Antipsychotic-like effect of the AMPA receptor antagonist LY326325 as indicated by suppression of conditioned avoidance response in the rat

Mathé, Jan M.; Fagerquist, M. V.; Svensson, Torgny H.

doi:10.1007/s007020050218

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…Along this line, selective AMPA receptor antagonists such as LY 326325 (6 -18 mg/kg) and GYKI152466 (20 mg/kg) have indeed shown antipsychotic-like effects in rats in the CAR test, and with a safe EPS liability profile [139,140]. More recently, albeit using a somewhat different experimental design, another AMPA receptor antagonist (CNQX) was also found to produce antipsychotic-like effects in rats in the CAR test.…”

Section: Ampa Receptor Antagonistsmentioning

confidence: 96%

Conditioned Avoidance Response in the Development of New Antipsychotics

Wadenberg¹

2010

CPD

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Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.

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Section: Ampa Receptor Antagonistsmentioning

confidence: 96%

Conditioned Avoidance Response in the Development of New Antipsychotics

Wadenberg¹

2010

CPD

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“…Thus, CNQX appeared to have a motor effect on the first session at the largest central dose tested in this study, but this effect appeared minimal on all other test sessions and doses. Doses of other AMPA receptor antagonists in previous literature have illustrated comparable blocks of avoidance responding with no failure and no catalepsy (Mathe et al, 1999;Svensson & Mathe, 2000), arguing against the hypothesis that AMPA receptor antagonists produce their effects solely through a motor effect.…”

Section: Discussionmentioning

confidence: 94%

“…In Experiment 2, little evidence for decreased avoidance responding was found with the systemic administration of CNQX. Although we used an injection–test interval consistent with previous research, systemic doses shown to attenuate avoidance responding at this interval were three to four times the largest dose used in the present study (Mathe et al, 1999; Svensson & Mathe, 2000). The high cost of CNQX limited our ability to test larger doses across multiple sessions.…”

Section: Discussionmentioning

confidence: 99%

“…From an extensive review of published studies, it appears that glutamatergic N-methyl-Daspartate (NMDA) receptors play an important role in the acquisition and that ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors play an important role in the expression of incentive learning . When administered to trained rats in CAR studies, AMPA receptor antagonists produced a disruption of avoidance responding reminiscent of the effect seen with antidopaminergic compounds (Mathe, Fagerquist, & Svensson, 1999;Svensson & Mathe, 2000). However, the extinction-like effect normally seen with dopamine receptor antagonists has never been evaluated with AMPA/kainate receptor antagonists, as testing has been restricted to one session and data were averaged over trials.…”

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confidence: 99%

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Differential effects of dopamine and AMPA receptor antagonists on the expression of conditioned avoidance responding in rats.

Boivin

Beninger

2008

Behavioral Neuroscience

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AMPA receptor antagonists disrupt avoidance responding, but their day-to-day effect on this behavior has not been elucidated. This study compared the multisession effect of the AMPA/kainate receptor antagonist CNQX with that of the typical antipsychotic haloperidol on the expression of avoidance responding. Rats (N = 199) were trained to move to safety on presentation of a tone in one-way active conditioned avoidance and were tested across 5 sessions. Intracerebroventricular (icv) injection of CNQX (20-min injection-test interval) produced a dose-dependent, immediate block of avoidance responding, compared with the extinction-like decline of avoidance responding produced by haloperidol (intraperitoneal [ip], 60-min injection-test interval; icv, 60 but not 20-min injection-test interval). Previous exposure to CNQX significantly reduced its efficacy, illustrating that its effects may not be specific to the conditioned safety-related stimuli that control responding in conditioned avoidance, as proposed for antidopaminergic compounds. The new multisession profile of disrupted avoidance responding illustrated by CNQX suggests different roles for glutamatergic and dopaminergic neurotransmission in conditioned avoidance responding. Results are consistent with a role for AMPA receptors in maintaining the expression of learning.

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“…For example, the AMPA receptor antagonist, LY-326325 was shown to attenuate amphetamine-induced stereotypy 138 and suppress conditioned avoidance response in rats. 139 In addition, administration of the AMPA/kainate receptor antagonist, LY-293558, partially reversed the impairment of working memory induced by subanesthetic doses of ketamine in rats 140 suggesting a possible utility of AMPA antagonists in the treatment of the cognitive deficits in schizophrenia, though further research is indicated. 40 Overall, it remains unclear if modulation of AMPA receptors by agonists, antagonists or allosteric modulators such as ampakines has therapeutic value in the treatment of schizophrenia although this is a highly active area of research.…”

Section: Other Ionotropic Glutamate Receptorsmentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

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While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

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Antipsychotic-like effect of the AMPA receptor antagonist LY326325 as indicated by suppression of conditioned avoidance response in the rat

Cited by 11 publications

References 19 publications

Conditioned Avoidance Response in the Development of New Antipsychotics

Conditioned Avoidance Response in the Development of New Antipsychotics

Differential effects of dopamine and AMPA receptor antagonists on the expression of conditioned avoidance responding in rats.

The pipeline and future of drug development in schizophrenia

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