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.

Latent Inhibition. Fig. 1. 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.

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.

► Muscarinic antagonists. Muscarinic antagonists such as ► scopolamine and atropine induce a schizophrenialike syndrome in humans, which includes positive

Latent Inhibition. Fig. 2. 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.

Latent Inhibition. Fig. 3. 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.

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-expo-sure-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.

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