Cardiac effects of benzodiazepine receptor agonists and antagonists in the isolated rat heart: a comparative study. The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference. Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus. Dimorphic features of the different alpha-containing GABA-A receptor subtypes in the cortico-basal ganglia system of two distantly related mammals (hedgehog and rat) Differential sensitivity to Zolpidem of IPSPs activated by morphologically identified CA1 interneurons in slices of rat hippocampus. Ambien online references

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Life Sci. 1998;63(16):1439-56.
Cardiac effects of benzodiazepine receptor agonists and antagonists in the isolated rat heart: a comparative study.

Zeegers A, van Wilgenburg H, Leeuwin RS.

Department of Pharmacology, University of Amsterdam, Academic Medical Center, The Netherlands.

Effects of PK 11195 and flumazenil on cardiac responses to diazepam, clonazepam and zolpidem were compared. Coronary flow rate was increased at relatively low doses of diazepam and decreased at higher doses. Clonazepam induced a dose-dependent increase, and zolpidem a decrease of coronary flow rate. PK 11195 reduced the diazepam-induced increase of coronary flow rate, and flumazenil was ineffective. Neither antagonist evoked substantial changes in the decrease of coronary flow rate. PK 11195, and less so flumazenil, antagonized the clonazepam-induced increase. PK 11195 and flumazenil only in their highest doses suppressed and respectively potentiated the zolpidem-induced decrease. Inotropy showed a biphasic response in the presence of diazepam, i.e. an initial transient decrease, followed by a dose-dependent increase in two steps. Clonazepam induced a similar response. Zolpidem increased the inotropy. The negative inotropic response induced by diazepam did not change significantly in the presence of PK 11195 or flumazenil. The positive inotropic response was suppressed by PK 11195, and less so by flumazenil. The negative response to clonazepam was antagonized by both PK 11195 and flumazenil; the positive response was not significantly changed. In the presence of lower doses of PK 11195, the zolpidem-induced response was potentiated, whereas higher doses produced reversal; flumazenil potentiated the response. In conclusion, the results support earlier suggestions, involving receptor mechanisms with cardiac effects of benzodiazepines. Both agonists and antagonists (inter)act in a different manner, suggesting that rather ambiguous receptor mechanisms are involved in benzodiazepine effects in the heart.

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Pharmacol Biochem Behav. 1999 Jan;62(1):159-64.
The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference.

Meririnne E, Kankaanpaa A, Lillsunde P, Seppala T.

National Public Health Institute, Department of Mental Health and Alcohol Research, Helsinki, Finland.

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

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Neurobiol Learn Mem. 2000 Mar;73(2):168-79.
Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus.

Herzog CD, Gandhi C, Bhattacharya P, Walsh TJ.

Department of Psychology, Rutgers University, New Brunswick, NJ 08903, USA.

Injection of GABA(A)/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABA(A) receptor are differentially localized to either GABAergic (alpha(1)/beta(2)/gamma(2)) or cholinergic (alpha(3)/beta(3)/gamma(2)) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague-Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 microg), or zolpidem (4, 8, or 12 microg) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HA-ChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 microg). However, intraseptal injection of 8 microg of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway. Copyright 2000 Academic Press.

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Exp Brain Res. 2000 Feb;130(3):309-19.
Dimorphic features of the different alpha-containing GABA-A receptor subtypes in the cortico-basal ganglia system of two distantly related mammals (hedgehog and rat)

Facciolo RM, Alo' R, Tavolaro R, Canonaco M, Franzoni MF.

Ecology Department, University of Calabria, Cosenza, Italy.

This investigation represents a first study dealing with the dimorphic differences of the main alpha-containing gamma-aminobutyric acid (GABA(A)) receptors in the brain of two distantly related mammals (hedgehog and rat). The labeling of these receptors in the presence of zolpidem (highly selective benzodiazepine agonist) and under the different degree of GABA(A)/benzodiazepine allosteric coupling activities accounted for a heterogeneous colocalization of alpha1-enriched and of alpha2/3-enriched and alpha5-enriched GABA(A) receptors in some areas of the cortico-basal ganglia system (including the important ventrolateral thalamic station) of both mammalian sexes. In the hedgehog, the greatest (P<0.001) GABA-dependent reduction of zolpidem inhibition constants was mostly registered in alpha1- and/or alpha5-enriched areas, such as the frontoparietal cortex lamina III (235%), ventrolateral thalamic nucleus (128%), and substantia nigra pars reticulata (110%) of the male. However, the greatest reductions in the rat were instead detected in the male substantia nigra pars reticulata (192%) and female striatum (120%), areas which are enriched either by the colocalization of alpha1- with alpha2/3-subunits or by all three alpha-subunits. These results support the contention that a sex-related alpha-containing GABA(A) receptor sensitivity constitutes an important element in the execution of skilled motor activities during the different socio-sexual behaviors of the two mammals.

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Eur J Neurosci. 2000 Feb;12(2):425-36.
Differential sensitivity to Zolpidem of IPSPs activated by morphologically identified CA1 interneurons in slices of rat hippocampus.

Thomson AM, Bannister AP, Hughes DI, Pawelzik H.

Department of Physiology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. alext

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