ORCID Profile
0000-0001-8906-2280
Current Organisation
Centre for Addiction and Mental Health
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 04-2000
DOI: 10.1016/S0006-3223(99)00267-X
Abstract: The dibenzoxazepine amoxapine was introduced as an antidepressant but has shown antipsychoticlike activity in a number of animal screening tests. A recent positron emission tomography study showed a 5-HT(2)/D(2) receptor occupancy profile of amoxapine that is very similar to that of established atypical antipsychotics. Schizophrenics display deficits in sensory gating mechanisms, such as prepulse inhibition (PPI) of the acoustic startle reflex. A similar deficit can be produced by dopamine (DA) and by 5-HT(2A/C) receptor agonists in rats. Antipsychotic compounds reverse this effect. Effects of amoxapine on apomorphine- or 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced disruption of PPI were studied in adult male Sprague-Dawley rats. The extrapyramidal side effect (EPS) liability of amoxapine was assessed using the inclined grid catalepsy (CAT) test. Statistical analyses were performed by analysis of variance (ANOVA) for fully repeated measures (PPI) and by the Kruskal-Wallis one-way ANOVA by ranks (CAT). Apomorphine (0.5 mg/kg) produced a significant reduction in PPI compared with the case of rats in the saline control group. Pretreatment with amoxapine (10 mg/kg) significantly attenuated the apomorphine-induced disruption of PPI. DOI (0.5 mg/kg) significantly reduced PPI compared with saline controls. Pretreatment with amoxapine (5 or 10 mg/kg) produced a significant attenuation of the DOI-induced disruption of PPI. Amoxapine by itself did not alter PPI. Amoxapine (5 or 10 mg/kg) did not produce CAT. The DA D(2)/5-HT(2) receptor antagonist amoxapine produced an antipsychoticlike reversal of both apomorphine- and DOI-induced disruption of PPI. Furthermore, the same doses of amoxapine that reversed disruption of PPI did not produce CAT. The results confirm and lend further support to the results of previous studies on amoxapine, suggesting that amoxapine might possess antipsychotic activity with little propensity for producing EPS.
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/S0920-9964(03)00009-4
Abstract: The aim of these studies was to examine whether hetamine-induced sensitization in rats could be used as an animal model to study the basis of certain abnormalities seen in schizophrenia. Specifically, these experiments examined whether rats subjected to a sensitizing regimen of hetamine would show the sensorimotor gating and greater hetamine-induced displacement of radio-raclopride binding deficit that is observed in schizophrenia. In the first experiment, animals were ided into two groups with each rat receiving an intraperitoneal injection of hetamine (AMPH) or saline (SAL) (1 ml/kg) three times per week for 3 weeks for a total of nine injections. AMPH dose was increased weekly from 1 mg/kg in the first week to 3 mg/kg in the third. Twenty-two days after the last injection, prepulse inhibition (PPI) of the acoustic startle response was tested. In addition, rats were tested for the effects of a challenge dose of 0.5 mg/kg AMPH on locomotor activity and [3H]raclopride (RAC) binding potential (BP) in the striatum. The tests for PPI confirmed that sensorimotor gating was disrupted in the AMPH-induced sensitized-state rats at baseline. The AMPH-sensitized rats also exhibited higher locomotor response to AMPH and a lower binding of striatal [3H]raclopride when challenged with the drug. The results were replicated and even more pronounced in rats that were treated with AMPH for 5 weeks, with doses ranging from 1mg/kg in the first week to 5 mg/kg in the fifth. These sensorimotor gating deficits and neurochemical (greater AMPH-induced displacement of radio-raclopride binding) abnormalities show similarities with the pathophysiology of schizophrenia and suggest that the AMPH-sensitized-state rats could be used to model certain aspects of schizophrenia.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.PNPBP.2007.08.025
Abstract: Schizophrenia is a serious psychiatric disorder which impacts a broad range of cognitive, behavioural and emotional domains. In animals, exposure to an intermittent, escalating dose regimen of hetamine induces a sensitized state that appears to share a number of behavioural and neurochemical similarities with schizophrenia. In humans repeated exposure to hetamine, or other psychomotor stimulants, can induce sensitization as well as psychosis. The following paper evaluates the evidence for the hetamine-induced sensitized state as an animal model of schizophrenia, focussing separately on the positive, cognitive and negative symptoms associated with this disease. Current evidence supports the use of hetamine sensitization as a model of the positive symptoms observed in schizophrenia. Additionally, there is increasing evidence for long-lasting cognitive deficits in sensitized animals, especially in the area of attention and/or cognitive flexibility. Other areas of cognition, such as long-term memory, appear to be unaltered in sensitized animals. Finally, little evidence currently exists to either support or refute the use of hetamine sensitization as a model of negative symptoms. It is concluded that hetamine sensitization likely impacts behaviour by altering the functioning of mesolimbic dopamine systems and prefrontal cortical function and can serve as a model of certain domains of schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 11-10-2006
