Data showing regional differences in rat brain monoaminergic function.

Chemical neurotransmitters (such as dopamine) modulate cognitive function via ascending projections to various cortical and sub-cortical brain regions. This report describes and links to a relatively large dataset (up to N = 112) compiled from control (untreated) brain samples taken during a series of experimental in vivo studies. The dataset is freely available, to explore the normal interrelationships between levels of neurotransmitter (e.g., dopamine, serotonin), across brain regions implicated in both normal reward and drug addiction, as well as in disorders such as schizophrenia (e.g., nucleus accumbens, prefrontal cortex). Most experimental studies run with a relatively small control group, so there is a lack of baseline data on the expected levels of neurotransmitters and their metabolites in different brain regions. Accordingly, the available dataset has been compiled from a number of studies run in the same laboratory, and using closely similar behavioural procedures, sampling selected brain regions of a priori interest. These collated data can be used to explore differences in the distribution of the monoamines and their metabolites, patterns of neurotransmitter intercorrelations, both between and within different brain structures and including some consideration of laterality effects.

The origins of individual differences in how learning is expressed in rats: A general-process perspective.

Laboratory rats can exhibit marked, qualitative individual differences in the form of acquired behaviors. For example, when exposed to a signal-reinforcer relationship some rats show marked and consistent changes in sign-tracking (interacting with the signal; e.g., a lever) and others show marked and consistent changes in goal-tracking (interacting with the location of the predicted reinforcer; e.g., the food well). Here, stable individual differences in rats' sign-tracking and goal-tracking emerged over the course of training, but these differences did not generalize across different signal-reinforcer relationships (Experiment 1). This selectivity suggests that individual differences in sign- and goal-tracking reflect differences in the value placed on individual reinforcers. Two findings provide direct support for this interpretation: the palatability of a reinforcer (as measured by an analysis of lick-cluster size) was positively correlated with goal-tracking (and negatively correlated with sign-tracking); and sating rats with a reinforcer affected goal-tracking but not sign-tracking (Experiment 2). These results indicate that the observed individual differences in sign- and goal-tracking behavior arise from the interaction between the palatability or value of the reinforcer and processes of association as opposed to dispositional differences (e.g., in sensory processes, "temperament," or response repertoire). (PsycINFO Database Record

The effect of retrosplenial cortex lesions in rats on incidental and active spatial learning.

The study examined the importance of the retrosplenial cortex for the incidental learning of the spatial arrangement of distinctive features within a scene. In a modified Morris water-maze, rats spontaneously learnt the location of an escape platform prior to swimming to that location. For this, rats were repeatedly placed on a submerged platform in one corner of either a rectangular (Experiment 1) or square (Experiments 2, 3) pool with walls of different appearance. The rats were then released in the center of the pool for their first test trial. In Experiment 1, the correct corner and its diagonally opposite partner (also correct) were specified by the geometric properties of the pool. Rats with retrosplenial lesions took longer to first reach a correct corner, subsequently showing an attenuated preference for the correct corners. A reduced preference for the correct corner was also found in Experiment 2, when platform location was determined by the juxtaposition of highly salient visual cues (black vs. white walls). In Experiment 3, less salient visual cues (striped vs. white walls) led to a robust lesion impairment, as the retrosplenial lesioned rats showed no preference for the correct corner. When subsequently trained actively to swim to the correct corner over successive trials, retrosplenial lesions spared performance on all three discriminations. The findings not only reveal the importance of the retrosplenial cortex for processing various classes of visuospatial information but also highlight a broader role in the incidental learning of the features of a spatial array, consistent with the translation of scene information.

Ro 04-6790-induced cognitive enhancement: no effect in trace conditioning and novel object recognition procedures in adult male Wistar rats.

The evidence for cognitively enhancing effects of 5-hydroxytryptamine6 (5-HT6) receptor antagonists such as Ro 04-6790 is inconsistent and seems to depend on the behavioral test variant in use. Trace conditioning holds promise as a behavioral assay for hippocampus-dependent working memory function. Accordingly, Experiment 1 assessed the effect of Ro 04-6790 (5 and 10mg/kg i.p.) on associating a noise conditioned stimulus paired with foot shock (unconditioned stimulus) at a 3 or 30s trace interval in adult male Wistar rats. Contextual conditioning was measured as suppression to the contextual cues provided by the experimental chambers and as suppression to a temporally extended light background stimulus which provided an experimental context. Experiment 2 assessed the effect of Ro 04-6790 (5 and 10mg/kg i.p.) on recognition memory as tested by the exploration of novel relative to familiar objects in an open arena. In Experiment 1, Ro 04-6790 (5 and 10mg/kg) was without effect on trace and contextual conditioning. In Experiment 2, there was no indication of the expected improvement under Ro 04-6790 at the same doses previously found to enhance recognition memory as measured in tests of novel object exploration. Thus, there was no evidence that treatment with the 5-HT6 receptor antagonist Ro 04-6790 acted as a cognitive enhancer in either trace conditioning or object recognition procedures. We cannot exclude the possibility that the experimental procedures used in the present study would have been sensitive to the cognitive enhancing effects of Ro 04-6790 in a different dose range, behavioral test variant, or in a different strain of rat. Nonetheless the drug treatment was not ineffective in that object exploration was reduced under 10mg/kg Ro 04-6790.

The rat retrosplenial cortex is required when visual cues are used flexibly to determine location.

The present study examined the consequences of retrosplenial cortex lesions in rats on two novel spatial tasks. In the first experiment, rats discriminated opposing room views from the same general location, along with their opposing directions of travel ('Perspective' task). Rats were trained with food rewards using a go/no-go design. Extensive retrosplenial cortex lesions involving both the granular and dysgranular areas impaired acquisition of this discrimination, which relied on distal visual cues. The same rats were then trained on a non-spatial go/no-go discrimination between different digging media. No lesion effect was apparent. In the final experiment, rats discriminated between two locations within a room ('Location' task) such that direction of travel at each location would be of less help in solving the problem. Both extensive retrosplenial lesions and selective dysgranular retrosplenial lesions impaired this Location task. These results highlight the importance of the retrosplenial cortex (areas 29 and 30), including the dysgranular cortex (area 30), for the effective use of distal visual cues to solve spatial problems. The findings, which help to explain the bias away from visual allocentric solutions that is shown by rats with retrosplenial cortex lesions when performing spatial tasks, also support the notion that the region assists the integration of different categories of visuospatial information.

Paradoxical effects of low dose MDMA on latent inhibition in the rat.

The cognitive effects of MDMA ('Ecstasy') are controversial, particularly in the case of acute administration of low doses. Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received non-reinforced pre-exposure, an effect typically abolished by amphetamines and enhanced by antipsychotics. LI enhancement has also been shown using the 5-HT reuptake blocker sertraline. In the present study, the effects of MDMA (6 mg/kg, known to increase 5-HT release) were tested using 10 and 40 pre-exposures to produce weak and strong LI in controls, respectively. MDMA (injected twice, prior to pre-exposure and conditioning) significantly enhanced LI in that the effect was clearly demonstrated after only 10 pre-exposures, when it was absent in the saline controls. On its own such a profile of action would be consistent with a procognitive effect of MDMA mediated by increased availability of 5-HT. However, paradoxically the same MDMA treatment reduced LI in the 40 pre-exposures condition. This component of action is likely attributable to MDMA's actions on catecholaminergic systems and is consistent with other evidence of its adverse effects. Moreover, there were small but significant reductions in 5-HT in medial prefrontal cortex (mPFC) and amygdala assayed 7 days post MDMA administration (2 × 6 mg/kg, 24 h apart).

Catecholaminergic depletion in nucleus accumbens enhances trace conditioning.

PURPOSE: To examine the effect of dopamine depletion in nucleus accumbens on trace conditioning; to distinguish the role of core and shell sub-regions, as far as possible. MATERIAL/METHODS: 6-hydroxydopamine was used to lesion dopamine terminals within the core and shell accumbens. Experiment 1 assessed conditioning to a tone conditioned stimulus that had previously been paired with footshock (unconditioned stimulus) at a 30s trace interval. Experiment 2 subsequently assessed contiguous conditioning (at 0s trace) using a light conditioned stimulus directly followed by the unconditioned stimulus. RESULTS: Both sham and shell-lesioned animals showed the normal trace effect of reduced conditioning to the trace conditioned stimulus but 6-hydroxydopamine injections targeted on the core subregion of the nucleus accumbens abolished this effect and enhanced conditioning to the trace conditioned stimulus. However, the depletion produced by this lesion placement extended to the shell. In Experiment 2 (at 0s trace), there was no effect of either lesion placement as all animals showed comparable levels of conditioning to the light conditioned stimulus. Neurochemical analysis across core, shell and comparison regions showed some effects on noradrenalin as well as dopamine. CONCLUSIONS: The pattern of changes in noradrenalin did not systematically relate to the observed behavioural changes after core injections. The pattern of changes in dopamine suggested that depletion in core mediated the increased conditioning to the trace conditioned stimulus seen in the present study. However, the comparison depletion restricted to the shell subregion was less substantial, and a role for secondarily affected brain regions cannot be excluded.

Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing.

Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to-be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0 mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0 µg/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates.

Reduced dopamine function within the medial shell of the nucleus accumbens enhances latent inhibition.

Latent inhibition (LI) manifests as poorer conditioning to a CS that has previously been presented without consequence. There is some evidence that LI can be potentiated by reduced mesoaccumbal dopamine (DA) function but the locus within the nucleus accumbens of this effect is as yet not firmly established. Experiment 1 tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of DA terminals within the core and medial shell subregions of the nucleus accumbens (NAc) would enhance LI under conditions that normally disrupt LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures (to a noise CS) and 2 conditioning trials. The vehicle-injected and core-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the medial shell, however, produced potentiation of LI, demonstrated across two extinction tests. In a subsequent experiment, haloperidol microinjected into the medial shell prior to conditioning similarly enhanced LI. These results underscore the dissociable roles of core and shell subregions of the NAc in mediating the expression of LI and indicate that reduced DA function within the medial shell leads to enhanced LI.

Catecholaminergic depletion within the prelimbic medial prefrontal cortex enhances latent inhibition.

Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received repeated non-reinforced pre-exposure. Investigations into the neural substrates of LI have focused on the nucleus accumbens (NAc) and its inputs from the hippocampal formation and adjacent cortical areas. Previous work has suggested that lesions to the medial prefrontal cortex (mPFC), another major source of input to the NAc, do not disrupt LI. However, a failure to observe disrupted LI does not preclude the possibility that a particular brain region is involved in the expression of LI. Moreover, the mPFC is a heterogeneous structure and there has been no investigation of a possible role of different regions within the mPFC in regulating LI under conditions that prevent LI in controls. Here, we tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of dopamine (DA) terminals within the prelimbic (PL) and infralimbic (IL) mPFC would lead to the emergence of LI under conditions that do produce LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures to a noise conditioned stimulus (CS) and two conditioning trials. Sham-operated and IL-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the PL, however, produced potentiation of LI. These results provide the first demonstration that the PL mPFC is a component of the neural circuitry underpinning LI.