Biomedical subjects

G A Higgins

Publications and source records attributed to G A Higgins.

At least 37 records · Page 2Linked to original sources

PubMed1999

Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats.

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed three per cage) in two behavioural paradigms: locomotor activity in a novel open field and prepulse inhibition (PPI) of the acoustic startle response. Subsequently, all rats were sacrificed and their brains removed. The hippocampus was sectioned and analysed immunohistochemically using an antibody to the synapse-specific protein synaptophysin, to gain an estimate of the synaptic content of selected hippocampal subfields. Isolates demonstrated locomotor hyperactivity and deficits in PPI relative to socially reared controls. Analysis of synaptophysin immunoreactivity suggested that isolates had significantly reduced synaptic content in the hippocampal dentate gyrus molecular layer, with smaller, non-significant reductions in the CA1 and CA3 regions. This pattern of change may be consistent with reduced neuronal input to the dentate gyrus via the entorhinal cortex, suggesting developmental changes in hippocampal-cortical circuitry. These preliminary studies extend the characterisation of isolation rearing as a model for the investigation of neurodevelopmental diseases such as schizophrenia.

Animals↗

PubMed1999

Increased neuronal damage in apolipoprotein E-deficient mice following global ischaemia.

There is accumulating evidence that apolipoprotein E (apoE) plays a role in regulating the response to and outcome following brain injury. The present study compared the histological outcome and recovery following an episode of global ischaemia in apoE-deficient mice and wild-type littermates (12-week-old males, n = 8 per group). Transient global ischaemia was induced for a period of 17 min and the animals were allowed to recover for 72 h. Transient global ischaemia induced selective neuronal degeneration in several brain regions in wild-type mice. There was statistically significant increased ischaemic neuronal damage in apoE-deficient mice compared with wild-type mice in six of the seven regions examined (hippocampal regions CA1, CA3/CA4 and dentate gyrus; thalamus; cortex and caudate nucleus; P < 0.05). The data substantiate a role for apoE in modifying the response of the CNS to acute injury.

Alleles↗

PubMed1998

Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats.

Lamotrigine is a novel anticonvulsant drug which also stabilises mood in bipolar illness via an unknown mechanism. We report the concentration-dependent inhibition of 5-hydroxytryptamine (5-HT) uptake in both human platelets and rat brain synaptosomes (IC50s were 240 and 474 microM, respectively) by lamotrigine. Synaptosomal uptake of noradrenaline (IC50 239 microM) and dopamine (IC50 322 microM) was also inhibited. Tetrodotoxin failed to modulate 5-HT uptake suggesting that sodium channel blockade does not mediate the lamotrigine effect. Lithium, sodium valproate, zonisamide, and carbamazepine all possess anti-manic activity but only the latter inhibited 5-HT uptake. The inhibition of the p-chloroamphetamine-induced 5-HT syndrome in rats suggests that lamotrigine also inhibits 5-HT uptake in vivo. These effects probably reflect an affinity for biogenic amine transporters. However, at present, it remains uncertain whether, at clinically effective doses, these effects contribute significantly to the efficacy of lamotrigine in bipolar illness.

Acetates↗

PubMed1998

Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse.

Using apolipoprotein E knockout mice derived from the Maeda source [Piedrahita J. A. et al. (1992) Proc. natn. Acad Sci. US.A. 89, 4471 4475], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hippocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term potentiation and amygdaloid kindling, and CNS repair, i.e. synaptic recovery in the hippocampus following deafferentation. In each study there was little difference between the apolipoprotein E knockout mice and wild-type controls of similar age and genetic background. Apolipoprotein E knockout mice aged eight months demonstrated accurate spatial learning and normal neurological function. Synaptophysin and microtubule-associated protein 2 immunohistochemistry and electron microscopic analysis of these animals revealed that the hippocampal synaptic and dendritic densities were similar between genotypes. The induction and maintenance of kindled seizures and hippocampal long-term potentiation were indistinguishable between groups. Finally, unilateral entorhinal cortex lesions produced a marked loss of hippocampal synaptophysin immunoreactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-type groups showed immunohistochemical evidence of reactive synaptogenesis, although the apolipoprotein E knockout group may have initially shown greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in processes of CNS plasticity and repair, or more likely, alternative (apolipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals.

