Biomedical subjects

J N Rawlins

Publications and source records attributed to J N Rawlins.

At least 55 records · Page 3Linked to original sources

PubMed1996

Systemic NMDA antagonist CGP-37849 produces non-specific impairment in a working memory task: the effect does not resemble those of AP5 and of lesions of the hippocampus or fornix.

The N-methyl-D-aspartate (NMDA) receptor antagonist CGP-37849 (D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), administered i.p. (2.0 and 4.0 mg/kg), impaired rats' performance in a delayed matching-to-sample working memory task. This task is sensitive to hippocampal/fornix lesions or intracerebroventricular (i.c.v.) administration of another NMDA antagonist, AP5 (2-amino-5-phosphono-pentanoic acid) in a stimulus-specific manner: the highest impairment when simple stimuli are used repeatedly; moderate impairment when complex stimuli are used repeatedly; and no impairment when complex stimuli are used in a pseudo-trial-unique fashion. The effect of CGP-37849, unlike those of surgical lesions and of AP5, was not stimulus-specific and therefore cannot be solely attributed to blockade of NMDA-dependent long-term potentiation (LTP) in the hippocampus. We infer that systemic administration of NMDA antagonists may affect a broad range of anatomical structures thereby interfering with other neural mechanisms of memory and motor performance.

2-Amino-5-phosphonovalerate↗

PubMed1996

Effects of aspiration lesions of hippocampus or overlying neocortex on concurrent and configural object discriminations in rats.

Rats with aspiration lesions of the hippocampus plus overlying neocortex or control lesions of this cortex alone were trained on five-pair concurrent object discriminations in an enclosed Y-maze and subsequently on an open maze. Acquisition of the former task was impaired only in rats with cortical lesions, but on the latter both groups were equally impaired. Recombining positive and negative stimuli into novel pairs did not disrupt performance. Acquisition of single-pair discriminations was normal or slightly impaired in lesion groups. The cortical, but not the hippocampal group, was impaired on the concurrent learning of a positive and a negative pattern configural task. Recombining stimuli did not impair performance of this task either. The study demonstrates that extensive damage to the hippocampal formation need not necessarily impair concurrent learning, and impairments seen in other studies may relate to details of experimental procedure.

Animals↗

PubMed1996

Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway.

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.

Animals↗

PubMed1996

Differential involvement of the shell and core subterritories of the nucleus accumbens in latent inhibition and amphetamine-induced activity.

Latent inhibition (LI) consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. In view of findings that LI is disrupted in acute schizophrenic patients and evidence from animal experiments pointing to the involvement of the mesolimbic dopamine (DA) system in this phenomenon, the present study investigated the effects of electrolytic lesions to the shell and core subterritories of the nucleus accumbens on LI in rats (Expt. 1). LI was indexed by the amount of suppression of drinking in the presence of a tone that was either pre-exposed or not prior to its pairing with reinforcement (a foot shock). Expt.2 tested the effects of the DA antagonist, haloperidol, on LI in shell- and core-lesioned animals. Expt. 3 tested the effects of shell and core lesions on spontaneous and amphetamine-induced locomotion. In Expt. 1, LI, i.e., lower suppression of drinking in the pre-exposed as compared to the non-pre-exposed animals, was obtained in the sham-operated condition. Core and shell lesions produced distinct effects on LI. Animals with core lesions developed LI, but exhibited an overall lower suppression of drinking in comparison to the sham-operated animals. In contrast, shell lesions led to a disappearance of LI. Expt. 2 replicated the differential effects of shell and core lesions on LI, although in this experiment, core lesion did not attenuate suppression of drinking. Haloperidol prevented shell-induced abolition of LI. In Expt. 3, shell- but not core-lesioned animals were more active than sham controls following amphetamine administration. These results provide evidence for functional differences between the shell and core subregions, as well as for the involvement of the mesolimbic DA system in LI.

Amphetamine↗

PubMed1996

Cannabis use correlates with schizotypy in healthy people.

