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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-conditioned 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.

Rats sustained electrolytic lesions either in the medial septal (MS) or lateral septal (LS) area or they were sham-operated. They were tested in the straight alley with food reward on either continuous (CRF) or partial (PRF) reinforcement at one trial a day and were injected with either 5 mg/kg chlordiazepoxide HCl (CDP) or with saline before the daily trial throughout the acquisition and extinction. The effects of the drug on resistance to extinction interacted with those of the LS lesion in ways which were consistent with the hypothesis that CDP acts via the lateral septal area if it is injected during acquisition on a PRF schedule. MS lesions produced only small changes in the effects of CDP. In general, CDP acted to reverse the effects produced by each lesion: Under those conditions in which MS lesions produced faster running speeds, CDP caused the lesioned animals to run slower; and under those conditions in which LS lesions produced slower running speeds, CDP caused the lesioned animals to run faster.

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 X 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.

Sodium amylobarbitone, scopolamine and septal and hippocampal lesions all reduce spontaneous alternation. However, septal lesions appear to reduce alternation of places more than body turns, while the reverse is true for hippocampal lesions. The present experiments tested the effects of amylobarbitone and scopolamine on place and body turn alternation. Medial and lateral septal lesions were also tested. The former block hippocampal theta rhythm but the latter do not. Amylobarbitone (20 mg/kg, IP) reduced alternation of body turns to chance levels when this was present in control animals, but it did not affect alternation of place. Scopolamine (1.2 mg/kg, IP) reduced both body turn alternation and place alternation. Medial septal lesions produced significant perseveration of body turns and produced a non-significant reduction in place alternation. Lateral septal lesions, tested in a small number of animals, did not appear to affect alternation. The treatments thus reduce spontaneous alternation in differing ways which can in part be accounted for in terms of their differing effects on hippocampal theta rhythm.

Adult offsprings of rats treated with daily injection of chlordiazepoxide (10 mg/kg, i.p.) during pregnancy showed a significant decrease in benzodiazepine receptors in the cortex and the cerebellum without apparent changes in receptor affinity. A reduced susceptibility to metrazol-induced epileptogenesis paralleled this change. These findings are discussed in relation to the differential vulnerability of various types of benzodiazepine receptors.

This study investigated the hypotheses that unpredictable prenatal stress has effects on the offspring, similar to those induced by perinatal administration of glucocorticoids and increases the vulnerability to stressful situations at adulthood. Rats were exposed to random noise and light stress throughout pregnancy. Offspring were tested for the development of spontaneous alternation behavior (SA) and at adulthood, their response to novel or aversive situations, open field, extinction and punishment following acquisition of an appetitive response and two-way active avoidance, were assessed. In prenatally stressed rats, the development of SA was significantly delayed. On repeated exposure to an open field they were less active; control rats had elevated plasma corticosterone (CCS) on days 2 and 4 of open field exposure, while prenatally stressed rats had significantly raised plasma CCS after each exposure (days 1-8). Furthermore, punishment-induced suppression of an appetitive response was enhanced. Acquisition of active avoidance was faciliated in female but reduced in male prenatally stressed offspring. It is suggested that random prenatal noise and light stress may cause impairment of development of hippocampal function which lasts into adulthood. This impairment is manifested as an increase in vulnerability and a decrease in habituation to stressful stimuli.

Rats were trained in a Y-maze on a two choice simultaneous brightness discrimination with light as S+ and dark as S- (position irrelevant). Animals in the Mastery group were trained until they reached criterion and were then switched to reversal, where the reinforcement contingencies of the original training were reversed. Animals in the Overtraining group received a further 110 trials before being switched to reversal. The administration of 1 mg/kg d-amphetamine facilitated dramatically reversal learning in Mastery group. Overtraining improved reversal in saline injected animals and slowed down reversal in amphetamine-treated animals. The drug also facilitated the acquisition of the initial brightness discrimination.

The possibility that Ro 15-1788, a specific benzodiazepine antagonist would reverse the anxiolytic effect of VPA (200 mg/kg) in the Geller-Seifter paradigm was tested, using male albino rats. VPA (200 mg/kg) induced disinhibition which was antagonized by a convulsant benzodiazepine, Ro 5-3663 (1 mg/kg), but not by imidazobenzodiazepine, Ro 15-1788 at doses of 10 mg/kg, or 30 mg/kg. However, Ro 15-1788 (30 mg/kg) did have a short lasting antagonistic effect on VPA when tested in a "condensed" form (see text) of the conflict test. The nature of the anticonflict potency of VPA is discussed.