Animals↗

PubMed1998

Characterization of perforant path lesions in rodent models of memory and attention.

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.

Animals↗

PubMed1998

Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors?

The dopamine D3/D2 receptor agonists 7-OH-DPAT, quinpirole, quinelorane, and PD128907, the mixed dopamine agonist apomorphine, the D2 agonist bromocriptine, and the D1/D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition (PPI) in Wistar rats. As dopamine agonist-induced hypothermia has been proposed as a model of D3 receptor function, and dopamine agonists are known to disrupt PPI, drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI. 7-OH-DPAT, quinpirole, quinelorane, PD128907, and apomorphine, reduced body temperature and disrupted PPI with a similar rank order of potency (quinelorane > quinpirole = 7-OH-DPAT > PD128907 = apomorphine). Bromocriptine and SKF38393 were ineffective in both models. In a separate study, the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI. In a final set of studies, the D2/D3 antagonist raclopride blocked both 7-OH-DPAT-induced hypothermia and 7-OH-DPAT-induced PPI disruption. The 5-HT1A antagonist WAY 100,135, and the peripheral D2-like antagonist domperidone had no effect. These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors; however, only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors.

Animals↗

PubMed1998

Comparison of various N-methyl-D-aspartate receptor antagonists in a model of short-term memory and on overt behaviour.

This study examined the effects on rat behaviour of antagonists acting at various sites on the N-methyl-D-aspartate (NMDA) receptor complex, i.e. the glutamate recognition site (CPP), ion channel (dizocilpine), glycine recognition site [(+)-HA-966] and the NR2B subunit-selective compound ifenprodil. Specifically, the effects of these agents were examined on working memory, assessed using the operant delayed match-to-position task (DMTP), and overt behaviour, assessed (a) in animals responding for food under a variable interval 20-s (VI20) schedule and (b) by spontaneous behaviour. Dizocilpine, CPP and (+)-HA-966 each reduced accuracy in the DMTP task independent of delay. At equivalent doses, changes in locomotor behaviour and VI20 responding were evident. In contrast, ifenprodil failed to impair accuracy in the DMTP task, even at doses that affected other performance measures and reduced VI20 responding. The relevance of these observations to neuroprotective and anticonvulsant doses of these compounds is considered.

Animals↗

PubMed1997

Investigations into the nature of a 7-OH-DPAT discriminative cue: comparison with D-amphetamine.

In the present study, separate squads of rats were trained to discriminate either the dopamine D3 receptor preferring ligand 7-hydroxy-2-(di-N-propylamino)-tetralin (7-OH-DPAT) (0.03 mg/kg) from saline, or D-amphetamine (0.3 mg/kg) from saline using a standard operant schedule (FR10 schedule reinforcement). Following stable acquisition of responding, tests of generalisation and antagonism were conducted. A number of dopamine agonists having high dopamine D2-like receptor (D2, D3 or D4) affinity generalised to the 7-OH-DPAT, but not amphetamine, cue. The dopamine D2/3 receptor agonist SKF38393 showed no generalisation to either drug cue. Subsequent correlational analysis suggested that this effect was most likely mediated through the dopamine D3 receptor. The dopamine D2/3 receptor antagonist raclopride significantly attenuated both cues. The failure of these drugs to generalise to amphetamine, suggest that there is little involvement of the dopamine D3 receptor subtype in mediating its discriminative stimulus properties.

Animals↗

PubMed1997

Evidence for recovery of spatial learning following entorhinal cortex lesions in mice.

The influence of entorhinal cortex lesions on behaviour and concommitant changes in synaptophysin immunoreactivity (IR) in the denervated dentate gyrus was assessed. Male, C57/B6 mice received either bilateral (BI), unilateral (UNI), or no lesion (SHAM) to the entorhinal cortex. At various stages post-lesion the animals were evaluated in tests to examine neurological and cognitive (spatial and cued learning, Morris water maze) function. UNI lesioned animals from 6-36 days post-lesion showed no neurological nor marked cued learning deficit, yet a profound spatial learning deficit. However by 70 days post-lesion, spatial learning ability was clearly evident. In contrast, BI lesioned animals showed severe spatial learning deficits throughout the test period (6-70 days), cued learning was also impaired. In parallel groups of UNI lesioned mice, 6-36 days post-lesion there was a marked reduction (-40%) in synaptophysin IR in the dentate gyrus molecular layer. However by 70 days post-lesion a clear increase in this measure was noted. Changes in the expression of the growth associated protein, GAP43, were also noted over this period. Taken together, the present results suggest some recovery of spatial learning following unilateral entorhinal cortex lesions in mice. This behavioural recovery of a hippocampally dependant task may be associated with a recovery of function related to the synaptic remodelling and elevation of synapse number in the denervated hippocampus, as evidenced by changes in synaptophysin and GAP43 IR.

