Benzodiazepine receptors cerebellum

Zolpidem (1) is an effective hypnotic agent indicated for the short-term treatment of insomnia. Zolpidem interacts with the GABAa receptor, and its pharmacological effect is blocked by the benzodiazepine-receptor antagonist fiumazenil (Sanger and Depoortere, 1998). Zolpidem displaces benzodiazepines more selectively from the cerebellum than the hippocampus or spinal cord, consistent with preferential interaction with the ajGABAA receptor subtype (sometimes referred to as the benzodiazepine coi receptor). Studies... 

Fry JP, Rickets C, Biscoe, TJ (1985) On the location of r-aminobutyrate and benzodiazepine receptors in the cerebellum of the normal C3H and mutant mouse. Neuroscience, 14, 1091-1101. 

Khan ZU, Gutierrez A, De Bias AL (1994) The subunit composition of a GABA /benzodiazepine receptor from rat cerebellum. J. Neurochem., 63, 31 -324. 

Meinecke DL, Tallman J, Rakic P (1989) GABAA/benzodiazepine receptor-like immunoreactivity in rat and monkey cerebellum. Brain Res., 493, 303-320. 

Palacios J. M. and Kuhar M. J (1982) Ontology of high-affinity GABA and benzodiazepine receptors in rat cerebellum an autoradiographic study. Bram Res 2, 531-539... 

Mice lacking the 8 subunit, which is mainly expressed in cerebellum and thalamus, display an attenuation of ssatrighting reflex time following the administration of the neurosteroids, alphaxalone and pregnanolone, while the responses to propofol, etomindate, ketamine and the benzodiazepine midazolam were unaffected. This demonstrates the role of GABAa receptors containing the 8 subunit for neurosteroid action. 

The initial observation was based on the fact that the triazolopyridazine CL 218,872 had a significantly higher affinity for receptors in the cerebellum (benzodiazepine type 1 receptor) than it had for receptors in the hippocampus (benzodiazepine type 11 receptor) (Klepner et al. 1979). CL 218,872 was also known to be an anxiolytic without sedative effects. The proposal was that anxiolysis was mediated by the receptors in the cerebellum, whereas sedation was mediated by receptors elsewhere. Subsequent work has shown that the case is not as simple as that. With the advent of molecular biology and coexpression studies, it has been established that the oc,p2y2 receptor is equivalent to the type 1 receptor. The type 11 receptors appear to be a more heterogeneous receptor class as 3p2y2/ P2y2 seem to display... 

All of these drugs, benzodiazepine and non-benzodiazepine alike, exert their effects only in presence of GABA, enhancing the action of GABA at its receptor. The highest concentration of these receptors is found in the neocortex, hippocampus, cerebellum, and throughout the limbic system (which is involved in producing both pleasant and unpleasant emotional responses). The presence of these receptors within the hippocampus may explain why benzodiazepines can produce amnesia. They may inactivate the neural circuits in this structure that are critical for the consolidation of memories. 

Somogyi P, Takagi H, Richards JG, Mohler H (1989) Subcellular localization of benzodiazepine/GABAA receptors in the cerebellum of rat, cat, and monkey using monoclonal antibodies. J. Neurosci, 9, 2197-2209. 

Zopiclone, the first compound of the cyclopyrrolone class to be marketed, possesses anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. It causes no dependence and no rebound insomnia. Zopiclone interacts with GABA receptors (see Figure 50). It is rapidly absorbed from the GI tract, and with an oral dose of 7.5 mg, it produces a peak-plasma concentration of 50 to 80 )tg/L. Zopiclone becomes metabolized to A-demethylzopiclone (inactive) and zopiclone-iV-oxide (active). Zopiclone exhibits a high affinity for benzodiazepine-binding sites in the cerebral cortex, hippocampus, and cerebellum, but does not interact with the peripheral benzodiazepine-binding sites. 

Palacios J M, Wamsley J K. and Kuhar M J (1981c) GABA, benzodiazepine, and histamine-Hi receptors in the guinea pig cerebellum effects of kainic acid injections studied by autoradiographic methods. Brain Res 214, 155-162... 

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