The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia

doi:10.1016/0166-4328(95)00154-9

Behavioural Brain Research

Volume 71, Issues 1–2, November 1995, Pages 19-31, IN3

https://doi.org/10.1016/0166-4328(95)00154-9 Get rights and content

Abstract

Latent inhibition (LI) consists in a retardation of conditioning seen when to-be-conditioned stimulus is first presented a number of times without other consequence. Disruption of LI has been proposed as a possible model of the cognitive abnormality that underlies the positive psychotic symptoms of acute schizophrenia. We review here evidence in support of the model, including experiments tending to show that: (1) disruption of LI is characteristic of acute, positively-symptomatic schizophrenia; (2) LI depends upon dopaminergic activity; (3) LI depends specifically upon dopamine release in n. accumbens; (4) LI depends upon the integrity of the hippocampal formation and the retrohippocampal region reciprocally connected to the hippocampal formation; (5) the roles of n. accumbens and the hippocampal system in LI are interconnected.

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Repeated subchronic treatment with the NMDA-receptor antagonist, phencyclidine, causes behavioural changes in rats, which resemble cognitive and negative symptoms of schizophrenia. However, its effects on behaviours modelling positive symptoms are less clear. This study investigated whether subchronic phencyclidine pretreatment affected latent inhibition: impaired conditioning following repeated preexposure of the to-be-conditioned stimulus.
Female Lister-hooded rats were pretreated with phencyclidine or saline twice/day for 5 days, then remained drug-free for 10 days before latent inhibition testing. Saline pretreated animals showed latent inhibition, as expected. However, phencyclidine pretreated animals showed no latent inhibition: the effect of preexposure was attenuated, with no change in basic learning. Thus subchronic phencyclidine pretreatment does disrupt latent inhibition, and, importantly, this occurs after withdrawal from the drug, implicating changes in brain function enduring well beyond the time that the drug is present in the brain.
In a separate task, discrimination of a novel object was significantly impaired by phencyclidine pretreatment confirming that five days of subchronic pretreatment was sufficient to invoke behavioural impairment previously reported after seven days pretreatment.
Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1)produces a schizophrenia-like phenotype in the rat
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Citation Excerpt :
Rats that over-expressed CNRIP1 in the vHipp exhibited a deficit in latent inhibition when compared to their respective controls, mimicking positive symptoms associated with schizophrenia. We were not able to directly correlate the latent inhibition with our readout of dopamine neuron activity (population activity); however, studies have demonstrated that latent inhibition relies on dopamine system function (Gray et al., 1995a; Young et al., 1993). Additionally, as a marker of negative symptoms, we measured social interaction time.
Adolescent cannabis use has been implicated as a risk factor for schizophrenia; however, it is neither necessary nor sufficient. Previous studies examining this association have focused primarily on the role of the cannabinoid receptor 1 (CB1R) with relatively little known about a key regulatory protein, the cannabinoid receptor interacting protein 1 (CNRIP1). CNRIP1 is an intracellular protein that interacts with the C-terminal tail of CB1R and regulates its intrinsic activity. Previous studies have demonstrated aberrant CNRIP1 DNA promoter methylation in post-mortem in human patients with schizophrenia, and we have recently reported decreased methylation of the CNRIP1 DNA promoter in the ventral hippocampus (vHipp) of a rodent model of schizophrenia susceptibility. To examine whether augmented CNRIP1 expression could contribute to the pathology of schizophrenia, we performed viral-mediated overexpression of CNRIP1 in the vHipp of Sprague Dawley rats. We then tested these rats for behavioral correlates of schizophrenia symptoms, followed by electrophysiology to determine the effects on the dopamine system, known to underlie psychosis. Here, we report that overexpression of vHipp CNRIP1 induces impairments in latent inhibition and social interaction, similar to those observed in individuals with schizophrenia and in rodent models of the disease. Furthermore, rats overexpressing vHipp CNRIP1 displayed a significant increase in ventral tegmental area (VTA) dopamine neuron population activity, a putative correlate of psychosis. These data provide evidence that alterations in CNRIP1 may contribute to the pathophysiology of schizophrenia, as overexpression is sufficient to produce neurophysiological and behavioral correlates consistently observed in rodent models of the disease.
Impaired contextual fear-conditioning in MAM rodent model of schizophrenia
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Citation Excerpt :
Deficits in latent inhibition in schizophrenia are inconsistent and appear dependent on medication status or disease duration (Gal et al., 2009; Lubow et al., 2000; Rascle et al., 2001; Swerdlow et al., 1996; Vaitl et al., 2002; Williams et al., 1998). However, there is compelling evidence from animal models that latent inhibition results in both increased dopamine release in the nucleus accumbens and requires intact processing in the ventral hippocampus, especially via the primary output of the ventral subiculum (Gray et al., 1995; Peterschmitt et al., 2005). Electrophysiological recordings from dopamine neurons in the ventral tegmental area are an indirect measure of underlying hippocampal hyperactivity in the MAM model (Lodge et al., 2009; Lodge and Grace, 2007) and other constructs (stress (Valenti et al., 2012), pilocarpine model of temporal lobe epilepsy (Cifelli and Grace, 2012), amphetamine (Lodge and Grace, 2008)).
