Phencyclidine does not disrupt latent inhibition in rats: implications for animal models of schizophrenia.

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning to ignore, or tune out, irrelevant stimuli. Three experiments investigated the effects of phencyclidine (PCP) on LI. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the preexposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 1 mg/kg PCP was administered either in the preexposure or in the conditioning stage or in both. Experiment 2 used 5 mg/kg PCP in the same procedure. In Experiment 3, 5 mg/kg PCP was administered throughout the LI procedure, including the test stage. In all three experiments, PCP did not affect LI. The implications of these findings for the development of animal models of schizophrenia are discussed.     

The sigma ligand BMY-14802 as a potential antipsychotic: evidence from the latent inhibition model in rats

Latent inhibition (LI) is a measure of retarded conditioning to a previously-presented nonreinforced stimulus, that is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs are known to produce two effects in this test paradigm: to antagonise amphetamine-induced disruption of LI, and to enhance LI when administered on their own. The present experiments tested the effects on LI of a potential antipsychotic, sigma ligand BMY-14802. The experiments used a conditioned emotional response (CER) procedure in rats licking for water, consisting of three stages: preexposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the preexposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In Experiment 1, 20 tone preexposures and two conditioning trials were given and the effects of 5, 15, and 30mg/kg BMY-14802 were assessed. Experiment 2 tested the effects of 15 and 30mg/kg on LI using ten preexposures and two conditioning trials. Experiment 3 investigated the effects of 15 and 30mg/kg on LI using 40 preexposures and extended conditioning consisting of five tone-shock pairings. Experiments 4 and 5 investigated antagonism of amphetamine-induced disruption of LI by 15 and 30mg/kg BMY-14802, respectively. BMY-14802 was found to antagonise amphetamine-induced disruption of LI and enhance LI when low numbers of preexposures and two conditioning trials were given, but not following extended conditioning. These results provide partial support for the suggestion that BMY-14802 may possess antipsychotic properties.     

Facilitation of latent inhibition by haloperidol in rats

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. Two experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI as a function of number of CS pre-exposures. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 40 CS pre-exposures were given. LI was obtained in both the placebo and haloperidol conditions, but the effect was much more pronounced under the drug. Experiment 2 used ten CS pre-exposures. LI was not obtained in the placebo animals but was clearly evident in animals injected with haloperidol. The implications of these findings for the effects of neuroleptics on learning are discussed.     

Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. The administration of haloperidol in both the preexposure and the conditioning stages was found to enhance LI in the conditioned emotional response (CER) procedure (Weiner and Feldon, 1986). The present experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI in a two-way avoidance procedure, consisting of two stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; and conditioning, in which the animals acquired a two-way avoidance response with the tone serving as the warning signal. Experiments 1 and 2 tested whether the administration of haloperidol confirmed to the preexposure stage, where learning to ignore the nonreinforced stimulus takes place, would suffice to enhance the LI effect. In Experiment 1, preexposure and conditioning were conducted 24 hr apart. LI was obtained in both the placebo and haloperidol conditions, but the effect was not more pronounced under the drug. In addition, haloperidol-treated animals exhibited impaired avoidance performance. In Experiment 2, preexposure and conditioning were given 72 hr apart. With this interval, haloperidol did not affect avoidance performance. However, also under these conditions, the magnitude of the LI effect was not larger in the haloperidol-treated groups, indicating that the administration of the drug in the preexposure stage alone did not suffice to enhance LI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abolition of the expression but not the acquisition of latent inhibition by chronic amphetamine in rats

The animal amphetamine model of schizophrenia has been based primarily on stereotyped behavior. The present study sought to demonstrate an amphetamine-induced deficit in attentional processes. To this end, the effects of acute and chronic (14 days) 1.5 mg/kg dl-amphetamine administration on the ability of rats to ignore irrelevant stimuli were examined using the paradigm of latent inhibition (LI) in a conditioned emotional response (CER) procedure. The procedure consisted of three stages: pre-exposure, in which the to-be-conditoned stimulus, tone, was presented without being followed by reinforcement; acquisition, in which the pre-exposed tone was paired with shock; and test, in which LI was indexed by animals' suppression of licking during tone presentation. Experiment 1 showed that chronic but not acute treatment abolished LI. Experiment 2 showed that animals receiving chronic amphetamine pretreatment but pre-exposed and conditioned without the drug, exhibited normal LI. In Experiment 3, animals which received chronic amphetamine pretreatment and were pre-exposed under the drug but conditioned without it, also showed normal LI. The implications of these results for the animal amphetamine model of schizophrenia are discussed.     