Rats were given sham operations, vehicle injections, or injections of the axon-sparing excitotoxin ibotenic acid into the septum. In Experiment 1, behavioural testing commenced 16 days after the operation; in Experiment 2 behavioural testing commenced following testing on another task, 31 days after the operation. The rats were trained to run in an alley for food reward given on every trial (Continuous Reinforcement, CR) or on a random fifty percent of trials (Partial Reinforcement, PR) and then the running response was extinguished. All the experimental groups showed the normal partial reinforcement extinction effect (PREE) in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. However the rats with ibotenic acid lesions also showed a significant decrease in resistance to extinction regardless of training condition. The same pattern of results was seen at each of the two post-operative testing times. The results were thus readily replicable, and entirely unlike previous reports of the behavioural effects on this task of conventional septal lesions of equivalent size. In Experiment 3, neurochemical analysis of the hippocampus in rats with ibotenic acid-induced lesions demonstrated that choline acetyl-transferase levels were reduced to the same extent as in rats with comparable conventional lesions.

In the latent inhibition (LI) paradigm, prior nonreinforced exposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects learning not to attend to, or ignore, stimuli which predict no significant consequences. The present experiment tested the effects of chlordiazepoxide (CDP) on LI using a conditioned emotional response (CER) procedure consisting of three stages given 24 hr apart: preexposure, in which the to-be-conditioned stimulus, tone, was 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. Preexposure and conditioning were given off-baseline. CDP (5 mg/kg) was administered only in preexposure, only in conditioning, in both stages or in neither. The administration of the drug during tone-shock conditioning conducted off-baseline markedly reduced animals' suppression to the tone in a subsequent licking test which was conducted without the drug. The administration of CDP during nonreinforced preexposure to the tone abolished the development of LI, i.e., drug-treated preexposed animals did not show reduced suppression as compared to drug-treated nonpreexposed animals. These results demonstrate that CDP: a) blocks the acquisition of classically conditioned fear and b) disrupts animals' ability to learn that stimuli predict no significant outcomes.

The effects of amphetamine on the partial punishment effect (PPE) at one trial per day, were examined. Two groups of animals were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially punished (PP) group received food reward on every trial but in addition, received footshocks of a gradually increasing intensity in the goal box on a random 50% of the trials. In the test stage, all animals received both food and footshock on each trial. dl-Amphetamine 1.5 mg/kg was administered in a 2 X 2 design, i.e. drug-no drug in training and drug-no drug in test. The partially punished animals exhibited increased persitence in running to the goal box during test, and this "partial punishment effect" was unaffected by amphetamine.

Rats were trained to run in an alley for food reward given on every trial (continuous reinforcement, CR) or on a random 50% of trials (partial reinforcement, PR) and were then extinguished. Sham-operated controls showed the normal partial reinforcement extinction effect (PREE), in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. The PREE was significantly reduced by lesions of the fornix-fimbria. The reduction was largely a consequence of a reduction in resistance to extinction in PR-trained rats with fimbria-fornix lesions. These results are discussed in the light of other experiments that have studied disconnections in the septo-hippocampal system.

Our experiments were designed with two purposes: (i) to examine the effects on one behaviour of differing interventions in the septo-hippocampal system; (ii) to compare these effects with those of minor tranquillizers. The behaviour studied (in rats) is extinction in the alley after continuous (CRF) or partial (PRF) reinforcement. Minor tranquillizers and large septal lesions produce three effects: (1) resistance to extinction is increased after CRF; (2) resistance to extinction is decreased after PRF; (3) the partial reinforcement extinction effect (PREE) is abolished. Small septal lesions fractionate this syndrome: either effect (1) or an actual increase in the size of the PREE is produced by medial septal lesions abolishing hippocampal theta; effects (2) and (3), but not (1), are produced by lateral septal lesions sparing theta. Dorso-medial fornix section, abolishing theta, reproduces the effects of medial septal lesions. Fimbrial section, sparing theta, reproduces some of the effects of lateral septal lesions. Minor tranquillizers produce a rise in the threshold for septal driving of hippocampal theta specifically at 7.7 Hz. This effect is reproduced by blockade of noradrenergic transmission or destruction of the dorsal noradrenergic bundle with 6-hydroxydopamine. This lesion reproduces all three behavioural changes listed above. These results suggest a model for the role of the septo-hippocampal system and its noradrenergic inputs in the PREE. This model is compared with other approaches to the septo-hippocampal system.

Overshadowing (Experiment 1) and blocking (Experiment 2) were investigated using a conditioned suppression paradigm in rats. Neither hippocampectomy nor cortical control lesions affected the extent to which a salient stimulus overshadowed a less salient one. Nor did the lesions affect the extent to which a stimulus that was highly correlated with shock overshadow a stimulus that was less well correlated with shock. Finally, the lesions did not alter the extent to which a previously reinforced stimulus blocked conditioning to another stimulus when both were presented as a reinforced compound stimulus. It is thus possible for hippocampectomized rats to show apparently normal overshadowing and blocking, at least under some testing conditions.

Rats were trained in a Y-maze on a two-choice simultaneous black-white discrimination with either black or white as S+. Animals were then transferred to one of three discrimination tasks. In task 1 (New S-), a new stimulus, either vertical or horizontal stripes, was substituted for the original S-. In task 2 (New S+), a new stimulus, either vertical or horizontal stripes as in task 1, was substituted for the original S+. In task 3 (New S+/S-) animals were trained on horizontal-vertical discrimination. The pre-trial administration of 1 mg/kg d-amphetamine facilitated the acquisition of the original black-white discrimination with both black as S+ and white as S+. Likewise, the drug improved performance in all three transfer conditions. However, the course of learning in the three transfer tasks was different in the placebo- and amphetamine-treated animals. Amphetamine-treated animals were disrupted more by a change in S+ than by a change in S-, whereas the opposite pattern was evident in the placebo controls. When both discriminative stimuli were changed, placebo animals exhibited pronounced decrement in performance, whereas amphetamine animals exhibited excellent learning. The implications of these findings for the effects of amphetamine on discrimination learning are discussed.

Previous experiments have implicated ascending noradrenergic systems in the development of the behavioural responses to different patterns of reward. In this report food deprived male Sprague--Dawley rats were trained to run a straight alley for good reward on a continuous reinforcement (CRF) or a partial reinforcement (PRF) schedule. Tyrosine hydroxylase measured in a partially solubilized preparation from hippocampus and hypothalamus at the end of acquisition was not different from controls, indicating that enzyme induction does not occur during either training schedules. However, hippocampal synaptosomal tyrosine hydroxylation rates from the CRF group was significantly higher than from either the PRF group or the handled controls. This indicates that at the end of the acquisition schedule the noradrenergic projection to hippocampus was more active in the CRF group than with the PRF group or the handled control.

Clonidine has been reported to exert anti-anxiety effects in animals and man similar to those of benzodiazepines. The present experiment examined the effects of clonidine administration on the partial reinforcement extinction effect (PREE) which is known to be sensitive to benzodiazepine action. 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 quasi-random 50% schedule. All animals were then tested in extinction. Clonidine 50 micrograms/kg was administered in a 2 X 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction exhibited by PRF animals as compared to CRF animals, was obtained in animals that received saline in acquisition, independently of drug treatment in extinction, as well as in animals that received clonidine in both acquisition and extinction, but not in animals that received clonidine in acquisition alone. The administration of clonidine in extinction alone increased resistance to extinction in both the CRF and PRF animals. The increase in resistance to extinction, typically obtained with benzodiazepine treatment, indicates that clonidine exerts anxiolytic effects, supporting the involvement of the noradrenergic system in anxiety. However, clonidine did not fully reproduce the effects of benzodiazepines on the PREE, suggesting that the two classes of drugs may act via different noradrenergic mechanisms.

The effects of amphetamine administration on the partial reinforcement extinction effect (PREE) 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. dl-Amphetamine 1.5 mg/kg was administered in a 2 X 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction exhibited by PRF animals as compared to CRF animals, was obtained in animals that received saline in acquisition, independently of drug treatment in extinction. In contrast, amphetamine administered in acquisition abolished the PREE irrespective of drug treatment in extinction. In addition, amphetamine administered in extinction alone increased resistance to extinction in PRF animals.

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.

Adult male and female offspring of rats injected daily with 10 mg/kg chlordiazepoxide during their pregnancy exhibited a facilitated acquisition of a two-way active avoidance response. Benzodiazepine receptor assays carried out on cortex and cerebral samples taken from experimental and control female rats showed a significant decrease in the density of benzodiazepine receptors, without changes in receptor affinity.