The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model.
Male offspring of dams treated with MAM (20 mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0–10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning.
Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7 min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block.
These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning.
An examination of the roles of glutamate and sex in latent inhibition: Relevance to the glutamate hypothesis of schizophrenia?
2017, Psychiatry Research
The present study examined the effects of the glutamate receptor antagonist MK-801, the glutamate receptor agonist N-methyl-D-aspartate (NMDA), and sexual dimorphism on latent inhibition to elucidate the glutamate hypothesis of schizophrenia. During the pre-exposure phase, 56 male and 65 female Wistar rats were intracerebroventricularly administered normal saline, MK-801 or NMDA, in the left ventricle and then exposed to a passive avoidance box (or a different context) in three trials over 3 days. Then, all of the rats were placed in the light compartment of the passive avoidance box and were allowed to enter the dark compartment, where they each received a footshock (1 mA, 2 s) in five trials over 5 days. Injections of the glutamate drugs NMDA and MK-801 did not affect latent inhibition. Sexual dimorphism did not occur in latent inhibition. The present data on the male rats indicated that the glutamate system did not affect latent inhibition, indicating that the glutamate system was not like the dopamine system in terms of mediating the positive symptoms of schizophrenia. The glutamate system might be involved in the negative and cognitive symptoms of schizophrenia. The results may provide information for novel treatments of the negative and cognitive symptoms of schizophrenia.
Can models of reinforcement learning help us to understand symptoms of schizophrenia?
2017, Decision Neuroscience: An Integrative Perspective
We aim to show that the principles and empirical observations relating to reward and reinforcement learning may be useful in considering schizophrenia. Though this is a complex illness in which the primary symptoms are expressed in terms of bizarre beliefs and perceptions, there is reason to suppose that the underlying deficits reside in brain systems known to be linked to learning, reward, and motivational processes. We consider two very different symptoms that are characteristic of schizophrenia. The first, delusions, refers to apparently irrational beliefs that arise and are held with extraordinary tenacity in the face of contradictory evidence. There is emerging evidence that such beliefs emerge from abnormal associative processes perhaps arising as a consequence of disturbed dopaminergic function. The second symptom, anhedonia, refers to the apparent lack of enjoyment in life. In fact, there is now good evidence that anhedonia may relate more to a motivation deficit and, as such, can be considered in the context of the same system as that implicated in delusions. We highlight the evidence in favor of these perspectives, showing that reinforcement learning may be key to understanding schizophrenia.
The dopaminergic response to acute stress in health and psychopathology: A systematic review
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Previous work in animals has shown that dopamine (DA) in cortex and striatum plays an essential role in stress processing. For the first time, we systematically reviewed the in vivo evidence for DAergic stress processing in health and psychopathology in humans. All studies included (n studies = 25, n observations = 324) utilized DA D2/3 positron emission tomography and measured DAergic activity during an acute stress challenge. The evidence in healthy volunteers (HV) suggests that physiological, but not psychological, stress consistently increases striatal DA release. Instead, increased medial prefrontal cortex (mPFC) DAergic activity in HV was observed during psychological stress. Across brain regions, stress-related DAergic activity was correlated with the physiological and psychological intensity of the stressor. The magnitude of stress-induced DA release was dependent on rearing conditions, personality traits and genetic variations in several SNPs. In psychopathology, preliminary evidence was found for stress-related dorsal striatal DAergic hyperactivity in psychosis spectrum and a blunted response in chronic cannabis use and pain-related disorders, but results were inconsistent. Physiological stress-induced DAergic activity in striatum in HV may reflect somatosensory properties of the stressor and readiness for active fight-or-flight behavior. DAergic activity in HV in the ventral striatum and mPFC may be more related to expectations about the stressor and threat evaluation, respectively. Future studies with increased sample size in HV and psychopathology assessing the functional relevance of stress-induced DAergic activity, the association between cortical and subcortical DAergic activity and the direct comparison of different stressors are necessary to conclusively elucidate the role of the DA system in the stress response.