The effects of the new antipsychotic, sertindole, on latent inhibition in rats

Latent inhibition (LI) is a measure of retarded conditioning to a previously presented non-reinforced stimulus, that is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs are known to produce two effects in this paradigm: to antagonize amphetamine-induced disruption of LI, and to facilitate the development of LI when administered on their own. The present experiments tested the effects on LI of the new neuroleptic, sertindole. The experiments used a conditioned emotional response procedure in rats licking for water, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by degree of suppression of licking during tone presentation. In Experiment 1 the effects of 0.31, 1.3 and 5.0mg/kg sertindole were assessed following pre-exposure to 40 non-reinforced tones. Experiment 2 tested the effects of 5mg/kg on LI following pre-exposure to 10 non-reinforced tones. Experiment 3 investigated antagonism of amphetamine-induced disruption of LI by 5.0mg/kg sertindole. The results demonstrated that sertindole (5.0mg/kg) possesses a neuroleptic-like profile in the LI model: it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.     

Latent inhibition is not affected by acute or chronic administration of 6 mg/kg dl-amphetamine

Latent inhibition (LI) is a behavioral paradigm in which animals learn to ignore a repeatedly presented stimulus not followed by meaningful consequences. We previously reported that LI was disrupted following the administration of 1.5 mg/kg dl-amphetamine. The present experiments investigated the effects of 6 mg/kg dl-amphetamine administration on LI in a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, the drug was administered in a 2×2 design, i.e. drug-no drug in pre-exposure and drug-no drug in conditioning. LI was obtained in all conditions. In Experiment 2, animals were given either 5 days of 6 mg/kg amphetamine pretreatment and amphetamine in pre-exposure and conditioning or 7 days of saline. LI was not obtained under amphetamine, but this outcome reflected a state-dependency effect. In Experiment 3, animals received either 5 days of amphetamine pretreatment and amphetamine in pre-exposure, conditioning and test or 8 days of saline. LI was obtained in both the placebo and amphetamine conditions. Experiments 4a and 4b compared the effects of two drug doses, 1.5 (4a) and 6 mg/kg (4b), administered in pre-exposure and conditioning. LI was abolished with the 1.5 mg/kg dose but not with the 6 mg/kg dose.     

Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperidol and ondansetron: Implications for a possible antipsychotic action of ondansetron

Latent inhibition (LI) is a behavioural phenomenon whereby preexposure to a stimulus without reinforcement interferes with the formation of subsequent associations to that stimulus. Using preexposure to a tone stimulus which subsequently serves as a conditioned stimulus for suppression of licking, we have confirmed that LI is disrupted by a low dose of amphetamine. Haloperidol was able to prevent this effect of amphetamine. Ondansetron, a selective and potent 5HT₃ receptor antagonist, was also shown to be effective at blocking the amphetamine-induced disruption of LI at a dose of 0.01 mg/kg, but not at 0.1 mg/kg. In addition, it was demonstrated that ondansetron could enhance LI; using only ten preexposures, no LI was obtained in the saline group, but was apparent in animals given ondansetron, an effect which has been previously shown with haloperidol. Haloperidol, at the higher dose used, reduced suppression of licking, however, ondansetron at the effective dose had no such effect. It is concluded that ondansetron is able to attenuate increases in dopamine activity, produced pharmacologically with amphetamine without affecting baseline dopamine activity. The implications of these findings for a possible antipsychotic action of ondansetron are discussed.     

Antagonism of amphetamine-induced disruption of latent inhibition by the atypical antipsychotic olanzapine in rats

The present study aimed at characterising the effects of the new antipsychotic olanzapine in a Latent Inhibition (LI) paradigm. A conditioned emotional response (CER) procedure was used, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was presented six times without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired twice with reinforcement (a foot shock); and test, in which LI was assessed by the suppression of licking during the tone presentation. In Experiment I, it was found that pre-treatment with an intermediate dose (0.312mg/kg) of olanzapine, but not with lower (0.003; 0.031mg/kg) or higher doses (0.625; 1.25mg/kg), restored LI in amphetamine-treated (1.5mg/kg) animals. This effect could not be attributed to a disruptive effect of olanzapine on CER learning, as olanzapine per se had no effect on this conditioning (Experiment 2). In Experiment 3, olanzapine did not antagonise the amphetamine-induced locomotor hyperactivity. As olanzapine has not only dopaminergic, but also serotonergic, adrenergic, histaminergic and cholinergic activities, the differential effects of olanzapine on amphetamine-induced disruption of LI and hyperactivity may reflect an action on several pharmacological targets, possibly interacting with one another.     