Two experimental procedures were employed to establish the reason why hippocampal lesions apparently block the development of tolerance for aversive events in partial reinforcement experiments, but do not do so in partial punishment experiments. Rats were trained to run in a straight alley following hippocampal lesions (HC), cortical control lesions (CC) or sham operations (SO), and resistance to extinction was assessed following differing acquisition conditions. In Experiment 1 a 4-8 min inter-trial interval (ITI) was used. Either every acquisition trial was rewarded immediately (Continuous Reinforcement, CR), or only a randomly selected half of the trials were immediately rewarded, the reward being delayed for thirty seconds on the other trials (Partial Delay, PD). This delay procedure produced increased resistance to extinction in rats in all lesion groups. In Experiment 2 the ITI was reduced to a few seconds, and rats were trained either on a CR schedule, or on a schedule in which only half the trials were rewarded (Partial Reinforcement, PR). This form of partial reinforcement procedure also produced increased resistance to extinction in rats in all lesion groups. It thus appears that hippocampal lesions only prevent the development of resistance to aversive events when the interval between aversive and subsequent appetitive events exceeds some minimum value.

Three experiments were carried out to test the long-term behavioral effects of 12 days administration of CDP (5 mg/kg/day) in rats. In the first two experiments, 4 weeks after the end of drug administration (CDP or placebo), and after 2 weeks of training to run a straight alley for food reward, animals were tested in extinction, i.e., following omission of reward (Expt. 1) or with punishment, i.e., 0.3 mA electric shock in addition to the food reward (Expt. 2). Drug-treated animals showed significantly increased resistance to extinction and to punishment compared with controls. In the third experiment, 10 weeks after drug administration, animals were exposed to 60 s of intense noise to induce audiogenic seizures. The convulsant metrazol was injected 5 min prior to successive sessions (10 min apart) with doses starting at 10 mg/kg an increased by 10 mg/kg each session up to 40 mg/kg. Drug-treated animals were significantly less susceptible to seizures than their placebo controls. These results suggest that chronic benzodiazepine treatment causes long-term neurochemical changes which are responsible for the observed behavioral effects.

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.

Latent inhibition (LI) is a behavioral paradigm in which nonreinforced pre-exposure to a stimulus retards subsequent conditioning to that stimulus. The development of LI is considered to reflect learning not to attend to, or ignore, irrelevant stimuli. In our previous studies investigating the effects of early handling on LI, we have shown that normal LI was obtained in handled males and females, as well as in nonhandled females. In contrast, nonhandled males failed to show LI. This finding pointed to a long-term attentional deficit in nonhandled males. Since there is evidence that the development of LI is mediated by the dopaminergic system, the present experiments tested the possibility that the attentional deficit of nonhandled males may be related to a dopaminergic dysfunction. Experiment 1 tested whether the administration of haloperidol, which was shown to enhance LI in normal animals, would reinstate the LI effect in nonhandled males. Infantile handled (Days 1-22) and nonhandled male and female rats were tested in maturity in the LI paradigm, using a conditioned emotional response procedure. Experiment 2 tested the locomotor response of handled and nonhandled males to 0.3, 1 and 2.5 mg/kg D-amphetamine. Experiment 1 showed that handled males, handled females and nonhandled females showed a normal LI effect, whereas nonhandled males failed to develop LI. Haloperidol enhanced LI in all the groups, but this effect was most dramatic in nonhandled males, in which the drug reinstated LI. Experiment 2 showed that nonhandled males exhibited a reduced locomotor response to D-amphetamine.

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.

A modified Geller-Seifter paradigm was employed to test in male albino rats the effects of subthreshold doses of amphetamine and chlordiazepoxide (CDP), administered separately or in combination, on shock induced suppression of food-reinforced lever-pressing. MK-801, a newly synthesized sympathomimetic with anxiolytic and anticonvulsant properties, was also tested. dl-Amphetamine in doses of 0.1, 0.2, 0.3, and 1.0 mg/kg had no anxiolytic nor anxiogenic effects, but at 1.0 mg/kg it increased non-conflict responding. CDP in doses of 0.1, 0.2, and 0.4 mg/kg had no significant effect on conflict and non-conflict responding. CDP in the dose of 0.8 mg/kg tended to increase conflict responding. Coadministration of amphetamine (0.2 mg/kg) and CDP (0.4 mg/kg) had a significant anti-conflict effect. MK-801 at 50 micrograms/kg and 100 micrograms/kg caused a significant increase in non-conflict responding. MK-801 at 50 micrograms/kg exerted also a significant anti-conflict effect. The disinhibitory effects of amphetamine coadministered with CDP were discussed in terms of a possible enhanced noradrenergic or dopaminergic activity and their interaction with GABA neurotransmission at GABA-benzodiazepine coupled sites.