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¹: Present address: The Swiss Institute of Technology, Laboratory of Behavioural Biology and Functional Toxicology, Institute of Toxicology, Schorenstrasse 16, Schwerzenbach 8603, Switzerland.

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Research reportThe role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia

Abstract

Pers. Indiv. Differ.

Neuropharmacology

Behav. Neural Biol.

Biol. Psychiatry

Brain Res.

Pharmacol. Biochem. Behav.

Biol. Psychiatry

Neuropsychologia

Behav. Res. Ther.

Biol. Psychiatry

Brain Res. Rev.

Brain Res.

Pharmacol. Biochem. Behav.

Pers. Indiv. Differ.

Brain Res.

Brain Res. Rev.

Neurobiol. Learning Memory

Brain Res.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Pharmacol. Biochem. Behav.

Neuroscience

The disorder of consciousness in schizophrenia

Schiz. Bull.

Differential performance of acute and chronic schizophrenics in a latent inhibition task

J. Nerv. Ment. Dis.

Dopamine release in the nucleus accumbens after systemic and intrahippocampal injections of 5HT-1 agonists which differentially affect attention in the rat

Br. J. Pharmacol.

The current status of the dopamine hypothesis of schizophrenia

Neuropsychopharmacology

The effects of ritanserin, RU 24 969 and 8-OH-DPAT on latent inhibition in the rat

J. Psychopharmacol.

Positive and negative schizophrenic symptoms and the role of dopamine

Br. J. Psychiatry

Latent inhibition and recall/recognition of irrelevant stimuli as a function of preexposure duration in high and low psychotic-prone normals

Br. J. Psychol.

On the preferential release of dopamine in the nucleus accumbens by amphetamine — further evidence obtained by vertically implanted concentric dialysis probes

Psychopharmacology

Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioural model of clinical drug action

Psychopharmacology

Animal models with construct validity for schizophrenia

Behav. Pharmacol.

Long-term attentional deficit in nonhandled males: Possible involvement of the dopaminergic system

Psychopharmacology

An animal model of attention deficit

Consciousness, information processing and schizophrenia

Br. J. Psychiatry

Delusions: investigations into the psychology of delusional reasoning

The effects of preexposure to a non-attended stimulus on subsequent learning: latent inhibition in adults

Bull. Psychonomic Soc.

Consciousness, schizophrenia and scientific theory

The contents of consciousness: a neuropsychological conjecture

Behav. Brain Sci.

The neuropsychology of schizophrenia

Behav. Brain Sci.

Research report
The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia