Lynne P. Marrow

Topographical organization of the nigrotectal projection in rat: Evidence for segregated channels

Recent evidence suggests that projections from the superior colliculus to the brainstem in rat are organized into a series of anatomically segregated output channels. To understand how collicular function may be modified by the basal ganglia it is important to know whether particular output modules of the superior colliculus can be selectively influenced by input from substantia nigra. The purpose of the present study was, therefore, to examine in more detail topography within the nigrotectal system in the rat. Small injections (10-50 nl) of a 1% solution of wheatgerm agglutinin conjugated with horseradish peroxidase were made at different locations within substantia nigra and surrounding structures. A discontinuous puff-like pattern of anterogradely transported label was found in medial and caudal parts of the ipsilateral intermediate layers of the superior colliculus. In contrast, the rostrolateral enlargement of the intermediate layers contained a greater density of more evenly distributed terminal label. Injection sites associated with this dense pattern of laterally located label were concentrated in lateral pars reticulata, while the puff-like pattern was produced by injections into ventromedial pars reticulata. Retrograde tracing experiments with the fluorescent dyes True Blue and Fast Blue revealed that injections involving the rostrolateral intermediate layers were consistently associated with a restricted column of labelled cells in the dorsolateral part of ipsilateral pars reticulata. Comparable injections into medial and caudal regions of the superior colliculus produced retrograde labelling in ventral and medial parts of the rostral two-thirds of pars reticulata. Both anterograde and retrograde tracing data indicated that contralateral nigrotectal projections arise from cells located in ventral and medial pars reticulata. The present results suggest that the main ipsilateral projection from substantia nigra pars reticulata to the superior colliculus comprises two main components characterized by regionally segregated populations of output cells and spatially separated zones of termination. Of particular interest is the apparent close alignment between terminal zones of the nigrotectal channels and previously defined populations of crossed descending output cells in the superior colliculus. Thus, the rostrolateral intermediate layers contain a concentration of terminals specifically from dorsolateral pars reticulata and output cells which project to the contralateral caudal medulla and spinal cord. Conversely, the medial and caudal intermediate layers receive terminals from ventral and medial pars reticulata and contain cells which project specifically to contralateral regions of the paramedian pontine and medullary reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticonvulsant role of nigrotectal projection in the maximal electroshock model of epilepsy—II. Pathways from substantia nigra pars lateralis and adjacent peripeduncular area to the dorsal midbrain

Lesion evidence suggests that the superior colliculus is essential for mediating the anticonvulsant properties of nigral suppression in the electroshock model of epilepsy. However, our companion paper [Redgrave et al. (1991) Neuroscience 46, 379-390] established that the region of dorsal midbrain where bicuculline was most effective in suppressing tonic hindlimb extension did not correspond well with the known distribution of nigrotectal terminals. The purpose of the present anatomical study was, therefore, to investigate in more detail ventral midbrain connections to the dorsal midbrain anticonvulsant zone in rat. Small injections (10-20 nl) of a 1% solution of wheatgerm agglutinin conjugated with horseradish peroxidase were made specifically into the region of dorsal midbrain where bicuculline was maximally effective. Numerous retrogradely labelled cells were found in substantia nigra pars lateralis and adjacent peripeduncular area but not in substantia nigra pars reticulata. Retrogradely labelled cells were also located in ventral zona incerta. When wheatgerm agglutinin-horseradish peroxidase injections were made into lateral substantia nigra, a region of anterogradely transported reaction product characteristic of nerve terminals was observed in the caudolateral deep layers and underlying reticular tissue; this area corresponded well to the dorsal midbrain anticonvulsant zone. These data suggest that, in the electroshock model of epilepsy, direct connections between substantia nigra pars lateralis and adjacent peripeduncular area and the dorsal midbrain anticonvulsant zone could be critical for mediating the anticonvulsant properties previously attributed to substantia nigra pars reticulata. During the course of this study, anterograde projections from substantia nigra pars lateralis and adjacent peripeduncular area to both superficial and intermediate layers of the ipsilateral superior colliculus were noted. Additional experiments using retrograde transport of the fluorescent tracer Fast Blue confirmed these projections.

Disruption of conditioned reaction time performance by dopamine receptor antagonists in the rat.