Abstract: Gestational methylazoxymethanol acetate (MAM) exposure has been suggested to produce neural and behavioral abnormalities similar to those seen in schizophrenia. In order to assess MAM treatment as a model of schizophrenia, pregnant female rats were injected with MAM (22 mg/kg) on gestational day 17 and their offspring were assessed in adulthood on a series of cognitive tasks. The first experiment involved an attentional set-shifting task, a rodent analog of the Wisconsin card sort task. In experiment 2, animals were tested on the 5-choice serial reaction time task, a rodent analog of the continuous performance task. In the final experiment animals were assessed on a differential reinforcement of low rate of responding 20 s schedule of reinforcement (DRL-20), a task that is sensitive to changes in inhibitory control. In the first experiment, MAM-treated animals required a greater number of trials than controls to successfully learn an extradimensional shift on the set-shifting task, and had difficulties in learning to reverse a previously acquired discrimination. In contrast, MAM-treated animals showed little impairment on the 5-choice task, aside from a modest but consistent increase in premature responding. Finally, MAM exposed animals showed substantial impairments in DRL performance. Post-mortem analysis of brain tissue showed significant decreases in tissue weight in the hippoc us, parietal cortex, prefrontal cortex, and dorsal striatum of MAM-treated animals. These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2005
DOI: 10.1007/S00213-005-2253-Z
Abstract: Schizophrenia has been linked to dysregulation of dopamine and glutamate transmitter systems. Attempts to model aspects of schizophrenia in animals have made use of treatments that primarily affect dopaminergic (e.g., hetamine, Amp) and glutamatergic (e.g., phencyclidine, PCP) function. In addition to exerting short-term acute effects, these agents also induce long-term effects, as seen, for ex le, in neurochemical and behavioural sensitization. The goal of this work was to compare Amp- and PCP-sensitized states on two measures of information processing that are impaired in schizophrenia, prepulse inhibition (PPI) of the acoustic startle reflex and latent inhibition (LI). Rats received injections of Amp, PCP or saline 3 days per week for 3 weeks. The Amp dose increased from 1 to 3 mg/kg, at the rate of 1 mg/kg each week. The PCP dose was 3 mg/kg throughout. After various periods of withdrawal rats were tested for PPI and LI. Repeated intermittent treatment with Amp or PCP resulted in augmented locomotor responses to challenge with each drug, providing an operational index that sensitization had occurred. Rats sensitized to Amp showed disrupted PPI when tested drug free at 3, 21 and 60 days of withdrawal. Amp-sensitized rats also showed abolition of the LI effect. Rats sensitized to PCP did not show deficits in any of these behaviours when tested drug free. Because disrupted PPI and LI have both been reported in schizophrenic patients, these results suggest that the Amp-sensitized state may represent a useful model for investigating the neural bases of information processing deficits in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2006
Abstract: Exposure to repeated, intermittent, escalating doses of hetamine in rats disrupts information processing in several tasks. Some of these deficits, notably impaired attentional set shifting, may reflect altered prefrontal cortex function. This study examined the effects of repeated treatment with hetamine on performance in the 5-choice serial reaction time test. This test measures sustained visual attention, a behavior that is known to require the prefrontal cortex. Rats were trained to respond to a brief light stimulus presented randomly in one of five spatial locations, with 100 trials per session. Once performance had stabilized rats were treated with escalating doses of hetamine (three injections per week for 5 weeks at 1-5 mg/kg per week) testing was continued on nondrug days, and for several weeks of withdrawal. During the hetamine-treatment and withdrawal phases accuracy of responding was unaffected, but errors of omission increased. Lengthening the stimulus duration abolished this effect. Reducing the stimulus duration also reduced response accuracy and this effect was more marked in hetamine-treated rats. Both reduced accuracy, and increased omissions, seen in hetamine-treated rats were reversed by injecting the D1 receptor agonist SKF38393 into the medial prefrontal cortex. This treatment also prevented the decline in accuracy in control animals that resulted from reducing the stimulus duration. These results, indicating that exposure to hetamine induces a long-lasting deficit in visual attention, add to a growing list of deficits suggesting that hetamine-sensitized state may model the cognitive deficit state in schizophrenia. The reversal of these deficits by a D1 receptor agonist provides further evidence that prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2006