Facilitation of latent inhibition by the atypical antipsychotic risperidone

The action of the atypical antipsychotic risperidone on latent inhibition (LI), an animal model of schizophrenia, was investigated. The parameters of the procedure were set at values insufficient to generate LI in control rats. On the first day, rats administered 0.5, 1.0, or 2.0 mg/kg ip risperidone or vehicle were preexposed (PE) to 10 tone presentations. On the second day, they were again injected with drug or vehicle and then submitted to two conditioned stimulus (CS; tone)-unconditioned stimulus (US; shock) pairings. On the third day, suppression of their drinking response under the CS was measured. Nonpreexposed (NPE) animals were submitted to the same procedure except for the tone preexposure. On the suppression test, LI was not observed in control rats as well as in animals given 0.5 mg/kg risperidone. Animals given 1.0 and 2.0 mg risperidone, however, displayed an LI effect. The facilitation of LI by risperidone gives additional support to the LI paradigm as an animal model of schizophrenia.     

Disruption of latent inhibition by acute administration of low doses of amphetamine

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. Three experiments investigated the effects of acute amphetamine administration on LI in rats. Experiments 1 and 3 used a conditioned emotional response (CER) procedure and Experiment 2 used two-way active avoidance procedure. Experiments 1 and 2 showed that, in both the CER and avoidance procedures, 1.5 mg/kg dl-amphetamine administered either in the preexposure or the conditioning stage alone did not disrupt LI. In contrast, amphetamine administered in both of the stages abolished LI. Experiment 3 showed that the abolition of LI was obtained when the preexposure and conditioning were given 24 hr apart but not when the two stages were given in one session.     

Serotonergic depletion increases conditioned suppression to background stimuli in the rat.

Dark Agouti rats were lesioned by intra-ventricular injection of 5,7-dihydroxytryptamine (DHT) and, 2 weeks later, learning was tested in a conditioned suppression of drinking procedure. Lesioned and vehicle-injected control rats were conditioned with a discrete stimulus (tone or light conditioned stimulus, CS) twice paired with footshock (unconditioned stimulus), with or without a 30-s trace interval between these events to produce strong and weak learning conditions (a trace conditioning effect). During this conditioning session, the alternate stimulus (light or tone) was presented continuously in the background. Since the 5,7-DHT lesion also reduced the baseline licking response in the experimental chambers, we used drinking during the first minute, when this non-specific effect was minimal, as the dependent variable. We tested conditioning to target CS and to the alternative experimental background stimulus in exactly the same way in the same rats. We found that a level of serotonergic depletion without any intrinsic action on the trace conditioning effect nevertheless increased conditioning to the alternative background stimulus, irrespective of trace interval or stimulus modality. Thus, for both light and tone stimuli, the effect of serotonergic depletion depended only on the discrete target versus diffuse background role of the stimulus in use. These findings have implications for the modification of human cognition by serotonergic drugs.     

Disruption and potentiation of latent inhibition by risperidone: the latent inhibition model of atypical antipsychotic action.

Latent inhibition (LI), that is, retarded conditioning to a stimulus following its nonreinforced pre-exposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Potentiation of LI by antipsychotic drugs (APDs) given in conditioning, under conditions that do not lead to LI in controls, is a well-established index of antipsychotic activity. Recently, we have shown that the atypical APD, clozapine, in addition disrupts LI if administered in pre-exposure, under conditions that lead to LI in controls. This study demonstrates the same behavioral profile for the atypical APD risperidone. LI was measured in a thirst-motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone previously paired with a foot shock in rats that received nonreinforced exposure to the tone prior to conditioning (pre-exposed (PE)) and rats for whom the tone was novel (non-pre-exposed (NPE)). We show that under conditions that did not yield LI in vehicle controls (40 pre-exposures and five conditioning trials), risperidone (0.25, 0.5, and 1.2 mg/kg) led to LI when administered in conditioning. Under conditions that led to LI in vehicle controls (40 pre-exposures and two conditioning trials), risperidone (0.25, 0.5, and 2.5 mg/kg) abolished LI when administered in pre-exposure; the latter effect was not evident with haloperidol. In addition, the effects of risperidone administered in both the pre-exposure and conditioning stages were dose-dependent so that the pre-exposure-based action was manifested at lower but not at higher doses. It is concluded that atypical APDs exert in the LI model a dual pattern of effects, which enables detection of their 'typical' action (conditioning-based LI potentiation) as well as a dissociation from typical APDs by their 'atypical' action (pre-exposure-based LI disruption). It is suggested that the former and latter effects are subserved by D2 and 5HT2A antagonism, respectively.     