The effects of the neuroleptics haloperidol, cis-flupenthixol and chlorpromazine, and the selective dopamine (DA) receptor antagonists raclopride and SCH 23390, were assessed in a conditioned reaction time task. In this operant task, rats were required to hold down a lever for a randomly determined hold duration (0.5–2.0 s) and to release the lever within 1 s of a light cue to ‘obtain food reinforcement. All drugs dose-dependently reduced the total number of lever presses and the number of rewarded responses, and all but chlorpromazine produced an abrupt cessation of responding before the end of the experimental session. However, there were variations in the ability of these drugs to impair lever release performance. Chlorpromazine and the selective D2 antagonist raclopride significantly elevated rewarded and total reaction times. The former drug also increased the number of delayed responses (i.e. those occurring with a latency of greater than I s) and reduced the percentage of rewarded responses occurring following light onset (percentage success), whilst raclopride also increased delayed reaction times. Haloperidol failed significantly to influence rewarded and total reaction times, as well as the percentage success measure. However, the lowest dose of haloperidol increased the number of delayed responses, indicating a subtle impairment of lever release performance. cis-Flupenthixol and the selective DI antagonist SCH 23390 failed significantly to influence any aspect of lever release performance. Only haloperidol and cis-flupenthixol increased the time rats took to move from the lever to the food hopper, whilst all drugs increased the time taken to return to the lever. Although feeding animals prior to the experimental session, or removing food pellets from the dispensers during the session, reduced overall response levels, the former did not influence any reaction time measure, whilst extinction only reduced percentage success. The present findings reveal that certain DA receptor antagonists impair conditioned lever release performance. However, this reaction time deficit is not obtained with all DA receptor antagonists, despite their consistent effects on other aspects of performance in the task.

A re-evaluation of social defeat as an animal model of depression

Social defeat by aggressive Tryon Maze Dull (TMD) rats, resulting in loss of rank of a previously dominant rat, has recently been advanced as a model of loss of self-esteem in humans. Since low self-esteem is a major symptom of depression, a further claim has been made that loss of rank can be used as a model of depression. In support of this claim, it has been suggested that loss of rank can be reversed by the antidepressant imipramine. However, antidepressant treatment has not yet been shown to reverse the effects of defeat for more than a single test session. Consequently, the present study was designed to more fully assess the effects of antidepressant treatment on the behaviour of defeated animals. Six pairs of male Lister Hooded (LH) rats were observed biweekly for 30 min at the onset of the dark phase of the light-dark cycle. In five of the six pairs, a stable social hierarchy (assessed by the observation of aggressive behaviours such as attacks and pushes, and submissive behaviours such as submissive posture) was established over a period of 10 weeks. The dominant animals of these five pairs were defeated once a week, in the home cage, by a singly housed male TMD for a period of 15 min. After 5 weeks of defeat by TMD, all five of the dominant animals showed an effect of defeat on behaviours relevant to status, although a reversal in status within the LH pairs was apparent in only one case. All defeated animals, regardless of whether or not defeat affected status, received daily injections of imipramine (5 mg/kg) for 5 weeks. Imipramine markedly worsened behaviours relevant to status in the treated animals. Indeed, animals treated with imipramine were more likely to lose encounters with their cage-mates. Consequently, the results cast doubt on the validity of social defeat as a model of depression, at least when the effects of defeat are assessed in terms of social status.

An evaluation of the use of defeat-induced loss of status in the rat as a model of loss of self-esteem and depression in humans

Social defeat by Tryon Maze Dull rats, resulting in loss of rank of a previously dominant rat, has recently been advanced as a model of loss of self-esteem and depression in humans. However, before loss of rank in animals can be assessed as a model of human depression, certain requirements must be fulfilled: (1) a situation must be developed in which rank can be determined, and this assessment must, under normal circumstances, remain stable if it is to be the baseline against which experimental manipulations are measured; (2) it must be established that defeat of a dominant animal does indeed cause a change in rank for that animal; and (3) once these practical requirements have been fulfilled, to be a “model of depression,” antidepressant treatment must be seen to reverse the loss of rank caused by defeat. Each of these points is considered in turn. (1) So far, a situation has not been discovered in which social hierarchies are produced that are both unequivocal and stable. (2) Defeat seems to have very variable effects, the variability being most likely due to natural variation in the quality of the defeat “experience” for the recipient. (3) Antidepressant treatment has not yet been shown to reverse the effects of defeat for more than a single test session. In addition, it has not been demonstrated that loss of rank actually produces a lowering of self-esteem in the animal as opposed to helplessness. If the change in self-perception does not change the value the animal attributes to itself, but rather the level of ability the animal attributes to itself, then the model breaks down. Consequently, at this time, the predictive validity of the model has not yet been established. Furthermore, its construct validity may be low. In summary, much more work is required before defeat-induced loss of status in the rat can be properly assessed as a model of loss of self-esteem and depression in humans, although it may be bedevilled by theoretical weaknesses even at this early stage. Aggr. Behav. 24:297–305, 1998.

Amelioration of some neuroleptic-induced deficits by the NMDA antagonist MK-801 in a conditioned reaction time task.