Abstract: Antipsychotic drugs work for patients only when given repeatedly. The overall temporal pattern of symptom improvement is not clear. Some recent data question the traditional 'delayed-onset' hypothesis and suggest that the onset of antipsychotic response may be relatively early, and the improvement may grow with repeated treatment. The present study systematically examined the time course of the antipsychotic effect and the underlying behavioral mechanisms using a conditioned avoidance response (CAR) model. Rats repeatedly treated with either typical (haloperidol) or atypical (olanzapine, risperidone) antipsychotics, but not anxiolytics (chlordiazepoxide), show an early-onset, progressive across-session decline in avoidance responding, which re-emerges when the treatment is stopped. This effect is dose-dependent, transferable between antipsychotics, and cannot be attributed to simple sedation or motor side effects. Furthermore, we found that the pattern of this drug-induced decline depends on the number of exposures to the conditioned stimulus in the presence of the drug, and is best understood as the result of drug-induced attenuation of the reinforcing effectiveness of the conditioned stimulus. We also found that repeated drug exposure can create a drug interoceptive state that allows the attenuated reinforcing property of the stimulus to be maintained over time. Together, these data provide preclinical support for the newly postulated 'early-onset' hypothesis, and suggest that the repeated antipsychotic CAR model may be useful for understanding the neurochemical and behavioral mechanisms underlying the clinical effects of antipsychotics in patients with schizophrenia.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.PBB.2009.05.010
Abstract: Schizophrenia is associated with increased rates of substance abuse that are thought to be the result of changes in cortical and mesolimbic dopamine activity. Previous work has shown that gestational methylazoxymethanol acetate (MAM) treatment induces increased mesolimbic dopamine activity when given around the time of embryonic day 17 (ED17), suggesting that MAM treatment may model some aspects of schizophrenia. Given that increased dopaminergic activity facilitates aspects of drug self-administration and reinstatement of drug seeking, the current experiments sought to assess cocaine self-administration in MAM treated animals. Experiment 1 examined the acquisition of cocaine self-administration in ED17 MAM and saline treated rats using a sub-threshold dose of cocaine. In experiment 2 ED17 MAM and saline treated animals were trained to self-administer cocaine and were then assessed under varying doses of cocaine (dose-response), followed by extinction and drug-induced reinstatement of responding. A subset of these animals was trained on a win-shift radial maze task, designed to detect impairments in hippoc al-dependent memory. In experiment 3, MAM and saline treated animals were assessed on a progressive ratio schedule of cocaine delivery. Finally, in experiment 4 MAM and saline treated animals were assessed on cocaine-induced locomotor activity across a range of doses of cocaine. MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2005
DOI: 10.1007/S00213-005-0157-6
Abstract: Repeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function. The present experiments were conducted to investigate the effects of sensitizing regimens of hetamine and phencyclidine (PCP) on attentional set shifting. Rats received injections of hetamine, PCP or saline three times per week for 5 weeks. Four weeks later, rats were trained to dig for food in one of two bowls, each bowl having an odour and a texture. Only one dimension (odour or texture) correctly predicted which bowl was baited. Rats were then tested on a series of discriminations including those requiring an intra-dimensional shift (IDS), an extra-dimensional shift (EDS) or a reversal of previously relevant and irrelevant stimuli. Rats sensitized to hetamine performed normally on the IDS, but were impaired on the EDS, as well as on reversal discriminations. PCP-sensitized rats were unaffected on any of the discriminations. In hetamine-sensitized rats the deficit at the EDS stage was reversed by infusion of the D(1) receptor agonist SKF38393 into the medial prefrontal cortex (mPFC). Results show that the hetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that hetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2010
