on the central nervous system (CNS) haloperidol and clozapine were tested with a short (45 or 30 min depending upon test) and a long (22–24 h) pretreatment time. The results demonstrated that haloperidol and clozapine following both 3 and 21 days of administration at the short pretreatment time inhibited the activity of vehicle-, PCP-, and AMPH-treated rats, whereas neither drug had consistent effects in any group at the long pre-treatment time. The data suggest that antipsychotics only inhibit PCP- and AMPH-induced behaviors in rodents by an acute drug-drug interaction, whereas any long-term effects of antipsychotic drug administration on the CNS cannot be revealed by PCP and AMPH in rodents.

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.0–10.0 mg/kg; intraperitoneally) after acute and subchronic (daily for 5 days) administration as well as the uncompetitive antagonists of the NMDA receptor of either high affinity, phencyclidine (0.5–4.0 mg/kg; subcutaneously (s.c.)) and (+)-MK-801 (0.03–0.25 mg/kg; s.c.), or low–moderate affinity, ketamine (2.0–16.0 mg/kg; s.c.) and memantine (0.15–20.0 mg/kg; s.c.), following daily administration for 3 days were tested in the social interaction test to determine their ability to reproduce the negative and positive symptoms measured by social isolation and stereotyped behavior, respectively. Second, the compounds were tested in the motility test following acute administration to determine their ability to induce locomotor hyperactivity reflecting the positive symptoms. In line with previous findings, all examined NMDA receptor antagonists produced social interaction deficits, locomotor hyperactivity, and stereotypy except memantine. Notably, this study found that MTEP following both acute and subchronic administration dose-dependently induced social isolation, but did not cause either locomotor hyperactivity or stereotypy. These data demonstrate that social behavior deficits in rats can be caused by both the blockade of the NMDA receptor and the inhibition of mGluR5, whereas mGluR5 antagonists may not independently be able to mimic the positive symptoms.

Effects of dopamine agonists and antagonists on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test

Abstract Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic psychosis. In animal models of schizophrenia, PCP induces locomotor hyperactivity, stereotyped behaviour and social isolation, and the purpose of the present study was to describe the ability of dopamine agonists and antagonists to mimic or interact with these PCP-induced behaviours in rats. The compounds were administered daily for 3 days in combination with vehicle or 2.0 mg/kg PCP and the rats were tested in the social interaction test on the last day of drug administration. The study showed that D1-agonists with relative differences in efficacy at the DA-stimulated adenylate cyclase had limited effects on the PCP-induced behaviours, whereas the D1-antagonist SCH 23391 could alleviate the PCP-induce social isolation following daily treatment for 3 days. However, following long-term treatment for 21 days, the rats develop tolerance to this effect. These data thus suggested that the D1-receptor system only had a modulatory effect on PCP. In contrast, the D2-receptor family may be more directly involved, because the D2/D3/D4-agonist quinpirole could mimic and potentiate the PCP-induced deficits in social behaviour, and the D2/D3-antagonist (−)sulpiride could alleviate the PCP-induced stereotyped behaviour and social isolation. However, a D4-antagonist did not affect the behaviour of vehicle- and PCP-treated rats, suggesting that this system plays a less direct role in the behavioural effects of PCP. In general, however, the effects of SCH 23391, quinpirole and (−)sulpiride on the PCP-induced behaviours were mirrored in the vehicle-treated control groups and it is therefore possible that non-specific effects may have been important.

Effects of diazepam, citalopram, methadone and naloxone on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test

Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. In the social interaction test PCP induces stereotyped behaviour and social isolation in rats, and these behaviours can be inhibited by antipsychotic drugs. In order to further evaluate the predictive validity of this model of schizophrenia the anxiolytic diazepam (0.02-17.5 micromol/kg; 0.005-5.0 mg/kg), the antidepressant citalopram (0.62-19.8 micromol/kg; 0.3-4.0 mg/kg), the opioid agonist methadone (0.36-5.8 micromol/kg; 0.13-2.0 mg/kg) and the opioid antagonist naloxone (0.34-22.0 micromol/kg; 0.13-8.0 mg/kg) were tested as examples of drugs without antipsychotic activity. The experiments demonstrated that these compounds did not specifically inhibit the behavioural effects of PCP. So far only antipsychotic drugs have been able to specifically inhibit the PCP-induced behaviours.

Postischemic hyperactivity in the mongolian gerbil correlates with loss of hippocampal neurons

Gerbils show a postischemic increase in locomotor activity that correlates to the extent of neuron loss in the hippocampal CA1 subfield. It has been suggested that this hyperactivity is predictive of neuron loss in the CA1. In this study the correlation between postischemic hyperactivity and neuron loss in several hippocampal subfields was investigated, and the theory that the hyperactivity is due to a reduced ability for spatial navigation was evaluated. Significant correlations were found between hyperactivity and neuron loss in several hippocampal subfields; the correlation was stronger for the CA3 than for the CA1 subfield, suggesting that postischemic hyperactivity can be used as a predictor of neuron loss in the CA3 rather than in the CA1. From observations of the pattern of hyperactivity within the test arenas and during the test period, this study challenges the spatial mapping theory of postischemic hyperactivity.

Impairment of working memory in the T-maze after transient global cerebral ischemia in the Mongolian gerbil

Using a T-maze, the influence of transient global cerebral ischemia on working memory in gerbils was investigated. Furthermore, it was examined whether a correlation exists between impairment in choice accuracy in the T-maze and neuron loss in the hippocampus. In two experiments, male Mongolian gerbils were tested in a previously learned delayed alternation T-maze task 1 week after a 4 min occlusion of the common carotid arteries. In both experiments memory was significantly impaired and in the second experiment, where the design allowed a separation between working and reference memory deficits, a selective impairment in working memory was seen. The results suggest that ischemia-induced disruption of delayed alternation in the T-maze in gerbils is a model which is relevant to the clinical manifestations of vascular dementia.

Transient cerebral ischemia inhibits juvenile recognition in the Mongolian gerbil.

This study introduces a social recognition test for Mongolian gerbils and describes the effect of transient global cerebral ischemia in this model. Adult male gerbils were exposed to an unfamiliar juvenile stimulus animal in two successive trials. The difference between the first and second exposures in duration of social investigation of the stimulus animal was used as a measure of social recognition. Recognition of the stimulus animal was seen after interexposure intervals (IEI) of 5 and 30 min, but not after 120 min. This is in concordance with data obtained in rats in a similar model. The capacity for social recognition was subsequently investigated in gerbils 1 week after 0 (sham), 4, or 8 min of bilateral occlusion of the common carotid arteries. An IEI of 30 min was used, as this IEI was within the time limit for recognition of the stimulus animal. Social recognition was impaired in both occlusion groups. The results suggest that the juvenile recognition test is a suitable model for testing amnesia in gerbils and that social olfactory memory is impaired by global cerebral ischemia.