Animals↗

PubMed1997

Absence of central cholinergic deficits in ApoE knockout mice.

ApolipoproteinE (ApoE) genotype has recently been identified as a major risk factor for Alzheimer's disease (AD) but the mechanism(s) by which ApoE isoforms influence this disease remain unclear. Recent studies suggest that mice deficient in ApoE may exhibit impaired central cholinergic function. Since this neurotransmitter system has traditionally been associated with the pathogenesis of AD, we have further investigated the impact of ApoE gene deletion on this system. Female ApoE knockout (ko) mice, age 12 months, were compared with wild type littermate controls using a range of behavioural, biochemical and histochemical techniques. Pre-treatment with the cholinomimetic, donepezil (E2020; 2.5-5 mg kg-1 IP), produced significant hypothermia and induction of tremor in both wild type and ApoE ko mice. The magnitude of change did not significantly differ between the groups. Cognitive testing in the Morris water maze revealed that both wild type and ApoE ko mice could learn the location of a hidden escape platform with similar rates of acquisition and accuracy. Similarly, the behaviour of both genotypes proved indistinguishable in a Y-maze spontaneous alteration procedure. The protocols used for both cognitive tests were then shown to be sensitive to the disruptive effects of scopolamine (but not scopolamine methyl bromide). Following behavioural testing, choline acetyltransferase (ChAT) activity was measured in the hippocampus, frontal and entorhinal cortex and striatum. In each case there was no difference between the genotypes. In addition, coronal sections of striatum and anterior hippocampal regions of ApoE ko and wild type mice showed similar patterns of acetylcholinesterase (AChE) staining, with no qualitative or obvious quantitative difference. Finally, analysis of plasma cholesterol levels confirmed ApoE genotype. In conclusion, using a combination of behavioural, histochemical and biochemical measurements, we have failed to detect any significant differences in central cholinergic activity between wild type and ApoE ko mice.

Acetylcholinesterase↗

PubMed1997

Differential effects of ondansetron and alpha-flupenthixol on responding for conditioned reward.

Previous experiments have suggested that 5-HT3 antagonists such as ondansetron may alter reward-related behaviour that is dependent in part upon raised mesolimbic dopamine activity. However, the evidence for this is far from conclusive. One major behavioural role of dopamine is in the control of behaviour elicited by conditioned rewarding stimuli. To date, the effects of 5-HT3 antagonists on this function of mesolimbic dopamine have not been examined. Two experimental procedures were employed to examine the effects of ondansetron (10 and 100 micrograms/kg) on the acquisition of responding for conditioned reward, and on the response potentiating effect of intra-accumbens d-amphetamine (10 micrograms). These effects were compared to those elicited by the dopamine antagonist alpha-flupenthixol (0.1 mg/kg). In the first procedure, rats were trained to associate food pellet delivery with a conditioned stimulus (CS). Rats subsequently allowed to respond on a lever delivering this CS, and on an inactive lever, showed a greater preference for the lever delivering the CS, indicating that this CS functioned as a conditioned reward (CR). Ondansetron administered during the conditioning phase did not alter subsequent responding for the CR, but alpha-flupenthixol induced a small but significant reduction in responding on the CR lever. These results suggest that blockade of dopamine receptors, but not 5-HT3 receptors interfere with the learning of stimulus reward relationships. In the second procedure, d-amphetamine injected into the nucleus accumbens markedly potentiated responding for CR. Ondansetron at 10 micrograms/kg induced a small attenuation of this effect, without altering responding in its own right. However, at a higher dose (100 micrograms/kg) ondansetron plus amphetamine treatment significantly enhanced responding on the inactive lever. At both doses, the net effect of ondansetron was to produce a subtle impairment in the allocation of responses such that the differential responding on the CR versus NCR lever was diminished. In contrast to these effects alpha-flupenthixol significantly attenuated d-amphetamine's selective enhancement of responding for conditioned reward, as well as impairing the ability of the conditioned reward to elicit and maintain behaviour. These results confirm the role of dopamine in responding for conditioned reward, and suggest a possible modulators role for 5-HT3 receptors in this process. However, the effects of ondansetron on the acquisition of, and responding for, conditioned reward are clearly different from those induced by blockade of dopamine receptors.

