Environmental animal models for sensorimotor gating deficiencies in schizophrenia: a review

Abstract.: Rationale: In schizophrenia research, the study of animal models has received considerable attention in the past 20 years. The value of animal models in pre-clinical research is widely recognised, largely because they can provide precious knowledge regarding the neurobiology of schizophrenia and can also be used for developing antipsychotic drugs. Prepulse inhibition (PPI; reduction in startle reflex induced by a prestimulus) is impaired in schizophrenic patients, a finding that has been associated with a loss of sensorimotor gating abilities. In rats, the schizophrenic-like PPI deficit can be induced by pharmacological or surgical manipulations targeting mainly the cortico-meso-limbic circuitry. Objectives: The literature was critically reviewed in an effort to determine the robustness and the relevance for schizophrenia of another category of animal models, based purely on manipulations of the social environment, that encompasses the neurodevelopmental hypothesis of schizophrenia. Specifically, we focused our attention on the long-term effects of such environmental models on sensorimotor gating processes as assessed in the PPI paradigm, with an attempt to evaluate their face, predictive and construct validity. Results: Our review of the literature leads to the conclusion that social deprivation performed directly after weaning (~21 days of age) is more likely to be a relevant model for PPI impairments in schizophrenia than pre-weaning manipulations. Conclusions: Although the robustness of such environmental models requires further study, these animal models offer the advantage of avoiding invasive manipulations, which allows for a variety of anatomical, electrophysiological, neuroendocrine or neurochemical investigations in the absence of confounding pharmacological or surgical effect

Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia

Rationale: Prenatal exposure to infection is a notable environmental risk factor in the development of schizophrenia. One prevalent hypothesis suggests that infection-induced disruption of early prenatal brain development predisposes the organism to long-lasting structural and functional brain abnormalities. Many of the prenatal infection-induced functional brain abnormalities appear to be closely associated with imbalances in the mesocorticolimbic dopamine system in adult life, suggesting that disruption of functional and structural dopaminergic development may be at the core of the developmental neuropathology associated with psychosis-related abnormalities induced by prenatal exposure to infection. Objectives: In this review, we integrate recent findings derived from experimental models in animals with parallel research in humans which supports this hypothesis. We thereby highlight the developmental perspective of abnormal DA functions following in-utero exposure to infection in relation to the developmental and maturational mechanisms potentially involved in schizophrenia. Results: Experimental investigations show that early prenatal immune challenge can lead to the emergence of early structural and functional alterations in the mesocorticolimbic DA system, long before the onset of the full spectrum of psychosis-associated behavioral and cognitive abnormalities in adulthood. Conclusions: Dopaminergic mal-development in general, and following prenatal immune activation in particular, may represent a primary etiopathological mechanism in the development of schizophrenia and related disorders. This hypothesis differs from the view that dopaminergic abnormalities in schizophrenia may be secondary to abnormalities in other brain structures and/or neurotransmitter systems. The existence of primary dopaminergic mechanisms may have important implications for the identification and early treatment of individuals prodromally symptomatic for schizophreni

Differential effects of post-weaning juvenile stress on the behaviour of C57BL/6 mice in adolescence and adulthood

Rationale: There is evidence that events early in post-weaning life influence brain development and subsequent adult behaviour and therefore play an important role in the causation of certain psychiatric disorders in later life. Exposing rodents to stressors during the juvenile period has been suggested as a model of induced predisposition for these disorders. Objective: This is the first study to examine behavioural and pharmacological changes in adolescence and adulthood following juvenile stress in mice. Materials and methods: Two cohorts of mice were simultaneously exposed to a stress protocol during postnatal days (PND) 25-30. Behavioural assessments reflecting emotional functions, cognitive functions, and psychostimulant sensitivity were then carried out at two time points: one cohort was tested during adolescence (PND 39-54; adolescent group), and the second cohort was tested during adulthood (PND 81-138; adult group). Results: In the adolescent mice, juvenile stress significantly attenuated conditioned freezing and led to decreased anxiety-like behaviour in the elevated plus maze, whereas no effect was observed on these tests in the adult mice. In contrast, adult mice exhibited poor avoidance learning following juvenile stress. When tested during adulthood, the mice stressed during the juvenile period showed a sensitised response to amphetamine compared to controls, whereas the response during adolescence was similar in stressed and control animals. Conclusions: Our results suggest that exposure to stressors during the juvenile period can exert long-term effects on the brain and behaviour and that these effects differ depending on whether the animals are tested during adolescence or adulthoo

