Involvement of the rat prefrontal cortex in a delayed reinforcement operant task

To determine whether the rat medial prefrontal cortex (PFC) is involved in delayed reinforcement operant behavior, we studied the effects of transient inactivation of the medial PFC (or the hippocampus as a control) during a delayed reinforcement lever-press task. We demonstrated the involvement of the PFC in this task: PFC inactivation but not hippocampal inactivation significantly impaired performance. In a separate experiment, we also recorded the prefrontal multiple unit activities during the task to determine the roles of the PFC in detail. Neuronal activity decreased during the delay period, suggesting that this decrease plays a role in delayed reinforcement operant behavior.     

Mouse hippocampo-prefrontal paired-pulse facilitation and long-term potentiation in vivo

To confirm neural plasticity of the mouse hippocampo-prefrontal cortex (PFC) pathway, paired-pulse facilitation (PPF) and long-term potentiation (LTP) induction were determined in the pathway. In addition, we tested whether the plasticity differs in projections of the pathway from the dorsal (upper) and ventral (lower) parts of the temporal hippocampus. The results showed PPF and LTP of this pathway, and these differed between the projections. The projection from the upper part showed stronger PPF and weaker LTP compared with that from the lower part. These results suggest that the mouse hippocampo-PFC pathway is involved in learning and memory, and contains projections related to different functions.     

Effects of short-lasting inactivations of the ventral hippocampus and medial septum on long-term and short-term acquisition of spatial information in rats

This study was aimed at testing the effects of a reversible inactivation of the hippocampal formation on long-term and short-term acquisition of spatial information. Rats chronically equipped with either bilateral cannulae into the ventral hippocampus or a single cannula into the medial septum had to locate, in a circular platform with 18 holes on the periphery, the unique hole leading to a hidden shelter in order to avoid bright light. In Expt. 1, following 16 days of training (1 trial/day, 24 h ITI) without physical intervention, the location of the correct hole was changed on both Days 17 and 23, and the rats were either sham-injected or injected with lidocaine. Both hippocampally and septally lidocaine-injected rats relearned the new location at a rate similar to corresponding sham-injected animals. In Expt. 2, a massed-trial version of the task was used, in which the rats had to learn a new hole location on each daily session (3 trials, ITI = 1 min). Animals were sham-injected or lidocaine-injected on alternate sessions. While sham-injected rats improved in orientational accuracy over successive trials, both hippocampally and septally lidocaine-injected rats failed to display any between-trial improvement. The impairment displayed by lidocaine-injected rats when their hippocampus was inactivated confirms the role of the hippocampus in short-term spatial memory (Expt. 2). In contrast, short-lasting inactivation of the hippocampus did not prevent long-term spatial learning (Expt. 1). These results suggest that the hippocampus could process information 'off-line' in the delay between temporally discontiguous learning trials, and show that short-term and long-term spatial learning rely on distinct neurobiological mechanisms.     

Intra-hippocampal lidocaine injections impair acquisition of a place task and facilitate acquisition of a response task in rats

While hippocampal lesions impair learning and memory in many tasks, such lesions also enhance learning and memory in other tasks. The present experiment examines the effects of inactivation of the hippocampus with lidocaine prior to learning, to find food in a place or response version of a four-arm plus-shaped maze. Rats received lidocaine injections 6 min prior to training. Rats were trained in a single session to a criterion of 9/10 correct responses. Compared to artificial cerebrospinal fluid (aCSF)-injected controls, rats with intra-hippocampal injections of lidocaine exhibited significantly retarded acquisition of place learning. In marked contrast, rats with intra-hippocampal injections of lidocaine exhibited significantly enhanced acquisition of response learning compared to their controls. In addition to showing that the hippocampus is important for learning the place task, these findings suggest that processing of information by the hippocampus interferes with learning a task dependent on a different neural system.     

A comparison of normal old rats and young adult rats with lesions to the hippocampus or prefrontal cortex on a test of matching-to-sample.

