Synonyms

Stimulus pre-exposure effect

Definition

Latent inhibition (LI) is the reduced efficacy of a previously exposed, inconsequential stimulus to generate a conditioned response when paired with reinforcement, compared with a novel stimulus. LI is extremely robust, appearing across many different learning paradigms and mammalian species, including humans.

While a variety of behavioral tasks are used to demonstrate LI in rodents, all of them share a basic procedure. In the first stage, pre-exposure, animals from each of two groups are placed in an environment that will later serve as the conditioning-test apparatus. Subjects in the “stimulus pre-exposed” (PE) group are repeatedly exposed to a stimulus (e.g., tone), which is not followed by a significant consequence. Subjects in the “nonpre-exposed” (NPE) group spend an equivalent amount of time in the apparatus without receiving the stimulus. Either immediately or a certain time after the pre-exposure time is completed, all subjects enter the conditioning stage of the procedure, in which the PE stimulus is paired with a reinforcer over a number of trials. Performance is assessed by examining some behavioral index of conditioned responding, either during the conditioning stage or in a third, test stage. LI is manifested in poorer performance of the PE when compared with the NPE group.

In terms of psychological processes underlying LI, it is believed that the pairing of stimulus–no event in the pre-exposure stage results in reduced attention to, or salience of, the stimulus, which subsequently interferes with the generation of the conditioned response resulting from the stimulus–reinforcement association in conditioning (Fig. 1).

Latent Inhibition. Fig. 1.
figure 1_344

Latent inhibition as a response competition phenomenon. In the pre-exposure stage, stimulus pre-exposed (PE) animals acquire a stimulus–no event association, which results in a conditioned response of inattention to the PE stimulus. Following conditioned attention theory (Lubow et al. 1981), inattention is treated as a classically conditioned response, acquired when stimuli are consistently followed by the lack of a consequence and governed by the same rules that govern association formation during classical conditioning. In the conditioning stage, the stimulus signals conflicting outcomes, no-event vs. reinforcement, that compete for behavioral expression (conditioned inattention response vs. the conditioned response acquired in conditioning). Which of the two associations gains behavioral control depends on factors that determine their relative behavioral impact during conditioning. The three most conspicuous factors are strength of pre-exposure (usually manipulated by changing number of stimulus pre-exposures but can involve any manipulation known to affect classical conditioning such as stimulus intensity, ISI, etc.), strength of conditioning (usually manipulated by changing the number of conditioning trials or intensity of reinforcement), and context (manipulated by changing the context between pre-exposure and conditioning), but there are other factors as well, such as the time interval between pre-exposure and conditioning or the motivational state of the animal in the two stages. Pharmacological LI experiments typically manipulate number of pre-exposures and/or conditioning trials.

Full size image

LI is a phenomenon of selective attention in the sense that it reflects a modulating effect of past experience on the current performance. Specifically, it reflects the ability of organisms to ignore stimuli that had been irrelevant in the past, in spite of their current relationship with a reinforcer. Since selective attention deficit is a hallmark cognitive deficit of schizophrenia and a central target for treatment, research that examined the effects of psychoactive drugs on LI in rodents has focused primarily on the use of LI to develop animal models of deficient attention in schizophrenia and the identification of anti-psychotic activity. The link between LI and schizophrenia is supported by the presence of LI abnormalities in schizophrenia patients.

Impact of Psychoactive Drugs

Disrupted and Persistent LI

While drug effects are typically measured as a reduction or an abolition of the target behavior in comparison with its presence in drug nontreated controls, pharmacology of LI has taken a different path from its very inception, focusing on both the disruption and the induction of the phenomenon. The latter effect, termed interchangeably LI potentiation, enhancement, or persistence, is indexed by comparison with the absence of LI in drug nontreated controls. Thus, psychoactive drugs can produce two poles of LI abnormality, namely, disrupted LI under conditions that lead to LI in normal rats and abnormally persistent LI under conditions that disrupt LI in normal rats (Fig. 2). Both disruption and persistence of LI can stem from drug action in the pre-exposure stage or in the conditioning stage. In addition to unraveling the psychological mechanism by which a given drug affects LI (alterations in the acquisition or the expression of inattentional response), stage-specific action allows for a refined discrimination between the effects of different drugs on LI.

