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Alpidem in an imidazopyridine derivative which binds selectively to the θ(BZ) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg). In the latter case the benzodiazepines chlordiazepoxide and triazolam did substitute for the ethanol cue. These results confirm that the discriminative stimulus effects of alpidem differ from those produced by benzodiazepines. The effects of alpidem are most similar to those of the other imidazopyridine derivative, zolpidem, and may be related to the selectivity of these drugs of the θ(BZ) receptor subtype. [ABSTRACT FROM AUTHOR]

Gamma-hydroxybutyric acid (GHBA) in doses that increased the striatal dopamine (DA) content of rat brain failed to increase the affinity of striatal tyrosine hydroxylase (TH) for its pterdine cofactor or to change the sensitivity of the enzyme to the inhibition by DA. Haloperidol (1 mg/kg) decreased the apparent Kof striatal TH for the pteridine cofactor. However, when GHBA was injected before haloperidol it prevented the decrease in the apparent Kof TH, in a dose related manner. In vitro GHBA (10 M) neither changed the stimulation of the striatal adenylyl cyclase by DA nor its inhibition by haloperidol. These results suggest that in striatal dopaminergic terminals the Kof TH for the pteridine cofactor is regulated by an molecular mechanism which requires that the impulse flow in the DA neurons is unimpaired. [ABSTRACT FROM AUTHOR]

Benzodiazepines and other compounds which act at benzodiazepine binding sites have been shown previously to attenuate the acquisition of conditioned fear in rodents when administered before the acquisition session, an effect which may parallel the disruption of human memory produced by anxiolytics and sedatives. Such an action is usually, but not invariably, produced by doses which have direct behavioural depressant effects. The present study was carried out to extend previous work by investigating the effects of the hypnotic benzodiazepine triazolam and the nonbenzodiazepines zolpidem and CL 218,872 on the acquisition of learned fear in mice. All these drugs reduced locomotor activity shortly after injection. They also produced disruptions of the acquisition of learned fear. Triazolam exerted behavioural effects similar to those found previously with other benzodiazepines, the doses which disrupted the acquisition of conditioned fear being similar to, or lower than, the doses which depressed locomotion. In contrast, the results indicated that zolpidem was more potent at reducing locomotion than at interfering with fear conditioning, a result which may reflect the preferential sedative action of zolpidem. [ABSTRACT FROM AUTHOR]

Zolpidem is a non-benzodiazepine hypnotic drug which displaces benzodiazepines from their binding sites in different brain structures. Previous work has demonstrated several differences between zolpidem and benzodiazepines, including differences between the stimulus properties of zolpidem and chlordiazepoxide. In the present study the discriminative stimulus properties of zolpidem were analysed by training rats to discriminate between this drug and saline. It was found that stimulus control developed readily with 2 mg/kg but not with 1 mg/kg zolpidem. The effect was dose-related, had a short duration of action and was antagonised by Ro 15-1788. Furthermore, stimulus control produced by zolpidem was associated with marked reductions in rates of responding. Injections of chlordiazepoxide, triazolam, lorazepam, zopiclone, CL 218,872 and pentobarbital produced dose-related responding on the zolpidem-associated lever but haloperidol did not. However, in general, the doses of those drugs which produced drug-lever responding also reduced response rates. It is possible that the above mentioned differences between the discriminative stimulus produced by zolpidem in rats and those produced by other sedatives may be due to a selective action of zolpidem on a sub-type of benzodiazepine binding site. [ABSTRACT FROM AUTHOR]

We studied the relationship between changes of 3′,5′-cyclic adenosine monophosphate (cAMP) and tyrosine hydroxylase (TH) activity in adrenal medulla of rats exposed to cold stress. Exposure of rats to 4° C produced a ten-fold increase of the cAMP content of adrenal medulla in about 30 min. This increase persisted for about one hour; the levels of cAMP returned to control value within 120 min in spite of the continued exposure to 4° C. In rats with monolaterally denervated (splanchnicotomized) adrenal, the exposure to 4° C produced only insignificant changes of cAMP concentration. During the exposure to 4° C we also observed an increase (about two times) of catecholamine turnover rate as measured by H-dopamine efflux from adrenal glands. This increased efflux persisted for 6 h of exposure to cold suggesting that the efflux of H-dopamine can increase without a simultaneous increase of cAMP concentrations. Exposure of rats to 4° C for two hour also increases (about two times) the TH activity as measured 24 h later. Exposure of the animals to 4° C for a time period longer than two hour (4 or 24 h) failed to produce further increases of TH activity. These results support the concept that the increase of cAMP concentrations in adrenal medulla may play a central role in initiating the chain of biochemical events modulating the synthesis of TH. [ABSTRACT FROM AUTHOR]

The electrically evoked, calcium-dependent release of H-acetylcholine from slices of rat striatum was inhibited in a concentration-dependent manner by (+)-amphetamine (0.2-20 μM). This inhibitory effect of (+)-amphetamine was unaffected by depletion of the endogenous stores, of dopamine by pretreatment with rescrpine (5 mg/kg, 24h). However, the combined treatment of reserpine with α-methyl-p-tyrosine (300 mg/kg) or NSD 1015 (100 mg/kg) reduced significantly these inhibitory effects of (+)-amphetamine. Similar results were obtained after chronic 6-hydroxydopamine lesions of the corpus striatum. The inhibition of H-acetylcholine release by (+)-amphetamine in rats pretreated with reserpine was potentiated in the presence of 10 μM pargyline. These results support the view that the inhibitory effects of (+)-amphetamine on the electrically-evoked release of H-acetylcholine are mediated by dopamine released from a special pool of newly synthetized transmitter rather than through a direct action on an amphetamine recognition site or receptor. [ABSTRACT FROM AUTHOR]