Animals↗

PubMed1997

Apolipoprotein E and Alzheimer's disease: a review of recent studies.

There are three isoforms of the 33-kDa protein apolipoprotein E (apoE), termed apoE2, apoE3, and apoE4, each encoded by distinct genes APOE2, APOE3 and APOE4, respectively. In 1993, the APOE genotype was identified as a risk factor for Alzheimer's disease (AD) and was subsequently acknowledged to account for approximately 60% of all cases. The influence of the APOE genotype in AD is clearly isoform dependent, APOE4 imparting susceptibility and APOE2 protection. Thus, patients homozygous for the E4 allele show a very strong likelihood of developing the disease by age 75, whereas patients carrying at least one E2 allele are unlikely to develop symptoms of AD by this age. A major issue in AD research is therefore to understand the functional differences between the ApoE isoforms, with the ultimate aim of designing the next generation of drugs to treat this disease. The purpose of the present article is to summarise some of this work. This review encompasses the rapidly developing molecular, cellular and behavioural research into ApoE, and attempts to highlight those findings we consider to be of particular significance.

Alzheimer Disease↗

PubMed1996

The teleos virtual environment toolkit for simulation-based surgical education.

In the past, surgical simulations have largely been created through the development of dedicated applications that require considerable programming and computer graphics skills. Advances in simulation-based surgical education have been limited by this dependence on computer graphics programming expertise. To lower barriers to the adoption of simulation-based training, we are developing tools based on Teleos, software technology that allows a wide variety of medical content developers to author surgical training simulations without programming.

Computer Graphics↗

PubMed1995

Reversal of dizocilpine-induced disruption of prepulse inhibition of an acoustic startle response by the 5-HT2 receptor antagonist ketanserin.

Prepulse inhibition can be reliably disrupted by non-competitive NMDA receptor antagonists such as dizocilpine. In recent study, we found that the potent D2/5-HT2 receptor antagonist, risperidone, but not the selective dopamine D2 receptor antagonist, raclopride, could reverse this disruption. The present study was therefore designed to examine the effect of the 5-HT2 receptor antagonist, ketanserin, against a dizocilpine-induced disruption of prepulse inhibition, as well as the behavioural stereotypy produced by this drug. Ketanserin (2 mg/kg) reversed the prepulse inhibition disruption produced by dizocilpine (0.15 mg/kg), as did the non-selective 5-HT1/5-HT2 receptor antagonist metergoline (1 mg/kg). Both drugs also attenuated some components of the behavioural stereotypy syndrome produced by dizocilpine (0.15 mg/kg). The present studies therefore suggest an interaction between 5-HT2 receptors and glutamatergic systems. This may be important for the antipsychotic profile of drugs having antagonist activity at 5-HT2 receptors.

Animals↗

PubMed1995

Further studies to examine the nature of dexfenfluramine-induced suppression of heroin self-administration.

The present series of experiments sought to investigate further the mechanism by which dexfenfluramine, a selective 5-HT releaser/reuptake inhibitor, reduces heroin self-administration by male Wistar rats. In experiment 1, the effect of combined intravenous heroin and intraperitoneal dexfenfluramine injections on operant responding for food was examined. In experiment 2, the maintenance of dexfenfluramine suppression of heroin self-administration following chronic (7 day) treatment was evaluated. Finally, in experiment 3, the ability of various 5-HT antagonists to block the dexfenfluramine suppression was examined. The results from experiment 1 suggest that sensorimotor deficits/malaise potentially associated with heroin/dexfenfluramine combinations are unlikely to account for the reductions in heroin self-administration. Experiment 2 suggested that the suppressant effect of dexfenfluramine on heroin responding may diminish rapidly following chronic treatment. Finally, central 5-HT1 and/or 5-HT2, but not 5-HT3, receptors may underlie the suppressant effects of dexfenfluramine on heroin self-administration.

