I. Weiner

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.

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.

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.

The effects of smoking on acoustic prepulse inhibition in healthy men and women

Abstract Acoustic prepulse inhibition (PPI) refers to the reduction of the startle reflex to an intense stimulus if it is preceded by a weak stimulus. Nicotine and smoking have been reported to enhance PPI in rats and in healthy men, respectively. We studied the influence of smoking on PPI in healthy men and women, comparing non-smokers, deprived smokers, and smokers smoking during the test session after deprivation or after ad libitum smoking. Smoking during the session enhanced PPI, without affecting startle reaction or habituation over time. In addition, the effect of smoking on PPI was gender dependent. In men, ad libitum smoking enhanced PPI compared with non-smokers, while, in women, deprivation reduced PPI and smoking restored PPI to the level of non-smokers.

Differential Effects of Prenatal Stress in Two Inbred Strains of Rats

The long-term effects of prenatal stress (three times daily restraint stress during the last week of gestation) on the behavioral response to stress, as assessed by novelty-induced locomotion, performance in the forced swim test, and the acquisition of a two-way active avoidance, were investigated in two inbred strains of rats, Fischer 344 (F344/NHsd/Zur) and Lewis (LEW/SsNHsd/Zur). Additional measures included birth weights, pain threshold on the hot plate, and basal and stress-induced corticosterone secretion. In all of the behavioral paradigms strain differences were found: LEW rats showed poorer acquisition of avoidance conditioning, displayed higher levels of activity on the open plate, less immobility time in the forced swim test, and lower pain thresholds in the hot-plate test compared with F344 rats. LEW rats had higher birth weights after prenatal stress, whereas F344 rats were lighter. Following prenatal stress the pattern of behavioral effects obtained in LEW rats in stress-related tests could be interpreted as improved coping abilities with stress, i.e., improved acquisition of active avoidance, less immobility in the forced swim test, and reduced novelty-induced locomotion. Prenatal stress was much less effective in inducing long-term behavioral changes in F344 rats, yielding only one effect, namely, enhanced novelty-induced locomotion in female F344 rats. Pain thresholds were increased as a consequence of prenatal stress, irrespective of strain and gender. Basal and stress-induced corticosterone release differed in the two strains, with LEW rats showing less stress-induced corticosterone release. Prenatal stress did not, however, affect basal or stress-induced corticosterone release. The results suggest that prenatal stress exerts long-term effects on behavior, which depend on the genetic background.

Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol

AbstractnRationale. Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure, and disrupted LI in the rat is considered to model an attentional deficit in schizophrenia. Blockade of NMDA receptor transmission, which produces behavioral effects potentially relevant to schizophrenic symptomatology in several animal models, has been reported to spare LI.nObjectives. To show that systemic administration of the non-competitive NMDA antagonist MK-801 will lead to an abnormally persistent LI which will emerge under conditions that disrupt LI in controls, and that this will be reversed by the atypical neuroleptic clozapine but not by the typical neuroleptic haloperidol, as found for other NMDA antagonist-induced models.nMethods. LI was measured in a thirst-motivated conditioned emotional response (CER) procedure by comparing suppression of drinking in response to a tone in rats which previously received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by two (experiment 1) or five (experiments 2–5) tone – foot shock pairings.nResults. MK-801 at doses of 0.1 and 0.2xa0mg/kg reduced conditioned suppression while no effect on suppression was seen at the 0.05xa0mg/kg dose. At the latter dose, intact LI was seen with parameters that produced LI in controls (40 pre-exposures and two conditioning trials). Raising the number of conditioning trials to five disrupted LI in control rats, but MK-801-treated rats continued to show LI, and this abnormally persistent LI was due to the action of MK-801 in the conditioning stage. MK-801-induced LI perseveration was unaffected by both haloperidol (0.1xa0mg/kg) and clozapine (5xa0mg/kg) administered in conditioning, and was reversed by clozapine but not by haloperidol administered in pre-exposure.nConclusion. MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly relevant to negative symptoms of schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration may model impaired attentional set shifting associated with negative symptoms of schizophrenia. Moreover, the finding that the action of MK-801 on LI and the action of clozapine are exerted in different stages of the LI procedure suggests that the MK-801-based LI model may provide a unique screening tool for the identification of novel antipsychotic compounds, whereby the schizophrenia-mimicking LI abnormality is drug-induced, but the detection of the antipsychotic action is not dependent on the mechanism of action of the pro-psychotic drug.