Latent Inhibition. Fig. 2.
figure 2_344

Two poles of LI abnormality. Based on the view of LI as a window phenomenon, namely, present under very specific and restricted conditions, two abnormalities can be produced in LI depending on the status of the phenomenon in control animals: disrupted LI under conditions producing LI in controls, and persistent LI under conditions preventing the expression of LI in controls. In psychological terms, the former reflects loss of normal ability to ignore irrelevant stimuli, whereas the latter reflects a failure to switch to respond to such stimuli when they become relevant.

Full size image

Models of LI Disruption and Persistence

DA agonists. The notion of a hyperactive dopamine system in schizophrenia is supported by the capacity of the DA releaser, amphetamine, to induce psychosis in healthy humans and exacerbate symptoms, as well as enhance striatal dopamine release in schizophrenia patients. Because amphetamine produces only positive (psychotic) symptoms, amphetamine-induced behavioral abnormalities in animals are considered to model positive symptoms. Consistent with the expectation that the capacity to ignore irrelevant stimuli would be lost in a psychotic-like state, amphetamine disrupts LI in both rodents and humans. Amphetamine-induced LI disruption is due to the drug's action in conditioning stage rather than in pre-exposure stage, indicating that increased dopamine transmission does not produce a psychotic-like state by increasing stimulus salience but rather by weakening the inhibiting effect of reduced stimulus salience on behavior. LI is disrupted also after, as well as during withdrawal from, repeated amphetamine administration. Results with direct DA agonists are inconsistent.

NMDA antagonists. The hypo-glutamatergic hypothesis of schizophrenia is derived from findings that noncompetitive NMDA antagonists such as phencyclidine (PCP) and ketamine provoke symptoms in human volunteers and exacerbate symptoms in schizophrenia patients, as well as abnormalities of glutamate neurotransmission in schizophrenia. Since NMDA antagonists also induce negative symptoms and cognitive impairments characteristic of endogenous schizophrenia, NMDA antagonist-induced behavioral effects in animals are considered to model negative/cognitive symptoms. Unlike amphetamine, low doses of noncompetitive NMDA antagonists, including PCP, ketamine, and MK-801, spare LI. While these results have led to the suggestion that NMDA antagonist-induced effects in LI cannot provide a valid model of the disorder, later studies have shown that NMDA antagonists affect LI in an opposite manner to that of amphetamine, namely, they induce persistent LI under conditions that prevent LI expression in controls (Fig. 3). Importantly, persistent LI is induced by doses of NMDA antagonists that do not produce the well-known deleterious effects of these drugs on associative learning. Higher doses that impair conditioning disrupt LI. NMDA antagonists produce LI persistence via effects in conditioning, indicating that NMDA blockade impairs rats’ capacity to switch response based on changed relationships between stimuli and outcomes. The latter is consistent with numerous demonstrations of inflexible behavior following NMDA blockade in rats and humans and supports the relevance of NMDA antagonist-induced persistent LI to cognitive/negative symptoms of schizophrenia, which are characterized by inflexible and perseverative behaviors.

Latent Inhibition. Fig. 3.
figure 3_344

Effects of ketamine on LI with weak and strong conditioning. LI was measured in a conditioned emotional response procedure in which rats were either PE to 40 tone presentations or not pre-exposed (NPE) prior to conditioning with 2 tone-shock trials (weak conditioning; Fig. 3a ) or 5 tone-shock trials (strong conditioning; Fig. 3b ). Time to complete 25 licks in the presence of the tone was used as a measure of fear conditioning to the tone. LI is manifested in faster times of the PE when compared with the NPE animals. The figures present mean times (logarithmically transformed) to complete 25 licks in the presence of the tone of PE and NPE rats treated with vehicle or ketamine. (a) Under conditions yielding LI in vehicle controls, ketamine spared LI at 8 or 20 mg/kg and disrupted LI at 60 mg/kg. (b) Under conditions preventing LI in vehicle controls, ketamine at doses of 2, 8, and 20 mg/kg led to persistent LI.