Rats with lesions to the dorsal hippocampus (HPC) or prefrontal cortex (PFC), normal old rats, and young adult controls were compared on a test of matching-to-sample. Subjects were presented with two lights in succession and were trained to press a lever when the lights were the same brightness and withhold a lever-press when they were different. The PFC and aged groups, but not the HPC group, were impaired when the comparison stimulus was presented immediately after the sample stimulus. When delays of 5 and 15 sec were introduced between the stimuli, the HPC and aged groups' performance deteriorated to chance levels. The PFC group's performance was not differentially affected by the delays. The results were consistent with previous findings that implicated the HPC in episodic memory and the PFC in working memory. The aged group was impaired on both types of memory, revealing signs of HPC and PFC dysfunction.     

Behavioral and morphological alterations following neonatal excitotoxic lesions of the medial prefrontal cortex in rats

The prefrontal cortex (PFC) is essential for executive functions in mammals. Damage of the developing PFC may partly be compensated over time, but may also lead to structural and functional deficits due to neurodevelopmental disturbances. The present study investigated the effects of excitotoxic lesions of the medial PFC (mPFC) in neonatal rats on brain morphology, myelination and behavior. Neonatal lesions were induced with ibotenate on postnatal day (pd) 7 and all animals were tested pre- and postpubertally for prepulse inhibition (PPI) of the acoustic startle reflex (ASR), locomotor activity and food preference. Furthermore, adult rats were tested for apomorphine sensitivity of PPI and for their performance in a progressive ratio operant response task. Neonatally lesioned animals showed a reduced volume of the mPFC, enlarged ventricles and a deficient myelination in some projection areas of the mPFC, including the thalamus, hippocampus, nucleus accumbens (NAC) and amygdala. PPI was enhanced in lesioned rats when tested as juveniles, but PPI-deficits induced by the dopamine receptor agonist apomorphine were exacerbated in adult rats after neonatal mPFC lesion. Furthermore, the break point in a progressive ratio task was lower in lesioned animals, whereas the total number of lever presses was initially increased, indicating an impulsive response of rats for food reward under a progressive ratio schedule after neonatal mPFC lesion. No effects were found on food preference and open field performance. These data support the hypothesis that neonatal mPFC lesions lead to disruptions of neurodevelopmental processes in a cortico-limbic-striatal network, which are manifested in adult animals as morphological and behavioral disturbances.     

The role of the medial prefrontal cortex of rats in short-term memory functioning: further support for involvement of cholinergic, rather than dopaminergic mechanisms

The putative involvement of the dopaminergic innervation of the medial part of the prefrontal cortex (PFC) in short-term memory functioning was investigated by evaluating the effects of local infusions of dopaminergic drugs into the ventral part of the medial PFC of rats in an operant delayed-matching-to-position (DMTP) task. Two separate groups of rats were tested after bilateral microinfusion of several doses of either the dopamine receptor agonist apomorphine (APO) or the dopamine receptor antagonist cis-flupenthixol (FLU) into the ventromedial PFC. In addition, all animals were tested after infusion of several doses of the muscarinic receptor antagonist scopolamine (SCO) and the dopamine D1 receptor antagonist SCH-23390 (SCH). The drugs tested affected DMTP performance differentially. APO had no effect on response accuracy, although it dose-dependently affected nose poke activity and response latencies. FLU and SCH both induced a dose-dependent, but delay-independent deterioration of response accuracy that was paralleled by increased in response latencies and decreases in nose poke frequencies, causing some animals to stop responding after infusion of the highest doses of both drugs. In contrast, SCO infusions into the ventromedial PFC induced a dose- and delay-dependent deterioration of response accuracy, that was accompanied by an increase in response latencies only. Taken together, these results provide additional support for the involvement of cholinergic, rather than dopaminergic mechanisms in short-term memory processes supported by the medial PFC of the rat, and they are not in favor of a functional dissociation between the dorsomedial PFC and the ventromedial PFC in this role.     

Preserved configural learning and spatial learning impairment in rats with hippocampal damage.