Facilitated extinction of appetitive instrumental conditioning following excitotoxic lesions of the core or the medial shell subregion of the nucleus accumbens in rats

The nucleus accumbens has been implicated in the control of goal-directed behaviour, including instrumental conditioning. Here, we evaluated the effect of N-methyl-d-aspartate (NMDA)-induced excitotoxic lesions restricted to either the core or the medial shell subregions of the nucleus accumbens (NAC) on extinction in rats using a trial discrete fixed ratio-5 (FR-5) appetitive operant procedure. Neither core nor shell lesions of the NAC affected the acquisition of instrumental responding. Both lesions facilitated the cessation of responding when the instrumental act no longer yielded reinforcement. Our results suggest that both the NAC core and medial shell contribute to the control of extinction learning of appetitively motivated instrumental behaviou

Are DBA/2 mice associated with schizophrenia-like endophenotypes? A behavioural contrast with C57BL/6 mice

Rationale: Due to its intrinsic deficiency in prepulse inhibition (PPI), the inbred DBA/2 mouse strain has been considered as an animal model for evaluating antipsychotic drugs. However, the PPI impairment observed in DBA/2 mice relative to the common C57BL/6 strain is confounded by a concomitant reduction in baseline startle reactivity. In this study, we examined the robustness of the PPI deficit when this confound is fully taken into account. Materials and methods: Male DBA/2 and C57BL/6 mice were compared in a PPI experiment using multiple pulse stimulus intensities, allowing the possible matching of startle reactivity prior to examination of PPI. The known PPI-enhancing effect of the antipsychotic, clozapine, was then evaluated in half of the animals, whilst the other half was subjected to two additional schizophrenia-relevant behavioural tests: latent inhibition (LI) and locomotor reaction to the psychostimulants—amphetamine and phencyclidine. Results: PPI deficiency in DBA/2 relative to C57BL/6 mice was essentially independent of the strain difference in baseline startle reactivity. Yet, there was no evidence that DBA/2 mice were superior in detecting the PPI-facilitating effect of clozapine when startle difference was balanced. Compared with C57BL/6 mice, DBA/2 mice also showed impaired LI and a different temporal profile in their responses to amphetamine and phencyclidine. Conclusion: Relative to the C57BL/6 strain, DBA/2 mice displayed multiple behavioural traits relevant to schizophrenia psycho- and physiopathology, indicative of both dopaminergic and glutamatergic/N-methyl-d-aspartic acid receptor dysfunctions. Further examination of their underlying neurobiological differences is therefore warranted in order to enhance the power of this specific inter-strain comparison as a model of schizophreni

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine

Rationale.: Psychomotor stimulants can induce psychotic states in humans that closely resemble those observed in patients with idiopathic schizophrenia. Attentional and sensorimotor gating impairments are observed in schizophrenic patients using the latent inhibition (LI) and prepulse inhibition (PPI) behavioral assays, respectively. Our previous studies demonstrated that after 4days of withdrawal from a period of amphetamine (AMPH) administration, animals exhibited disrupted LI but normal PPI. Objective.: The aim of the present study was to test PPI in AMPH-withdrawn rats under experimental conditions similar to those used to best demonstrate locomotor sensitization following AMPH withdrawal. Methods.: We examined the effects on PPI of (1) pairing drug injections with PPI test-associated cues, (2) administration of a low-dose dopamine agonist challenge and (3) testing following longer withdrawal periods (23, 30, 60days). Results.: Although none of these conditions revealed a disruption of PPI in AMPH-withdrawn rats, we did observe that the acoustic startle response was reduced during a restricted time period following AMPH withdrawal. Similar to our previous findings, AMPH-withdrawn animals showed disrupted LI on day16 of withdrawal and locomotor sensitization to a challenge injection of AMPH after 62days of withdrawal. Conclusion.: We conclude that the effects of repeated AMPH on PPI are not modulated by the same experimental parameters known to be important for eliciting locomotor sensitization and that withdrawal from the schedule of AMPH administration used in this study models only specific cognitive dysfunctions linked to schizophrenic symptoms, since LI was disrupted but PPI was not affecte