Reversal and nonreversal shifts under amphetamine

Rats were trained in a Y maze on a two-choice simultaneous brightness discrimination with light as S+ and dark as S− (position irrelevant). Half of the animals were then switched to reversal, where the reinforcement contingencies of the original training were reversed, and the other half were switched to nonreversal, in which they learned a simultaneous right-left discrimination. Nonreversal was acquired faster than reversal in saline injected animals. The administration of 1 mg/kg d-amphetamine did not affect the acquisition of the initial brightness discrimination and of nonreversal. In contrast, the drug facilitated dramatically reversal learning.The results indicate that amphetamine enhances the attention to, or the associability of, the discriminative stimuli, leading to rapid learning to these stimuli under changed contingencies of reinforcement.

The effects of haloperidol on the partial reinforcement extinction effect (PREE): implications for neuroleptic drug action on reinforcement and nonreinforcement

The effects of haloperidol 0.1 mg/kg on the partial reinforcement extinction effect (PREE) paradigm at one trial a day, were examined. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasirandom 50% schedule. All animals were then tested in extinction. Haloperidol 0.1 mg/kg was administered in a 2 × 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction of partially reinforced as compared to continuously reinforced animals, was obtained in all four drug conditions. The administration of haloperidol in acquisition increased markedly resistance to extinction in CRF animals. The administration of the drug in extinction decreased resistance to extinction in both CRF and PRF animals. The results are explained in terms of two independent actions of haloperidol: the well-known effect of reduction in the effectiveness of reinforcement as well as enhancement of the effectiveness of nonreinforcement.

The abolition of the partial reinforcement extinction effect (PREE) by amphetamine: Disruption of control by nonreinforcement

Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received a food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. d-Amphetamine 1 mg/kg was administered to PRF animals in acquisition in a 2 X 2 design, i.e., drug-no drug on reinforced trials and drug-no drug on nonreinforced trials. In four CRF groups, the drug was administered in the same sequence as in the PRF groups. Following acquisition, all animals were given 4 days of CRF retraining and tested in extinction. No drug was given in retraining and extinction. The PREE, i.e., increased resistance exhibited by PRF animals as compared to CRF animals, was obtained in groups which received placebo on all acquisition trials or amphetamine on rewarded trials and placebo on nonrewarded trials. The PREE was abolished when amphetamine was administered throughout the acquisition trials or on nonrewarded trials, irrespective of drug treatment on rewarded trials.

The effects of amphetamine on a multitrial partial reinforcement extinction effect (PREE) in an operant chamber

Two experiments investigated the effects of d-amphetamine (1 mg/kg) on the partial reinforcement extinction effect (PREE) in an operant chamber using a discrete multitrial procedure. Experiment 1 used a random 50% partial reinforcement (PRF) schedule. Experiment 2 used two 40% PRF schedules: one schedule maximized the number of nonreinforced trials preceding any given reinforced trial (maximum N-length of four) and the second maximized the number of N-R transitions (N-length of one). In both experiments, the continuously reinforced (CRF) animals received a reward on every trial. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in the random 50% PRF and the schedule maximizing N-length in both the placebo and amphetamine-treated animals. Both drug and no-drug animals failed to exhibit PREE on the schedule maximizing N-R transitions. These results show that on a PRF schedule with short intertrial intervals, amphetamine-treated animals are not impaired in their capacity to learn sequences of events and to associate the outcomes of preceding trials with subsequent consequences.