Cannabis use or high scores on self-report schizotypy questionnaires predict an increased risk of developing clinical psychosis. We tested whether cannabis use correlated with schizotypal and other personality traits in 211 healthy adults. Subjects who had used cannabis showed higher scores on schizotypy, borderline and psychoticism scales than never-users. Multivariate analysis, covarying lie scale scores, age and educational level indicated that high schizotypal traits best discriminated subjects who had used cannabis from never-users, whether or not they reported having used other recreational drugs. These results indicate that cannabis use is related to a personality dimension of psychosis-proneness in healthy people.

Adult↗

PubMed1995

Effects of the competitive NMDA receptor antagonist CGP 37849 on performance of reference and working memory tasks by rats.

The effects of the competitive NMDA receptor antagonist CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) were tested in rats performing (1) a nonspatial working memory task, and (2) a reference memory task that was either partly or fully learnt. CGP 37849 attenuated accuracy in all three tests, suggesting that sensorimotor effects may obscure any drug effects on memory itself.

2-Amino-5-phosphonovalerate↗

PubMed1995

Both electrolytic and excitotoxic lesions of nucleus accumbens disrupt latent inhibition of learning in rats.

Evidence indicating a role for the nucleus accumbens in the development of latent inhibition of learning has accumulated. Two experiments were conducted using Wistar rats to investigate this role directly. Experiment 1 used a conditioned emotional response paradigm to assess the effects of discrete electrolytic lesions in the shell region of the nucleus accumbens. Latent inhibition was attenuated by this lesion. In order to determine the contribution made by damage to fibers en passage associated with electrolytic lesions, Experiment 2 assessed the effects of NMDA-induced lesions in the shell of the nucleus accumbens in the same task. Latent inhibition was again significantly attenuated. These findings support the proposition that an intact nucleus accumbens is necessary for the normal development of latent inhibition.

Animals↗

PubMed1995

Potentiation of amphetamine-induced locomotor activity following NMDA-induced retrohippocampal neuronal loss in the rat.

The present experiment assessed the locomotor response to a low dose (1 mg/kg) of systemic D-amphetamine in rats with cytotoxic lesions of the retrohippocampus (entorhinal and extra-subicular cortices), compared with vehicle-operated shams and unoperated controls. Under spontaneous and saline conditions, both the sham and the lesioned animals were more active than unoperated controls, and they did not differ from each other. Systemic D-amphetamine produced increased locomotion in all groups, but this effect was potentiated in animals with retrohippocampal lesions; two control groups did not differ from each other in their response to the drug. The present results are consistent with the suggestion that cell loss within the retrohippocampal region could affect the functional response of nucleus accumbens to amphetamine. The results are discussed in terms of the interaction between the retrohippocampus and nucleus accumbens in the control of mesolimbic dopamine release and the possible implications for schizophrenia.

Animals↗

PubMed1995

The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia.

Latent inhibition (LI) consists in a retardation of conditioning seen when the to-be-conditioned stimulus is first presented a number of times without other consequence. Disruption of LI has been proposed as a possible model of the cognitive abnormality that underlies the positive psychotic symptoms of acute schizophrenia. We review here evidence in support of the model, including experiments tending to show that: (1) disruption of LI is characteristic of acute, positively-symptomatic schizophrenia; (2) LI depends upon dopaminergic activity; (3) LI depends specifically upon dopamine release in n. accumbens; (4) LI depends upon the integrity of the hippocampal formation and the retrohippocampal region reciprocally connected to the hippocampal formation; (5) the roles of n. accumbens and the hippocampal system in LI are interconnected.

Animals↗

PubMed1995

Serial position effects and duration of memory for nonspatial stimuli in rats.

Recognition memory for lists of nonspatial items was tested in rats using a nonmatching-to-sample task. The recency effect at short retention intervals disappeared as the interval increased, but primacy did not develop although responding was still above chance up to 2 hr after 10-s sample times. Neither proactive nor retroactive interference was apparent. Rats transferred the nonmatching-to-sample rule to completely novel stimuli. The study failed to replicate the prominent U-shaped serial position curve found in a similar study by P. Reed, T. Chih-Ta, J.P. Aggleton, and J.N.P. Rawlins (1991), for which E.A. Gaffan and D. Gaffan (1992) had found the data less variable than expected. Evidence of primacy in this procedure remains insubstantial.