Restoration of latent inhibition by olanzapine but not haloperidol in entorhinal cortex-lesioned rats

RATIONALE: Latent inhibition (LI) refers to the decrease in conditioned response induced by the repeated non-reinforced pre-exposure to the conditioned stimulus before its pairing with the unconditioned stimulus during the conditioning stage. LI has been considered as a relevant animal model for the study of the biological bases of schizophrenia. LI has recently been demonstrated to depend on the integrity of the entorhinal cortex, as lesioning of this area disrupted LI. OBJECTIVES: The present study aimed to verify whether the classical neuroleptic haloperidol and/or the atypical antipsychotic olanzapine would prevent the effect of entorhinal cortex lesioning. METHODS: LI was studied in an off-baseline conditioned emotional response (CER) paradigm in which a tone is paired with a footshock. Entorhinal cortex lesions were produced by the electrolytic method. After a recovery period, both lesioned and control rats received either haloperidol (0.3 mg/kg), olanzapine (0.3 mg/kg) or vehicle before both the pre-exposure and conditioning stages of the experiment. RESULTS: In control rats, pre-exposure to the tone induced LI, which was affected by neither haloperidol nor olanzapine. Lesioning of the entorhinal cortex produced a deficit of LI, which was restored by olanzapine but not by haloperidol. CONCLUSIONS: This result suggests a dissociation of the anatomical and pharmacological targets of the two drugs. The possible involvement of dopamine D3 receptors in the effects of olanzapine is discussed.     

Clozapine and haloperidol reinstate latent inhibition following its disruption during amphetamine withdrawal.

Latent inhibition (LI) is a behavioral phenomenon whereby repeated exposure to a non-reinforced stimulus retards subsequent conditioning to that stimulus. Deficits in LI may reflect an inability to ignore irrelevant stimuli and are studied as a model of the cognitive/attentional abnormalities found in schizophrenia. We recently determined that pretreatment with escalating doses of the indirect dopamine agonist amphetamine (AMPH; 3 daily injections ip, 1-5 mg/kg, over 6 days) disrupts LI in rats tested in a 2-way active avoidance paradigm during withdrawal. In the present study, we evaluated the effects of the atypical neuroleptic clozapine and the typical neuroleptic haloperidol on the expression of LI on day 4 of AMPH withdrawal. Neuroleptic injections were given either 45 min prior to each of two tone preexposure sessions and a subsequent tone-shock avoidance test session, or only prior to the test session. As expected, saline-injected control groups showed LI during the test session, as reflected by significantly reduced avoidance in tone preexposed vs. non-preexposed rats. In contrast, animals pretreated with escalating doses of AMPH did not show LI, due to the improved avoidance of the preexposed animals. Both haloperidol (0.03 mg/kg) and clozapine (5 mg/kg) largely reversed the disruptive influence of AMPH on LI regardless of whether these drugs were administered prior to both preexposure and test sessions or only prior to the test session. These results provide pharmacological validation for an AMPH withdrawal model of schizophrenic symptoms.     

The effects of pipradrol on the acquisition of responding with conditioned reinforcement: A role for sensory preconditioning

Previous studies have shown that pipradrol enhances the acquisition of responding with conditioned reinforcement. The present experiments replicated this finding and assessed the possible role of nonspecific stimulus change, feeding in the test environment and procedure consisted of three phases: Operant rates of pressing two levers, one of which produced a 3-s tone, were measured in the pre-exposure phase; the tone was paired with food in the four conditioning sessions; and conditioned reinforcement was demonstrated in the test phase by a relative increase in pressing the tone lever. A group (N=8) receiving food but no tone during the conditioning phase also increased responding on the tone lever in the test phase and this effect was enhanced in a group (N=8) receiving pipradrol prior to the test. A group (N=8) receiving neither tones nor pellets during conditioning and pipradrol prior to test failed to show a change in lever bias, ruling out the possibility that pipradrol produced a nonspecific enhancement of responding for stimulus change. It was hypothesized that the conditioned reinforcement effect seen in the food-alone groups resulted from sensory preconditioning. According to this hypothesis, the tone was conditioned to environmental stimuli during the pre-exposure phase; subsequent presentation of pellets resulted in a learned association between environmental stimuli and food, leading to increased responding for the tone in the test phase. The results of two control experiments supported this view. One group (N=8) received no tone in the pre-exposure phase, pellets alone in the conditioning phase and then pipradrol prior to test. The second group (N=8) received pellets alone in the conditioning phase, but under altered environmental stimulus conditions, and then was given pipradrol prior to test. Neither group showed evidence of conditioned reinforcement. It was concluded that pipradrol enhanced acquisition of responding with conditioned reinforcement even if the conditioned reinforcing stimulus was established with sensory preconditioning procedures.     