Animals↗

PubMed1995

Effect of scopolamine on visual attention in rats.

In the present study, the effects of scopolamine (SCOP) were determined upon the performance of rats in the five-choice serial reaction time task, a test of attention analogous to the continuous performance test in man. Rats were trained to detect and respond to brief flashes of light presented randomly in one of five locations until a stable level of performance was reached. SCOP (0.03-0.1 mg/kg SC) was administered 30 min prior to testing under standard conditions of stimulus presentation. SCOP reduced response accuracy at the highest dose and dose-dependently increased omissions and perseverative responses. However, these effects were mimicked by scopolamine methylbromide (SCOPMBr) which might suggest a peripheral site of action. When the task difficulty was increased by manipulating the stimulus presentation parameters, i.e. reduced stimulus intensity, duration or temporal predictability, SCOP (0.075 mg/kg SC) failed further to impair performance accuracy. However, in two separate experiments, SCOP (0.075 mg/kg SC) robustly increased the distractibility caused by a burst of loud white-noise occurring unpredictably during the intertrial-interval: SCOP significantly decreased accuracy and increased omissions, magazine latency, premature and perseverative responses compared with vehicle and the equivalent dose of SCOPMBr. These findings provide further evidence of a role for the central cholinergic system in attention.

Animals↗

PubMed1995

Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs.

Prepulse inhibition (PPI) of an acoustic startle response is impaired in schizophrenics. PPI can also be studied in the rat, and is impaired by dopamine (DA) D2/3 receptor agonists such as apomorphine. This disruption is reversed by DA antagonists, leading to proposals that this approach may be a useful means to identify novel antipsychotics. There is also evidence to suggest a role of serotonergic (5-HT) and glutamatergic systems in schizophrenia, and accordingly PPI can be disrupted by the 5-HT2 agonist DOI, and the non-competitive NMDA antagonist, dizocilpine. In the present study we have examined the effect of four antipsychotic drugs, haloperidol (0.1-0.3 mg/kg), raclopride (0.03-0.3 mg/kg), risperidone (0.3-3 mg/kg) and clozapine (0.0001-10 mg/kg), against the PPI disruptions induced by apomorphine (0.5 mg/kg), DOI (3 mg/kg) and dizocilpine (0.15 mg/kg). Furthermore, these drugs have been examined for their ability to restore a PPI deficit produced by housing rats under conditions of social isolation. All drugs except clozapine reversed an apomorphine-induced disruption. However, clozapine and risperidone, but not raclopride and haloperidol, reversed a DOI-induced disruption. Only risperidone was effective in restoring a PPI deficit produced by dizocilpine. In contrast to the drug-induced disruptions which were differentially sensitive to the various neuroleptics, isolation-induced disruptions were restored by each drug. These results support the idea that non-drug induced disruptions of PPI, such as social isolation, may be a more viable approach to identify novel antipsychotics.

Animals↗

PubMed1995

Influence of prefeeding and scopolamine upon performance in a delayed matching-to-position task.

The present study compared the influence of prefeeding (0, 10, 20 g or an unlimited amount of food pellets for a 90 min period prior to testing) with the effects of scopolamine (0, 0.03, 0.075 or 0.1 mg/kg s.c.) and scopolamine methylbromide (0.1 mg/kg s.c.) upon performance in the food reinforced delayed matching-to-position (DMTP) task. In preliminary studies using separate groups of rats, both scopolamine (but not scopolamine methylbromide) and prefeeding impaired choice accuracy in a seemingly delay-independent manner. Both treatments also increased omissions. However, while prefeeding increased all task latencies, scopolamine only increased sample latency. In a subsequent experiment, an intermediate dose of scopolamine (0.075 mg/kg s.c.) was directly compared with prefeeding in the same animals. Both treatments impaired choice accuracy, however, the effects of scopolamine were significantly larger than prefeeding. Conversely, prefeeding caused significantly greater omissions and larger increases in task latencies compared with scopolamine. These findings demonstrate some dissociation between the effects of scopolamine and prefeeding in the DMTP task, suggesting that the actions of scopolamine are not entirely due to reduction in motivation. Furthermore, the effects of scopolamine are likely to be centrally mediated.

Animals↗