This study was undertaken to compare the effect of hippocampal neurotoxic lesions in rats on two behavioral tasks, one a test of spatial learning, and the other an operant discrimination task that is acquired by forming nonspatial configural associations. Lesions of the hippocampus were made with microinjections of ibotenic acid. After postoperative recovery, rats were trained initially to locate a camouflaged escape platform in a water maze using distal spatial cues. Rats also were trained in the maze apparatus with a visible escape platform under conditions in which spatial information was made irrelevant to performance, i.e., cue learning. In an operant task, the same rats were then trained on a discrimination that included simultaneous feature positive and feature negative components (trial types XA+, A-, XB-, B+). After completion of this nonspatial configural learning task, rats received additional training in the water maze using a new platform location for spatial learning. To the extent that proficient performance in both the maze and operant tasks depends on a common function of the hippocampus, i.e., configural learning, the expectation was that hippocampal lesions would prove equally detrimental to performance in both tasks. Contrary to this expectation, lesioned rats were severely impaired in spatial learning but readily acquired the operant discrimination, even exhibiting some evidence of enhanced performance on this nonspatial configural learning task. Performance of the lesioned rats during cue training in the water maze was also enhanced relative to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of the dorsal subiculum and rostral basolateral amygdala in cocaine cue extinction learning in rats

Memory system circuitry may regulate how cues associated with cocaine are extinguished, and understanding neurosubstrates of extinction may lead to the development of improved treatment strategies for cocaine addiction. Sites within the hippocampus and amygdala were investigated for their role in regulating cocaine cue extinction learning. Initially, rats were trained to self-administer cocaine under a second-order reinforcement schedule (cocaine and cocaine cues present) followed by a 2-week abstinence period. Using lidocaine, rats next underwent bilateral inactivation of the dorsal subiculum (dSUB) or rostral basolateral amygdala (rBLA), asymmetric inactivation of the dSUB and rBLA, unilateral inactivation of the dSUB or rBLA, or ipsilateral inactivation of the dSUB and rBLA prior to cocaine cue extinction training sessions (only cocaine cues present) on two consecutive days. Relative to vehicle, bilateral and asymmetric lidocaine treatments in the dSUB and rBLA slowed cocaine cue extinction learning. Specifically, vehicle-treated rats exhibited a significantly larger difference in responding from Day 1 to Day 2 of extinction training than lidocaine-treated rats. In comparison, unilateral or ipsilateral lidocaine treatments in the dSUB and rBLA did not slow cocaine cue extinction learning. Rats treated with lidocaine and vehicle exhibited a similar difference in responding from Day 1 to Day 2 of extinction training. These results indicate that sites within the hippocampus and amygdala need to be functionally active simultaneously in at least one brain hemisphere for acquisition of cocaine cue extinction learning. These results further suggest that a serial circuit within each hemisphere mediates acquisition of cocaine cue extinction learning.     

Ventral hippocampal lesions affect anxiety but not spatial learning

Rats with cytotoxic ventral hippocampal lesions which removed approximately 50% of the hippocampus (including dentate gyrus) starting from the temporal pole, displayed a reduction in freezing behaviour following the delivery of an unsignalled footshock in an operant chamber. This was more plausibly a result of reduced susceptibility to fear than a result of a lesion-induced increase in general motor activity. There was no consistent difference between sham and lesioned animals in spontaneous locomotor activity, or locomotion following acute or chronic treatment with amphetamine. In contrast, ventral hippocampal lesioned animals were quicker to pass from the black to the white box during a modified version of the light/dark exploration test, and were quicker to begin eating during tests of hyponeophagia. Furthermore, rats with ventral hippocampal lesions defecated less than their sham counterparts both during open field testing and in extinction sessions following contextual conditioning. In contrast to these clear lesion effects, there were no signs of any spatial learning impairment either in the watermaze or on the elevated T-maze. Taken together these results suggest that the ventral hippocampus may play a role in a brain system (or systems) associated with fear and/or anxiety, and provide further evidence for a distinct specialisation of function along the septotemporal axis of the hippocampus.     

A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso-lateral striatum

The objectives of this research were to further delineate the neural circuits subserving proposed memory-based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context-specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context-specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso-lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.     