Animals↗

PubMed1995

Latent inhibition in rats is abolished by NMDA-induced neuronal loss in the retrohippocampal region, but this lesion effect can be prevented by systemic haloperidol treatment.

Latent inhibition (LI) refers to the retardation in learning about the significance of a neutral stimulus that results from its nonreinforced preexposure. There is evidence that electrolytic or aspiration lesions of the hippocampal formation can disrupt LI (see I. Weiner, 1990). It has been suggested that this effect may stem from the interruption of a projection from the retrohippocampal region to the nucleus accumbens (A. J. M. Clark et al., 1992). The present experiment assessed this possibility by comparing LI in rats with retrohippocampal N-methyl-D-aspartate (NMDA) lesions extending from the entorhinal cortex to the ventral subiculum to that seen in vehicle controls and unoperated controls. LI was abolished by the retrohippocampal lesion. The effect of the lesion on LI was prevented by treatment with systemic haloperidol (0.2 mg/kg). The results are discussed with respect to an animal model of schizophrenia.

Animals↗

PubMed1995

Fornix-fimbria section and working memory deficits in rats: stimulus complexity and stimulus size.

Rats were trained on delayed matching-to-sample (DMS) with goalboxes containing complex objects as stimuli. On reaching the preoperative learning criterion, the rats were allocated to conventional fornix-lesioned or control groups. In a series of postoperative DMS experiments, different kinds of stimuli were used, ranging from complex object boxes to large, simple black or white goalboxes, with 3 transitional types in between. Lesions impaired choice accuracy whenever the rats were tested with large, simple goalboxes, but not with smaller boxes of otherwise identical construction. A brief, final experiment showed no amelioration of the lesion-induced impairment when complex objects were added to large, simple goalboxes. The results are discussed in terms of spatial and nonspatial accounts of hippocampal function.

Animals↗

PubMed1994

Working memory tasks in five-choice operant chambers: use of relative and absolute spatial memories.

Rats were trained to nose poke into illuminated holes to perform 1 of 2 different spatial working memory tasks (relative recency or reward history) in a 5-choice operant chamber. A series of experiments indicated that choice accuracy on both tasks depended on (a) the holes' spatial separation, and (b) their relative rather than absolute positions. The results suggest that accurate choice depended on using a motor mediation strategy to turn, so as to encounter the target (correct) hole before encountering the alternative (wrong) hole. The drugs administered to the rats, d-amphetamine, scopolamine, and CGP-37849 impaired choice accuracy on these tasks, even though task performance had not appeared to depend on explicit memory for the sample responses. This suggests that parallel drug effects obtained on other operant matching- or nonmatching-to-position tasks may not have reflected truly amnesic effects of the drug treatments.

2-Amino-5-phosphonovalerate↗

PubMed1994

The effects of hippocampal formation ablation or fimbria-fornix section on performance of a nonspatial radial arm maze task by rats.

Rats with fimbria-fornix section or complete hippocampal aspiration lesions were postoperatively compared to unoperated controls in a nonspatial working memory task using an enclosed plus maze. Initial training (stage 1) was on a continuous two-choice nonmatching to sample task, using pseudo-trial-unique stimuli. Subsequent testing (stages 2-4) always had four boxes available at each choice opportunity, with each goal arm containing a distinctive goalbox. The positions of these boxes were interchanged between choice opportunities, so as to ensure that their relative positions were variable. Extramaze cues were as far as possible excluded. Choices of goalboxes that had not yet been visited within each test session were rewarded. In stage 2, the goalboxes were complex in design, and rats with lesions chose as accurately as controls. In stage 3, within-session interference effects were demonstrated, but these effects were not exacerbated by the lesions. Stage 4 demonstrated that when goalboxes that were simple in design were used the rats in both lesion groups showed a substantial impairment of choice accuracy, even though choice accuracy using complex goalboxes remained unimpaired. This extended previous work demonstrating that hippocampal dysfunction can be associated with nonspatial working memory impairments when large boxes differing in surface texture and appearance are used as stimuli, even though no such impairments are seen when smaller boxes containing complex objects are used. Further experiments will be needed to establish the critical features underlying these nonspatial working memory deficits.