The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice

Rationale: Inhibition of the glycine transporter 1 (GlyT1) activity increases extra-cellular glycine availability in the CNS. At glutamatergic synapses, increased binding to the glycine-B site located in the N-methyl-d-aspartate receptor (NMDAR) can enhance neurotransmission via NMDARs. Systemic treatment of 2-chloro-N-[(S)-phenyl [(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734), a selective GlyT1 inhibitor, is effective against social recognition impairment induced by neonatal phencyclidine treatment and enhances pre-pulse inhibition in a mouse strain (DBA/2) with intrinsic sensorimotor gating deficiency, suggesting that SSR504734 may be an effective cognitive enhancer. Objective: The objective of the study was to examine if SSR504734 exhibits a promnesic effect on working memory function in wild-type C57BL/6 mice using an automatic continuous alternation task. Materials and methods: Hungry mice were trained to alternate their nose pokes between two food magazines across successive discrete trials in an operant chamber in order to obtain food reward. Correct choice on a given trial thus followed a non-matching or win-shift rule in relation to the preceding trial, with manipulation of the demand on memory retention, by varying the delay between successive trials. Results: Pre-treatment with SSR504734 (30mg/kg, i.p.) improved choice accuracy when the delay from the previous trial was extended to 12-16s. Furthermore, a dose-response analysis (3, 10, 30mg/kg) revealed a clear dose-dependent efficacy of the drug: 3mg/kg was without effect, whilst 10mg/kg led to an intermediate enhancement in performance. Conclusion: The present findings represent the first demonstration of the promnesic effects of SSR504734 under normal physiological conditions, lending further support to the suggestion of its potential as a cognitive enhance

Hyperactivity, decreased startle reactivity, and disrupted prepulse inhibition following disinhibition of the rat ventral hippocampus by the GABAA receptor antagonist picrotoxin

Abstract.: Rationale: Functional imaging studies have revealed overactivity of the hippocampus in schizophrenic patients. Neuropathological data indicate that hyperactivity of excitatory hippocampal afferents and decreased hippocampal GABA transmission contribute to this overactivity. In rats, excitation of the ventral hippocampus, e.g. by NMDA, results in hyperactivity and disruption of sensorimotor gating measured as prepulse inhibition (PPI) of the acoustic startle response, behavioral effects related to psychotic symptoms in humans. Objective: The present study examined whether disinhibition of the ventral hippocampus by the GABAA antagonist picrotoxin would result in similar psychosis-related behavioral disturbances (hyperactivity, decreased PPI) as NMDA stimulation. Methods and results: Wistar rats received bilateral infusions of subconvulsive doses of picrotoxin (100 or 150ng/0.5µl per side) into the ventral hippocampus and were then immediately tested for open field locomotor activity or startle reactivity and PPI. Only the higher dose induced hyperactivity and decreased PPI. Both doses decreased acoustic startle reactivity to a similar extent. The decreased PPI appeared not to result from decreased startle reactivity, but was associated with a diminished potency of the prepulses to inhibit the startle reaction to the startle pulse, indicating a sensorimotor gating deficit. All effects were temporary, i.e. disappeared when the rats were tested 24h after infusion. Conclusions: Decreased GABAergic inhibition in the ventral hippocampus of rats yielded psychosis-related behavioral effects, very similar to those induced by NMDA stimulation. Thus, a concurrence of decreased GABAergic inhibition and increased afferent excitation in the hippocampus of schizophrenic patients might contribute to psychotic symptom