Abstract: All antipsychotics work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis however, there is little evidence for a change in receptor number or pharmacological nature of D2Rs. Recent data suggest that D2Rs form dimers in-vitro and in-vivo, and we hypothesized that schizophrenia, as well as preclinical models of schizophrenia, would demonstrate altered dimerization of D2Rs, even though the overall number of D2Rs was unaltered. We measured the expression of D2Rs dimers and monomers in patients with schizophrenia using Western blots, and then in striatal tissue from rats exhibiting the hetamine-induced sensitized state (AISS). We further examined the interaction between D2Rs and the dopamine transporter (DAT) by co-immunoprecipitation, and measured the expression of dopamine D2 High receptors with ligand binding assays in rat striatum slices with or without acute hetamine pre-treatment. We observed significantly enhanced expression of D2Rs dimers (277.7 ± 33.6%) and decreased expression of D2Rs monomers in post-mortem striatal tissue of schizophrenia patients. We found that hetamine facilitated D2Rs dimerization in both the striatum of AISS rats and in rat striatal neurons. Furthermore, hetamine-induced D2Rs dimerization may be associated with the D2R-DAT protein-protein interaction as an interfering peptide that disrupts the D2R-DAT coupling, blocked hetamine-induced up-regulation of D2Rs dimerization. Given the fact that hetamine induces psychosis and that the AISS rat is a widely accepted animal model of psychosis, our data suggest that D2R dimerization may be important in the pathophysiology of schizophrenia and may be a promising new target for novel antipsychotic drugs.
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.BBR.2007.12.032
Abstract: Exposure to an intermittent, escalating dose of hetamine induces a sensitized state that, both behaviourally and neurochemically, mirrors several features linked to the positive symptoms of schizophrenia. Increasingly it is being realized that cognitive deficits are a core component of schizophrenia therefore we sought to assess the effects of inducing an hetamine-sensitized state on memory (working and long-term) and cognitive flexibility, two cognitive domains impaired in schizophrenia. Rats were exposed to a sensitizing regimen of hetamine (1-5 mg/kg three times per week for 5 weeks escalating at 1mg/kg per week) or saline. In experiment 1, animals were tested on an operant delayed non-match to position task (working memory). Experiment 2 used a standard fixed-platform location water maze task (long-term memory), while experiment 3 used a variable-platform location water maze task (long-term memory and working memory). Amphetamine-sensitized animals were not impaired on any of these tasks. In experiment 4, animals were assessed on a strategy selection task in which they were first required to learn to locate a food reward using a particular learning strategy (place or response) then to learn to shift to an alternate learning strategy (response or place). Amphetamine-sensitized animals were not impaired on this task. In the final experiment animals were found to be impaired in performance of the extra-dimensional shift component of an attentional set-shifting task. These results suggest that while hetamine sensitization does not produce memory impairments similar to those seen in schizophrenia, it does produce strong impairments in set-shifting, suggesting changes in prefrontal function similar to those seen in schizophrenia.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.BIOPSYCH.2004.12.013
Abstract: There is growing interest in detecting and treating schizophrenia during the "prodrome," before the symptoms are fully manifested. The objective of this study was to develop a putative model of the prodrome and study the effects of medications on it. Rats were treated with different regimens of hetamine to produce full sensitization (full syndrome) and partial sensitization (to model the prodromal state) and were then treated with typical and atypical antipsychotics and a D1 antagonist to mimic early intervention. After several weeks of withdrawal, locomotor activity in response to hetamine and behavioral deficits (prepulse inhibition [PPI] and latent inhibition [LI]) were examined. Animals that received the full sensitization showed significant increase in locomotor activity and a disruption in both PPI and LI. Animals treated with a partial regimen showed only a muted phenotype. The animals that received "early intervention" did not show progression from the prodromal to the full-blown phenotype. The partial regimen of hetamine injections provided a modified phenotype that could be regarded as a representative of the "prodromal" state. Early intervention, instituted once the prodromal state was already developed, prevented further progression into the full phenotype analogous to schizophrenia.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Paul Fletcher.