Functional neuroimaging of emotionally intense autobiographical memories in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) affects regions that support autobiographical memory (AM) retrieval, such as the hippocampus, amygdala and ventral medial prefrontal cortex (PFC). However, it is not well understood how PTSD may impact the neural mechanisms of memory retrieval for the personal past. We used a generic cue method combined with parametric modulation analysis and functional MRI (fMRI) to investigate the neural mechanisms affected by PTSD symptoms during the retrieval of a large sample of emotionally intense AMs. There were three main results. First, the PTSD group showed greater recruitment of the amygdala/hippocampus during the construction of negative versus positive emotionally intense AMs, when compared to controls. Second, across both the construction and elaboration phases of retrieval the PTSD group showed greater recruitment of the ventral medial PFC for negatively intense memories, but less recruitment for positively intense memories. Third, the PTSD group showed greater functional coupling between the ventral medial PFC and the amygdala for negatively intense memories, but less coupling for positively intense memories. In sum, the fMRI data suggest that there was greater recruitment and coupling of emotional brain regions during the retrieval of negatively intense AMs in the PTSD group when compared to controls.     

Extradural compression of the sensorimotor cortex delays the acquisition but not the recalling of a lever-pressing task in Wistar rats

The learning and recalling of a lever-press task (LPT) after brief unilateral extradural compression (EC) of the right sensorimotor cortex was studied in Wistar rats. All rats, regardless of the time-point for EC, were trained to lever press for food from D(day)1 to D6. On D8, the position of the active lever was changed to the right side of the operant box and performance was tested until D14. Total and active lever presses, as well as % errors were used to analyse the performance. Rats submitted to EC 24 h before initiating the LPT schedule (na?ve-compressed group) showed delayed task acquisition and impaired performance until D10. No significant impairments were detected by D3 on a beam-walking test, excluding paresis as the cause to the delay. Rats submitted to EC after they learned the LPT (trained-compressed group) showed only mildly impaired post-compression performance with no effects on the recalling of the task. Using a progressive ratio LPT, the maximum number of presses to obtain a food-pellet (breaking point) was significantly reduced 24h after EC suggesting reduced motivation for the task early after brain injury. The delayed acquisition of the LPT in na?ve-compressed rats was accompanied by consistent cortical, striatal and thalamic degeneration detected by Fluoro-Jade and anti-glial fibrillary acidic protein (GFAP) staining, whereas the improvement in the performance of this group was accompanied by a reduction of the cortical damage on D10. Recall of the LPT in trained-compressed rats was not altered by EC, suggesting the contribution of compensatory mechanisms.     

Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory

Lesions restricted to the dorsal, but not the ventral, hippocampus severely impair the formation of spatial memory. This dissociation was first demonstrated using the water maze task. The present study investigated whether the dorsal and the ventral hippocampus are involved differentially in spatial reference and spatial working memory using a four-baited/four-unbaited version of the eight-arm radial maze task. This test allows the concurrent evaluation of reference and working memory with respect to the same set of spatial cues, and thereby enables a within-subjects within-task comparison between the two forms of memory functions. Rats with N-methyl-d-aspartic acid-induced excitotoxic lesions of the dorsal hippocampus, ventral hippocampus or both were compared with sham and unoperated controls. We showed that dorsal lesions were as effective as complete lesions in severely disrupting both reference and working spatial memory, whereas rats with ventral lesions performed at a level comparable with controls. These results lend further support to the existence of a functional dissociation between the dorsal and the ventral hippocampus, with the former being preferentially involved in spatial learning.     

Cocaine self-administration is not dependent upon mesocortical α1 noradrenergic signaling

The rewarding properties of psychomotor stimulants are traditionally thought to be independent of norepinephrine. Recent findings, however, suggest that local noradrenergic signaling through α1 receptors in the medial prefrontal cortex and the ventral tegmental area - brain regions critically important in natural and drug rewards - is in a position to influence stimulant reward. Despite this controversy, the contribution of this targeted signaling to stimulant self-administration has not been directly assessed. We have thus examined whether pharmacological blockade of α1 receptors in the medial prefrontal cortex and ventral tegmental area alters cocaine self-administration. Rats were trained to lever-press for cocaine (1.0 mg/kg/infusion) under a fixed ratio 1 schedule of reinforcement for 10 days. After training, the rats received a bilateral microinjection of an α1 noradrenergic antagonist (terazosin: 1.0, 5.0, or 10 mM/side), a D1 dopaminergic antagonist (SCH23390: 12.3 mM/side), or saline into either the medial prefrontal cortex or ventral tegmental area immediately before a cocaine self-administration session. Although SCH23390 significantly increased cocaine self-administration when injected into either brain region, terazosin, at all doses and sites tested, failed to alter this behavior. Thus, the maintenance of cocaine self-administration appears to be under the influence of D1 dopaminergic, rather than α1 noradrenergic, signaling at these mesocortical sites.     