Rats were trained in a Y-maze on a two-choice simultaneous brightness discrimination with light as S+ and dark as S- (Stage 1), and were then switched to reversal, where the reinforcement contingencies of the original training were reversed (Stage 2). d-Amphetamine, 1 mg/kg, was administered in a 2 X 2 design, i.e., drug-no drug in Stage 1 and drug-no drug in Stage 2. The administration of the drug in Stage 1 improved the acquisition of the initial brightness discrimination and facilitated reversal learning independently of the drug administered in Stage 2. In addition, the administration of the drug in Stage 2 only improved performance towards the end of reversal training. The results indicate that amphetamine enhances the attention to, or the associability of, the discriminative stimuli, leading to a rapid learning to these stimuli under changed contingencies of reinforcement.

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.

Intracerebral injections of ibotenate were used to produce, in rats, extensive cell loss in the hippocampus and dentate gyrus (complete hippocampal, CH), in the CH plus subiculum (SUB + CH), or in the subiculum plus entorhinal cortex (SUB + EC). These rats and sham-operated controls were trained to run in a straight alley for food reward delivered on a continuous (CR) or partial (PR) reinforcement schedule. In controls PR training gave rise to the well-known partial reinforcement extinction effect (PREE), i.e., greater resistance to extinction than that observed in CR-trained animals. Previous work had shown that large aspiration lesions of the hippocampal formation eliminate the PREE by increasing resistance to extinction in CR-trained animals and decreasing resistance to extinction in PR-trained animals. In the present experiments the PREE survived CH lesions, which increased resistance to extinction in both CR and PR training conditions; these effects were observed in the start and run (but not goal) sections of the alley. In contrast, subicular cell loss (in both SUB + CH and SUB + EC groups) abolished the PREE (but in the goal section only) by increasing resistance to extinction in the CR condition and decreasing resistance to extinction in the PR condition. In addition, some of the effects of PR training on start and run speeds during acquisition were altered by the CH and SUB + CH lesions. These results confirm previous data showing that the hippocampal formation plays a role in mediating the behavioural effects of PR training, but require modification of the model previously proposed to account for these data.

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.

Latent inhibition (LI) is a behavioral paradigm in which repeated exposure to stimuli not followed by meaningful consequences renders these stimuli ineffective for subsequent learning. The development of LI is considered to reflect learning not to attend to, ignore, or tune out irrelevant stimuli. The present study investigated the differences in the development of LI between handled and nonhandled males and females. Infantile handled (Days 1-22) and nonhandled, male and female Wistar rats were tested in maturity in the LI paradigm. The LI procedure consisted of two stages: pre-exposure, where animals received 60 presentations of the to-be-conditioned stimulus (tone) and test, where the animals acquired a two-way active avoidance response with the tone serving as the warning signal. Handled animals reached higher percentage of avoidance responses as compared with nonhandled animals. Latent inhibition was obtained in both the handled and the nonhandled females, but only the handled males showed the LI effect. Nonhandled males failed to develop LI. The results indicate that the effects of handling are evident in learning tasks that do not involve motivational-emotional variables, i.e., learning to ignore irrelevant stimuli; handling differentially affects males and females, with a much greater impact on males and the nonhandling procedure has significant deleterious consequences on adult behavior.

We have previously shown that sera from patients with Alzheimer's disease (AD) contain a significantly high level of antibodies to the cell bodies (Perikarya; PK) but not to the nerve terminals (synaptosomes) of purely cholinergic neurons from the electric fish Torpedo. In the present study we examined the effect of repeated immunization of rats with either of these antigens for one year. Immunoblot studies revealed that sera of cholinergic PK immunized rats contained a high level of antibodies to cholinergic PK proteins, in particular to a 200 kilodalton protein, to which there are specifically high levels of antibodies in AD. Sera from rats immunized with cholinergic synaptosomes and from control rats contained very low levels of these antibodies. Behavioral studies performed one year after the initial immunization revealed that the cholinergic PK immunized rats were impaired in spatial learning and memory tasks (Morris swim test and T-maze alternation) when compared to control rats and that the synaptosome-immunized rats showed no such deficit. In contrast, the three groups performed similarly in general activity, active avoidance and conditioned emotional response tests. Further experiments revealed that the cholinergic PK immunized rats displayed a significant deficit in short term memory. The association of antibodies to cholinergic neurons with cognitive deficits in this rat model suggests that such antibodies may be involved in the pathogenesis of AD.