Blockade of latent inhibition following pharmacological increase or decrease of GABA(A) transmission

The latent inhibition (LI) phenomenon refers to the retardation in learning of an association between a stimulus and a consequence if that stimulus had been previously experienced without consequence. An earlier study demonstrated that the benzodiazepine receptor agonist chlordiazepoxide (CDP), when administered before the phase of preexposure to the to-be-conditioned stimulus, impaired animals' ability to develop LI. The present study was designed to investigate the effect of the anxiogenic drugs pentylenetetrazole (PTZ) and the benzodiazepine partial inverse agonist Ro15-4513 on LI. Both anxiogenics, in contrast to CDP, are known for their GABA inhibitory action. The effects produced by the combined administration of a GABAergic function facilitator and inhibitor (CDP/PTZ and CDP/Ro15-4513) were also investigated. Both anxiogenic drugs led to an attenuation of LI, and, similarly to CDP, this attenuation was exclusively due to their administration prior to the preexposure stage of the experiment. However, this effect was abolished when anxiolytic and anxiogenic drugs were administered together, suggesting a pharmacological rather than behavioral summation of effects. These data also demonstrate the bidirectional GABAergic modulation of the LI phenomenon: both increased and decreased GABA(A) receptor activation led to reduced LI, thereby suggesting that an optimal receptor activation level is necessary for the normal establishment of LI.     

The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin.

Latent inhibition (LI), i.e., retarded conditioning to a stimulus following its nonreinforced preexposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Typical and atypical antipsychotic drugs (APD's) potentiate LI, but to date the model has not dissociated between them. This study demonstrates such a dissociation using haloperidol (0.1 mg/kg), clozapine (5 mg/kg), and ritanserin (0.6 mg/kg) administered in preexposure and/or conditioning. Under conditions which did not yield LI in vehicle controls (40 preexposures and five conditioning trials), both haloperidol and clozapine, but not ritanserin, led to LI when administered in conditioning. Under conditions which led to LI in vehicle controls (40 preexposures and two conditioning trials), clozapine and ritanserin, but not haloperidol, abolished LI when administered in preexposure. It is suggested that LI potentiation via conditioning detects the "typical" action of APD's whereas LI disruption via preexposure detects the "atypical" action of APD's.     

Assessing the relationship between latent inhibition and the partial reinforcement extinction effect in autoshaping with rats

Results from a variety of independently run experiments suggest that latent inhibition (LI) and the partial reinforcement extinction effect (PREE) share underlying mechanisms. Experiment 1 tested this LI=PREE hypothesis by training the same set of rats in situations involving both nonreinforced preexposure to the conditioned stimulus (LI stage) and partial reinforcement training (PREE stage). Control groups were also included to assess both LI and the PREE. The results demonstrated a significant, but negative correlation between the size of the LI effect and that of the PREE. Experiment 2 extended this analysis to the effects on LI and the PREE of the anxiolytic benzodiazepine chlordiazepoxide (5 mg/kg, i.p.). Whereas chlordiazepoxide had no effect on LI, it delayed the onset of the PREE. No evidence in support of the LI=PREE hypothesis was obtained when these two learning phenomena were compared within the same experiment and under the same general conditions of training.     

Latent inhibition is unaffected by direct dopamine agonists.

Latent inhibition (LI) refers to the finding that nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects a process of learning not to attend, or ignore, irrelevant stimuli. Previous experiments showed that LI was disrupted by low but not high doses of amphetamine, and facilitated by neuroleptic drugs. The present experiments sought to investigate the role of dopamine D1 and D2 receptors in LI disruption. Experiments 1 and 2 showed that the selective D1 agonist, SKF-38393 (1, 5, 10 mg/kg) and the selective D2 agonist, quinpirole (0.1, 0.3, 1.0 mg/kg), did not affect LI. Experiment 3 showed that both low (0.3 mg/kg) and high (1.5 mg/kg) doses of the mixed D1-D2 agonist, apomorphine, failed to affect L1. These results show that L1 is not disrupted by direct stimulation of DA receptors and suggest that the differential effect exerted on this phenomenon by apomorphine (and possibly SKF-38393 and quinpirole) and amphetamine is related to the direct versus the indirect agonist action of these drugs. In addition, apomorphine at the dose of 0.03 mg/kg, which is believed to activate preferentially DA autoreceptors, did not produce neuroleptic-like facilitation of LI. The implications of the results of the involvement of DA mechanisms in L1 are discussed.