Full size image

Muscarinic antagonists. Muscarinic antagonists such as scopolamine and atropine induce a schizophrenia-like syndrome in humans, which includes positive symptoms and cognitive impairments. Recent focus on cognitive impairments in schizophrenia has promoted attention to the cholinergic system because of its well-known role in cognition. Scopolamine can produce both LI disruption and persistence as a function of dose. Low doses of scopolamine disrupt LI, supporting the pro-psychotic quality of this agent. The mechanisms underlying this psychotic-like state differ however from those of amphetamine because scopolamine disrupts LI via effects at the pre-exposure stage. High doses of scopolamine spare LI under conditions yielding LI in controls, and induce persistent LI under conditions that prevent LI expression. The latter action is exerted in conditioning. Thus, scopolamine mimics both positive and negative/cognitive symptoms by disrupting normal attentional processing, low doses preventing the development of inattention and high doses producing attentional perseveration.

Antipsychotics. In rodents, antipsychotics (APDs) are typically investigated for their ability to antagonize the effects of other drugs, but in research concerned with APD effects on LI, their direct influences on LI are also of central importance. Specifically, LI in nontreated rodents is used for indexing antipsychotic activity as well as for discriminating between typical and atypical APDs. The former is achieved under conditions of weak or absent LI in controls. Under these conditions, both typical and atypical APDs produce persistent LI. This effect, produced by a wide range of APDs differing in their in vivo and in vitro pharmacology, is also obtained in humans, and is the most widely used index of antipsychotic action in LI. The LI potentiating action of APDs is exerted at the conditioning stage, and is mediated by D2 blockade. Although APD-induced LI potentiation is very robust, it does not discriminate between typical and atypical APDs. Such discrimination is manifested under conditions that produce LI in controls. Whereas typical APDs do not affect LI, atypical APDs can, depending on dose and stage of administration, disrupt LI. The LI disruptive action of atypical APDs is exerted in the pre-exposure stage and is due to their 5HT2A receptor antagonism. The pre-exposure-based 5HT2 antagonistic action competes with the conditioning-based D2 antagonistic action of these drugs. Since 5HT2 antagonism predominates at lower doses and D2 antagonism occurs at higher doses, depending on the dose, atypical APDs can potentiate, spare, or disrupt LI. The competition between the D2 and 5HT2 antagonism of atypical APDs has critical implications for interpreting the effects of these drugs on LI in animals and humans, as well as the clinical efficacy of these drugs.

In addition, since DA blockade is therapeutic against positive symptoms associated with abnormally increased DA function, but is ineffective for and may worsen negative symptoms associated with reduced DA function, recently it has been suggested that dopaminergic blockade-induced persistent LI, as exemplified by haloperidol-induced LI persistence, can model not only alleviation of positive symptoms but also induction of negative symptoms.

Reversal of Disrupted and Persistent LI

The four schizophrenia-relevant aberrations of LI, i.e., those induced by amphetamine, NMDA antagonists, and low and high-dose scopolamine, have been tested with typical and atypical antipsychotics to assess the predictive validity of these models for the identification of clinical treatments for schizophrenia. In recent years, new therapeutic strategies for schizophrenia, considered/hoped to improve negative symptoms and cognitive dysfunction, have emerged. These strategies include enhancement of NMDA transmission via the glycineB modulatory site on the NMDAR, either directly by agonists such as glycine transporter and D-serine, or indirectly by inhibiting the glycine transporter (GlyT1), and enhancement of cholinergic transmission using acetylcholinesterase inhibitors such as physostigmine, muscarinic agonists such as xanomeline, and alpha-7 nicotinic receptor agonists. Table 1 summarizes the distinct responses of five LI models (including haloperidol-induced persistence) to typical and atypical APDs, NMDA function enhancers, and cholinergic function enhancers.

Latent Inhibition. Table 1. Summary of representative antipsychotic and other putative treatments tested against models of disrupted and persistent LI.
Full size table

