Effects of the noncompetitive NMDA receptor antagonist MK-801 on classical eyeblink conditioning in mice

Takatsuki, Kanako; Kawahara, Shigenori; Takehara, Kaori; Kishimoto, Yasushi; Kirino, Yutaka

doi:10.1016/s0028-3908(01)00113-7

Cited by 36 publications

(30 citation statements)

References 38 publications

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“…In accordance with other learning tasks, animals with systemic injection of (+)MK-801 (Thompson and Disterhoft 1997;Takatsuki et al 2001), mutant mice lacking the NMDA receptor subunit ⑀1 , and those with reduced expression of ⑀2 subunits (Takehara et al 2004) all exhibit severe impairments in acquisition during trace eyeblink conditioning. In the present trace eyeblink conditioning study, we have shown that APV infusions into the mPFC severely impaired acquisition and partially impaired consolidation, but did not impair expression of well-learned CRs.…”

Section: Discussionmentioning

confidence: 61%

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning

Takehara‐Nishiuchi¹,

Kawahara²,

Kirino³

2005

Learn. Mem.

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Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily conditioning using local microinfusion of the GABA A receptor agonist muscimol or the NMDA receptor antagonist APV into the rat mPFC. Muscimol infusions into the mPFC before daily conditioning significantly retarded CR acquisition and reduced CR expression if applied after sufficient learning. APV infusion also impaired acquisition of CRs, but not expression of well-learned CRs. When infusions were made immediately after daily conditioning, acquisition of the CR was partially impaired in both the muscimol and APV infusion groups. In contrast, rats that received muscimol infusions 3 h after daily conditioning exhibited improvement in their CR performance comparable to that of the control group. Both the pre-and post-conditioning infusion of muscimol had no effect on acquisition in the delay paradigm. These results suggest that the mPFC participates in both acquisition of a CR and the early stage of consolidation of memory in trace, but not delay eyeblink conditioning by NMDA receptor-mediated operations.

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Section: Discussionmentioning

confidence: 61%

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning

Takehara‐Nishiuchi¹,

Kawahara²,

Kirino³

2005

Learn. Mem.

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“…Based on the distribution of these NMDA receptor subunits, the investigators concluded that acquisition of the conditioned eyeblink response does not depend on NMDA receptors in the cerebellar cortex, but does depend on these receptors in hippocampus and/or deep cerebellar nuclei. NMDA receptor antagonists also impair trace eyeblink classical conditioning that is hippocampus dependent (Takatsuki et al, 2001;Thompson and Disterhoft, 1997).…”

Section: Nmda Receptor Antagonism and Eyeblink Classical Conditioningmentioning

confidence: 99%

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Woodruff-Pak

Tobia

Jiao³

et al. 2006

Neuropsychopharmacol

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Combinations of drugs approved to treat Alzheimer's disease (AD) were tested in older rabbits with delay eyeblink classical conditioning, a form of associative learning severely impaired in AD. In Experiment 1 (n ¼ 49 rabbits), low doses (0.1, 0.5, 1.0, and 0.0 (vehicle) mg/kg) of memantine (Namendat) were tested. These three doses neither improved nor impaired acquisition at a statistically significant level. The 0.5 mg/kg dose had the greatest effect numerically and did not cause sensitization or habituation in explicitly unpaired controls. In Experiment 2 (n ¼ 56), doses of galantamine (Razadynet; 3.0 mg/kg) and donepezil (Ariceptt; 0.75 mg/kg) that had comparable magnitudes of cholinesterase inhibition were tested alone and in combination with 0.5 mg/kg memantine. Older rabbits treated with galantamine and with galantamine + memantine learned significantly better than vehicle-treated rabbits, but adding memantine did not improve learning over galantamine alone. Older rabbits treated with donepezil or a combination of memantine and donepezil did not learn significantly better than rabbits treated with vehicle. Galantamine has two mechanisms of action: mild cholinesterase inhibition and allosteric modulation of nicotinic acetylcholine receptors (nAChRs). When equated for cholinesterase inhibition, galantamine had significant efficacy in the eyeblink conditioning model system, but donepezil did not, indicating that modulation of nAChRs may be the mechanism that significantly ameliorates learning deficits in this model. In the absence of AD neuropathology in older rabbits, memantine had no efficacy alone or in combination with the other drugs.

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“…Scavio et al (1992) reported that posttraining intravenous injections of amphetamine, chlorpromazine, and scopolamine, which retarded CR acquisition, had no effect on extinction, whereas the NMDA receptor antagonist ketamine accelerated acquisition and decreased the rate of extinction. Kehoe et al (1996) further elaborated the involvement of NMDA receptors by demonstrating that pretraining injections of MK-801 completely prevent eyeblink extinction (but, see Takatsuki et al 2001). Rabbits were administered MK-801 or saline prior to 6 d of extinction, during which MK-801-treated animals expressed virtually no CRs.…”

Section: The Nmda Receptormentioning

confidence: 99%

Brain Mechanisms of Extinction of the Classically Conditioned Eyeblink Response

Robleto¹,

Poulos²,

Thompson³

2004

Learn. Mem.

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It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus (US). However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction as an active learning process distinct from acquisition. Experimental data in eyeblink conditioning suggest that plastic changes specific to extinction may play an important role in this process. Both cerebellar and hippocampal systems may be involved in extinction of these memories. The nature of this phenomenon and identification of the neural substrates necessary for extinction of originally learned responses is the topic of this review.

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Effects of the noncompetitive NMDA receptor antagonist MK-801 on classical eyeblink conditioning in mice

Cited by 36 publications

References 38 publications

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Brain Mechanisms of Extinction of the Classically Conditioned Eyeblink Response

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