Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and α2-adrenergic agonists

Adenosine A1 Receptor Agonists Block the Neuropathological Changes in Rat Retrosplenial Cortex after Administration of the NMDA Receptor Antagonist Dizocilpine

“…In vivo microdialysis study indicated that the administration of dizocilpine (0.5 mg/kg) increased significantly the extracellular levels of ACh in rat retrosplenial cortex, as previously reported (Kim et al, 1999). Pretreatment with CCPA (1 or 3 mg/kg, i.p.)…”

“…It has been reported that systemic administration of GABAergic agonists (diazepam and pentobarbital), the a 2 -adrenergic agonist clonidine, and the novel metabotropic glutamate receptor agonist LY 379268 significantly suppressed both dizocilpine-induced neuronal vacuolization and ACh release in the rat retrosplenial cortex (Kim et al, 1999;Okamura et al, in press). Interestingly, local injection of clonidine to the retrosplenial cortex did not reduce extracellular Ach levels or the number of vacuolized neurons, whereas local injection to the basal forebrain, where the majority of the cortical-projecting cholinergic neurons exist, significantly reduced the number of vacuolized neurons (Farber et al, 2002).…”

“…Heat shock protein HSP-70, which is known as a sensitive marker of reversible neuronal damage, was induced in the retrosplenial cortex of the rat brain after administration of noncompetitive NMDA receptor antagonists such as dizocilpine, PCP, ketamine, and memantine (Sharp et al, 1991(Sharp et al, , 2001Hashimoto et al, 1996Hashimoto et al, , 1997Tomitaka et al, 1996Tomitaka et al, , 2000. Furthermore, it has been reported that the NMDA receptor hypofunction state induced by administering NMDA receptor antagonist dizocilpine causes excessive release of acetylcholine (ACh) in retrosplenial cortex, and that g-aminobutyric acid A (GABA A ) agonists or a 2 -adrenergic agonists prevent such release (Kim et al, 1999). Studying the circuitry and receptor mechanisms of neurotoxicity of dizocilpine, Farber et al (2002) hypothesized that dizocilpine-induced neurotoxicity involves increased glutamatergic and cholinergic activity at the retrosplenial cortex, and it is reasonable to also hypothesize that activation of adenosine A 1 receptors, which inhibit the release of neurotransmitters including ACh, would have a neuroprotective effect in this model.…”

The Effects of Clonidine on Discrete-Trial Delayed Spatial Alternation in Two Rat Models of Memory Loss

“…Jackson et al (2004) have shown that MK-801, at the doses used in the present study, increases irregular firing and decreases organized burst firing of neurons in the prefrontal cortex. These chaotic changes in neuronal firing may reflect excessive cortical neurotransmitter (eg acetylcholine, glutamate, dopamine) release evoked by NMDA antagonists (Kim et al, 1999;Moghaddam and Adams, 1998) Clonidine, on the other hand, has been shown to suppress elevations in neurotransmitter release induced by various perturbations, including MK-801 (Acquas et al, 1998;Jellish et al, 2005;Kim et al, 1999). Clonidine's suppressive effect on neurotransmitter release may be due to its direct action on presynaptic terminals (Kamisaki et al, 1992) or indirect effects on neuronal firing (Kawahara et al, 2001).…”

Alpha-2 Adrenoceptor Activation Inhibits Phencyclidine-Induced Deficits of Spatial Working Memory in Rats

“…Increasing evidence supports the notion that neurochemical changes secondary to NMDA receptor hypofunction directly mediate these cognitive deficits, inasmuch as pharmacologic strategies working on nonglutamatergic systems can be effective at alleviating cognitive impairments in NMDA antagonist-treated animals (Jentsch and Anzivino, 2004;Verma and Moghaddam, 1996). For example, activation of dopaminergic and cholinergic systems triggered by NMDA blockade mediate both behavioral and neurotoxic effects of PCP and related drugs (Kim et al, 1999;Verma and Moghaddam, 1996), and an overall increase in excitatory glutamatergic transmission is thought to link NMDA receptor hypofunction to altered function of these reticular systems (Moghaddam et al, 1997).…”