Interhippocampal synthesis of lateralized place navigation engrams

Rats were trained in a water maze in a dark room with the extramaze cues restricted to only dimly back-lit shapes. We used lidocaine to reversibly lesion the dorsal hippocampus and this controlledcue room in order to examine interhippocampal synthesis of lateralized place engrams. Experiment 1 showed that lidocaine injected into both hippocampi effectively abolished place navigation for up to 25 min but not at 45 min. In experiment 2, each day under lidocaine blockade of one hippocampus, pretrained rats were trained in the water maze to locate the target according to two cues (e. g., AB). Two hours later, the contralateral hippocampus was inactivated and the rats were trained to the same location with two other cues (CD). On day 5, intact brain retrieval was tested in one of three conditions: ACQ (e. g., AB), one of the pairs of cues used in acquisition training; SYNTH (e. g., AC), one cue from each of the pairs used in acquisition; CONT (e. g., AE), one cue that was used in acquisition training and a novel cue. The results show that the hippocampi learned the two tasks independently and similarly [latency (L) at the asymptote = 7 s]. Retrieval performance was at the asymptote for ACQ (AB) and SYNTH (AC) (L = 6 and 7, respectively) but was disrupted for CONT (L = 12). In experiment 3 as in experiment 2, the rats were trained, under unilateral blockade, to a new place for 4 days. On day 5, retrieval with the trained hippocampus blocked was worse (L = 11) than with the untrained side blocked (L = 5). We conclude that interhippocampal synthesis of lateralized place engrams is automatic and highly efficient. © 1995 Wiley-Liss, Inc.     

Specific role of the posterior dorsal hippocampus-prefrontal cortex in short-term working memory

Working memory in rats involves neural projections from the hippocampus (HP) to the prefrontal cortex (PFC), based on delayed task experiments in a radial-arm maze, in which the time span of working memory is longer than seconds. To determine whether the HP–PFC pathway is involved in short-term (on the order of seconds) working memory function, we lesioned the PFC and/or HP, and measured performance in an operant delayed alternation task. The posterior dorsal (pdHP) and ventral HP (vHP) were assessed separately. The bilateral PFC and bilateral pdHP ibotenate lesions produced significant working memory deficits, but the vHP lesion did not. Unilateral pdHP lesions combined with a PFC lesion in the opposite hemisphere reproduced the effects of bilaterally symmetrical lesions. By contrast, unilateral lesions of the pdHP combined with a PFC lesion in the same hemisphere had no effect on delayed alternation. These results indicate that the pdHP–PFC pathway is essential for working memory on the order of seconds in rats, and suggest that the pdHP and vHP pathways to the PFC play different behavioral roles.     

Differential effects on delayed non-matching-to-position in rats of microinjections of muscarinic receptor antagonist scopolamine or NMDA receptor antagonist MK-801 into the dorsal or ventral extent of the hippocampus