Amphetamine- and low scopolamine-induced disrupted LI, although reflecting distinct psychological processes, are reversed by both typical and atypical APDs as well as by glycinergic enhancers. Scopolamine- but not amphetamine-induced LI disruption is reversed by physostigmine. MK801-induced persistent LI is reversed by atypical APDs (e.g., clozapine and risperidone) but not by typical APDs, as found with other NMDA antagonist-induced behavioral deficits, and in line with the differential efficacy of typical and atypical APDs in the clinic. MK801-induced persistent LI is also reversed by a wide range of compounds that potentiate NMDA transmission including glycine, d-serine, D-cycloserine (DCS), and GlyT1 inhibitors GDA, ALX5407, and the novel GlyT1 inhibitors SSR103800 and SSR504734. Importantly, MK801 is the only model that discriminates between atypical APDs and glycinergic compounds as the former reverse this abnormality via effects at pre-exposure and the latter via effects in conditioning. Finally, the novel alpha7-nAChR partial agonist SSR180711 (4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate-hydrochloride) is also effective in this model. Scopolamine-induced persistent LI is reversed by physostigmine and xanomeline, as well as glycinergic enhancers, but is resistant to both haloperidol and clozapine. While the inefficacy of haloperidol is expected based on its ineffectiveness in models of negative/cognitive symptoms including MK801-induced persistent LI, the inefficacy of clozapine is unexpected and sets this abnormality apart from MK801-induced as well as all other known instances of drug-induced LI persistence. Haloperidol-induced persistent LI is reversed by atypical APDs clozapine and risperidone but is resistant to glycine and physostigmine (Fig. 4). In addition, haloperidol-induced persistent LI is the only persistent LI that is alleviated by amphetamine, like negative symptoms in the clinic.

Latent Inhibition. Fig. 4.
figure 4_344

Effects of clozapine, glycine, or physostigmine on haloperidol-induced persistent LI. Mean times (logarithmically transformed) to complete 25 licks in the presence of the tone of PE and NPE rats treated with vehicle or haloperidol (hal) and pre-treated with clozapine (5 mg/kg), glycine (800 mg/kg), or physostigmine (0.15 mg/kg). No LI was evident in the vehicle control but there was LI in rats treated with haloperidol. Haloperidol-induced persistent LI was antagonized only by clozapine. Clozapine and glycine but not physostigmine led to LI persistence in vehicle-treated rats.

Full size image

Using Pharmacology of Disrupted and Persistent LI to Model Domains of Pathology in Schizophrenia

Disrupted and persistent LI can be seen as two poles of dysfunctional attentional control, namely, a failure to inhibit attention to irrelevant stimuli and a failure to re-deploy attention when previously irrelevant stimuli become relevant. The former would likely give rise to the aberrantly increased salience perception and distractibility that are associated with psychotic symptoms, whereas the latter would result in the cognitive inflexibility and impaired attentional shifting that are associated with negative/cognitive symptoms. Indeed, both disrupted and excessively strong LI are found in schizophrenia patients, the former associated with acute psychosis and the latter associated with predominance of negative symptoms.

Based on their distinct pharmacological profiles, LI abnormalities produced by amphetamine, haloperidol, NMDA antagonists, and scopolamine have been suggested to represent four domains of pathology in schizophrenia (Table 2). Amphetamine- and scopolamine-induced disrupted LI represents the domain of positive symptoms, the only domain responsive to both typical and atypical APDs. Notably, disrupted LI is responsive to APDs irrespective of the mechanisms underlying the disruption. NMDA antagonist-induced persistent LI represents a (hypoglutamatergia-driven) domain of negative/cognitive symptoms that respond to atypical APDs and cognitive enhancers but not to typical APDs. Scopolamine-induced persistent LI represents a domain of cognitive impairments that are resistant to APDs. This model may have utility in identifying effective treatments for APD-resistant cognitive impairments in schizophrenia. However, given its insensitivity to APDs, the model is likely to represent a class of behavioral inflexibility that is common to a variety of neuropsychiatric disorders, including Parkinson’s disease (PD), and obsessive compulsive disorder (OCD). Indeed, both PD and OCD patients display abnormally enhanced LI. Finally, haloperidol-induced persistent LI represents a domain of (hypodopaminergia-driven) negative symptoms that are treatable by atypical antipsychotics but are resistant to cognitive enhancers. This abnormality may represent a class of cognitive/behavioral inflexibility that is selective to schizophrenia. The domain-specific LI model fits the future directions of drug development for treatment of schizophrenia, which will use polypharmacy strategies, with independent therapeutic agents for each domain of pathology.

Latent Inhibition. Table 2. Five pharmacological LI models proposed to model five domains of pathology of schizophrenia.
Full size table

Cross-References

Acetylcholinesterase Inhibitors as Cognitive Enhancers

Antipsychotic Drugs (APDs)

Attention

Cognitive Enhancers

Excitatory Amino Acids (NMDA)

Muscarinic Agonists and Antagonists

Nicotinic Agonists and Antagonists

Psychomotor Stimulants (Amphetamine)

Schizophrenia

Schizophrenia: Animal Models