&NA; Using a reaction time task sensitive to neuroleptic disruption, we have examined the ability of the non‐competitive NMDA antagonist MK‐801 (0.01‐0.16 mg/kg) to reverse impairments induced by chlorpromazine (2.0 mg/kg). Rats were required to depress a lever for a randomly determined duration, and release it within 1 sec of a light cue in order to obtain food reward. Chlorpromazine reduced the overall number of lever presses, caused an early cessation of responding, slowed lever release in response to an external cue, and increased the time taken to reach the food hopper after a correct response. MK‐801 differentially influenced these impairments, with no dose of drug completely normalising behaviour. The reduction in response levels and early termination of responding were partially reversed by MK‐801, whilst certain doses of the drug completely reversed the increased time taken to reach the food hopper. Although MK‐801 increased the likelihood that chlorpromazine‐treated rats would release the lever within the 1 sec criterion time to obtain reinforcement, reaction times with the drug combination were still slower than observed in the control session. Therefore, MK‐801 appears to be less effective in reversing the chlorpromazine‐induced deficit in movement initiation than certain other aspects of performance in this task. These findings are less promising than those from other studies which have been used to suggest a clinical use of NMDA antagonists in the treatment of idiopathic and neuroleptic‐induced parkinsonism.

ENCOUNTERS WITH AGGRESSIVE CONSPECIFICS ENHANCE THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE IN THE RAT

Evidence suggests that stress enhances the behavioural actions of cocaine in the rat. Paradoxically, however, encounters with aggressive conspecifics lead to a pattern of cocaine self‐administration indicative of a reduced functional impact of the drug. Hence, we examined the effects of aggressive encounters on another behavioural measure‐locomotor activity. Encounters between Lister Hooded rats and rats of the aggressive Tryon Maze Dull strain significantly enhanced the locomotor‐activating effects of cocaine (20 mg/kg) in the Lister Hooded rats. The results suggest that the discrepant findings derived from self‐administration studies are a property of the paradigm rather than a property of the stressor.

Internet Self-Efficacy and Visual Search Strategies: The Use of Eye Tracking Technology in the Development of Web-Based Learning Resources

Higher Education is increasingly relying on e-learning as a means of providing students with teaching and learning resources. Almost inevitably, this means that students interact with these learning resources through the medium of the computer screen. Although there have been significant advances in the design and implementation of on-line resources, exactly how students interact with these resources is a relatively new field of research. In this study, students were asked to interact with three types of virtual learning environment, i.e. BlackBoard, IngentaConnect and Wikipedia, while their eye movements were scanned and recorded using a Tobii 1750 eye tracking system. The data gathered was analysed dynamically, statistically, and graphically in order to identify search patterns and “hot spots” within the online information source. The data was also correlated with a measure of Internet self-efficacy, the Web User Self-Efficacy scale (WUSE). Preliminary findings suggest that qualitative data obtained in this type of study may prove more useful than quantitative data.

The corticosteroid synthesis inhibitor metyrapone markedly enhances the behavioural effects of d-amphetamine

The clinically utilized corticosteroid synthesis inhibitor metyrapone attenuates the behavioural effects of cocaine in the rat. Given the potential therapeutic implications of this interaction, we felt it important to determine if metyrapones action would generalize to another widely abused psychostimulant, namely d‐amphetamine. However, rather than producing attenuation, metyrapone preadministration (3 100 mg/kg) markedly enhanced both the locomotor activating and stereotypy‐inducing actions of d‐amphetamine (dose equivalent to 2.5 mg/kg free base). The fact that the corticosteroid synthesis inhibitor trilostane did not affect the behavioural action of d‐amphetamine suggests that inhibition of corticoid synthesis does not underlie the action of metyrapone. Instead, it is argued that inhibition of debrisoquine hydroxylase (cytochrome p450 2D1), an enzyme involved in the metabolism of d‐amphetamine, represents the critical mechanism of action.

Certain clinically-utilized antibiotics enhance the behavioural effects of cocaine.

Cytochrome P‐450s (CYPs) belonging to subfamilies 2B and 3A are the major CYPs involved in the N ‐demethylation of cocaine in the rat. However, the effects of inhibitors of these enzymes on the behavioural actions of cocaine are unknown. Hence, the effects of the CYP 3A inhibitors troleandomycin and erythromycin, and the CYP 2B (and 3A) inhibitor chloramphenicol, were examined on the locomotor activating effects of cocaine (20 mg/kg i.p.). Troleandomycin, chloramphenicol and erythromycin all potentiated the locomotor activating effects of cocaine, although the effect was only statistically significant for the first two drugs. Since variation exists in the human population with respect to the catalytic activity of CYP 3A isozymes, which are the principal cocaine N ‐demethylators in humans, inhibition of CYP 3A by troleandomycin in the rat may be useful as a model of the human cocaine “poor metabolizer” phenotype.