The binding of radiolabelled cocaine, an inhibitor of dopamine uptake, to the post-mortem human putamen was studied and compared to that in the rat striatum. Saturation analysis of [3H]cocaine binding to the human putamen revealed the presence of a high affinity component of binding with a Kd of 0.21 mumol/l and a Bmax of 1.47 pmol/mg protein. In addition a low affinity component (Kd = 26.4 mumol/l) was demonstrated, having a Bmax of 42.2 pmol/mg protein. Also in the rat striatum [3H]cocaine binding was both of high affinity (Kd = 0.36 mumol/l, Bmax = 5.56 pmol/mg protein) and low affinity (Kd = 25.9 mumol/l, Bmax = 35.6 pmol/mg protein). A pharmacological characterisation of high affinity [3H]cocaine binding to rat striatal membranes clearly indicates an association with the neuronal dopamine transporter. The IC50 values of 8 selected drugs for inhibition of [3H]cocaine binding in the rat striatum were highly significantly correlated with their potency to inhibit [3H]dopamine uptake into slices of the rat striatum. [3H]Cocaine binding was stereospecifically inhibited by (+)nomifensine and (+)diclofensine which were 50-80-fold more active than their respective (-)isomers. Drugs with dopamine releasing activity were more potent at inhibiting [3H]dopamine uptake than at competing for the high affinity site of [3H]cocaine binding. A highly significant correlation was found between IC50 values for [3H]cocaine binding in the rat striatum and the human putamen. Further evidence in support of an association of [3H]cocaine binding in the rat striatum with the dopamine transporter was obtained from lesion studies. Thus, intranigral 6-hydroxydopamine administration produced a marked (67%) decrease in striatal [3H]cocaine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Zolpidem is a novel non-benzodiazepine related hypnotic, which possesses an imidazopyridine structure. This drug has preferential affinity for the 3H-diazepam binding site in the rat cerebellum, while it is only weakly active at inhibiting 3H-Ro 5-4864 binding to the rat kidney. The potency of zolpidem at displacing 3H-Ro 15-1788 binding to rat cerebral cortex membranes is enhanced in the presence of GABA. On the sleep pattern of the electrocorticogram in the curarised rat, zolpidem induces a physiological type of slow wave sleep with rapid onset of action. Zolpidem differs from classical benzodiazepine drugs, in possessing an atypical binding profile to 3H-benzodiazepine receptors, and because it does not affect the sleep patterns.

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The regional distribution of [3H]zolpidem, a novel imidazopyridine hypnotic possessing preferential affinity for the BZD1 (benzodiazepine subtype 1) receptor, has been studied autoradiographically in the rat CNS and compared with that of [3H]flunitrazepam. The binding of [3H]zolpidem to rat brain sections was saturable, specific, reversible, and of high affinity (KD = 6.4 nM). It occurred at a single population of sites whose pharmacological characteristics were similar to those of the benzodiazepine receptors labeled with [3H]flunitrazepam. However, ethyl-beta-carboline-3-carboxylate and CL 218,872 were more potent displacers of [3H]zolpidem than of [3H]flunitrazepam. The autoradiographic brain distribution of [3H]zolpidem binding sites was qualitatively similar to that previously reported for benzodiazepine receptors. The highest levels of [3H]-zolpidem binding sites occurred in the olfactory bulb (glomerular layer), inferior colliculus, ventral pallidum, nucleus of the diagonal band of Broca, cerebral cortex (layer IV), medial septum, islands of Calleja, subthalamic nucleus, and substantia nigra pars reticulata, whereas the lowest densities were found in parts of the thalamus, pons, and medulla. Comparative quantitative autoradiographic analysis of the binding of [3H]zolpidem and [3H]flunitrazepam [a mixed BZD1/BZD2 (benzodiazepine subtype 2) receptor agonist] in the CNS revealed that the relative density of both 3H-labeled ligands differed in several brain areas. Similar levels of binding for both ligands were found in brain regions enriched in BZD1 receptors, e.g., substantia nigra pars reticulata, inferior colliculus, cerebellum, and cerebral cortex lamina IV. The levels of [3H]zolpidem binding were five times lower than those of [3H]flunitrazepam binding in those brain regions enriched in BZD2 receptors, e.g., nucleus accumbens, dentate gyrus, and striatum. Moreover, [3H]zolpidem binding was undetectable in the spinal cord (which contains predominantly BZD2 receptors). Finally, like CL 218,872 and ethyl-beta-carboline-3-carboxylate, zolpidem was a more potent displacer of [3H]flunitrazepam binding in brain regions enriched in BZD1 receptors than in brain areas enriched in BZD2 receptors. The present data add further support to the view that zolpidem, although structurally unrelated to the benzodiazepines, binds to the benzodiazepine receptor and possesses selectivity for the BZD1 receptor subtype.

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