Analysis of Variance↗

PubMed1993

The effects of hippocampectomy on performance by rats of a running recognition task using long lists of non-spatial items.

Unoperated rats, or rats with cortical control lesions or hippocampal aspiration lesions, were trained on a non-spatial delayed non-matching-to-sample task. Once the non-matching rule had been learned, the task was modified so as to assess list memory, with list lengths of up to 32 items. Hippocampectomy induced a significant drop in choice accuracy, that was independent of list length; nonetheless, hippocampectomised rats still performed at better than chance levels. The cortical control lesion appeared to induce an intermediate (though generally non-significant) deficit. It was concluded that hippocampectomy leaves rats still capable of choosing with considerable accuracy on non-spatial working memory tasks that use trial-unique or 'pseudo-trial-unique' stimuli, even under experimental conditions in which a heavy memory load is imposed.

Animals↗

PubMed1993

Determinants of non-spatial working memory deficits in rats given intraventricular infusions of the NMDA antagonist AP5.

Two series of experiments using rats assessed the effects of intraventricular administration of the NMDA antagonist AP5 on performance of non-spatial working memory tasks. The first series used a continuous delayed non-matching to sample (DNMS) design; the second series used a discrete trial delayed matching to sample (DMS) design. Performance was assessed at retention intervals ranging from approximately 5 to 90 sec. The subjects had acquired the behavioural tasks before drug testing commenced. In the DNMS series, minipumps containing vehicle, 5, 10 or 15 nM D-AP5 were implanted. Every 10 days, each rat's minipump was removed and replaced with a fresh pump containing a new drug dose in a counterbalanced design, so that all rats were tested under all four conditions. There were no drug effects on performance at any retention interval. In the DMS series, there were three different basic task variants. Minipumps filled either with 15 mM D-AP5 or vehicle solution were implanted. Vehicle rats performed at approximately pre-operative levels; AP5 rats were impaired only on task variants using repeated stimulus presentations within session. There was no interaction between retention interval and drug treatment. This pattern of results closely resembles that seen following hippocampectomy or fornicotomy, as would be expected if this drug, administered intraventricularly, selectively affected hippocampal function.

2-Amino-5-phosphonovalerate↗

PubMed1993

Critical determinants of nonspatial working memory deficits in rats with conventional lesions of the hippocampus or fornix.

Rats with conventional lesions of the hippocampus or fornix were compared postoperatively with controls on nonspatial memory tasks. Neither lesion impaired delayed matching-to-sample (DMS) performance in a discrete-trial task involving "pseudo-trial-unique" complex stimuli. An impairment emerged if a single pair of complex stimuli was used throughout each day's session, and the greatest impairment was obtained with the use of a single pair of less complex stimuli throughout each day's test. Transfer to a continuous DMS task with no explicit intertrial interval produced a different pattern because both lesion and control levels of performance were depressed when two complex stimuli were used repeatedly. A final, separate discrimination learning experiment showed that hippocampectomized rats readily discriminated between the stimuli associated with the greatest lesion-induced DMS deficit. Hippocampal dysfunction thus produces clear deficits on non-spatial memory tasks under appropriate test conditions.

Animals↗

PubMed1992

Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats.

Rats with radiofrequency lesions of the fimbria/fornix or with extensive aspiration lesions of the hippocampal region (the hippocampus proper, dentate gyrus, and subicular complex) were tested on their performance of a delayed non-matching to position task which had been learnt before surgery. On a given trial, one of two sample levers was presented in a random manner. Following a response on this lever and a subsequent delay, both levers were presented and reward was now contingent on a response on the lever that was not used as the sample. Both lesions produced equivalent performance deficits on this test of spatial working memory, the pattern of these deficits being consistent with a mnemonic impairment. The lack of difference between these two groups on a variety of performance measures indicates that hippocampal connections passing through the fornix are not only necessary for this test, but that non-fornical hippocampal connections appear unable on their own to maintain accurate responding.

Animals↗