Glutamatergic NMDA and cholinergic muscarinic receptors are thought to contribute to cognitive processes mediated by the hippocampus. Evidence from lesion studies suggests that, despite cytoarchitectural uniformity within the hippocampus, information processing may not be uniform along the septo-temporal axis. The present study examined whether blockade of NMDA or muscarinic receptors in hippocampal subregions produced regional dissociations in the disruption of performance on an operant, spatial delayed non-matching-to-position (DNMTP) paradigm that also assessed vigilance. Rats were extensively pretrained on DNMTP, then bilaterally cannulated into either the dorsal or ventral hippocampus. Following retraining, scopolamine or MK-801 were administered prior to sessions. MK-801 administered into dorsal hippocampus produced delay-independent deficits in DNMTP delayed choice. Neither scopolamine administered into the dorsal or ventral hippocampus, nor MK-801 administered into the ventral hippocampus, produced significant disruption of DNMTP delayed choice. However, some dissociations were evident in other measures of vigilance. Scopolamine into the dorsal and ventral hippocampus increased errors of omission, scopolamine into the ventral hippocampus decreased sample response accuracy, and MK-801 into the dorsal hippocampus decreased sample response accuracy and increased response bias. These results are consistent with the suggestion that subregions of the hippocampus may be involved in different aspects of information processing and also suggest that the cholinergic inputs to the hippocampus may be functionally independent of NMDA receptor-mediated neurotransmission.     

Hebb-Williams performance and scopolamine challenge in rats with partial immunotoxic hippocampal cholinergic deafferentation

Recent studies suggested that the cholinergic innervation of the hippocampus is not crucial for spatial learning, but it might be important for other forms of learning. This study assessed the effects of partial immunotoxic cholinergic lesions in the medial septum and concurrent scopolamine challenge in a complex learning task, the Hebb-Williams maze. Long-Evans rats were given intraseptal injections of 192 IgG-saporin (SAPO). Rats injected with phosphate-buffered saline (PBS) served as controls. Starting 25 days after surgery, behavioural performance was assessed in the Hebb-Williams maze test without prior or after injection of scopolamine (0.17 or 0.5 mg/kg, i.p.). In SAPO rats, histochemical analysis showed a 40-45% decrease in the density of hippocampal AChE staining. The number of ChAT-positive cell bodies in the medial septum was also significantly decreased (-56%) and there was a non-significant reduction of the number of parvalbumine-positive neurons. The behavioural results demonstrated that the lesions induced small but significant learning deficits. At 0.17 mg/kg, scopolamine produced more impairments in SAPO rats than in PBS-injected rats, suggesting an additive effect between the partial lesion and the drug. These observations indicate that the Hebb-Williams test may be more sensitive to alterations of septohippocampal cholinergic function, than radial- or water-maze tasks. They also show that subtle learning deficits can be detected after partial lesions of the cholinergic septohippocampal pathways. Finally, the data from the scopolamine challenge are in keeping with clinical results showing higher sensitivity to muscarinic blockade in aged subjects in whom weaker cholinergic functions can be presumed.     

Behavioural effects of neonatal lesions of the medial prefrontal cortex and subchronic pubertal treatment with phencyclidine of adult rats

According to the neurodevelopmental hypothesis of schizophrenia, early brain damage renders the brain vulnerable to adverse effects during puberty, which precipitate the disease in young adults. Animal models can be used to test this hypothesis. We investigated the potentially independent or interactive effects of neonatal (postnatal day 7) excitotoxic lesions of the rat medial prefrontal cortex (mPFC) and subchronic pubertal phencyclidine (PCP)-treatment on adult rat behaviour. Sham-lesioned (vehicle-injection) and naive (unoperated) rats served as controls. On postnatal days 42-48 rats were systemically injected with 5 mg/kg PCP or vehicle twice daily. Behavioural testing started at postnatal day 70. Rats were tested for locomotor activity (open field), anxiety (elevated plus maze), social behaviour (conditioned place preference for cage-mates), reward-related operant behaviour [progressive ratio (PR)] and spatial learning (four-arm baited eight-arm radial maze task). Nissl-stained sections revealed considerable regeneration of much of the lesioned tissue in the mPFC, however, with disturbed cytoarchitecture. Locomotor activity was increased by neonatal lesions but reduced after pubertal PCP-treatment. Neonatal lesions alone increased operant behaviour in the PR-test and reduced anxiety in the elevated plus maze. In contrast, PCP-treatment disturbed social behaviour while neonatal lesions had no effect. Different aspects of leaning and memory in the radial maze task were independently disturbed after neonatal lesions and PCP-treatment. Neonatal lesions and pubertal PCP-treatment differentially affected adult rat behaviour and no interactions were found.