Maisy Tang

Agonistic action of a benzodiazepine antagonist: Effects of Ro 15-1788 and midazolam on hypertonic NaCl intake

Rats adapted to a 23-hr water deprivation regimen were allowed a daily 1-hr water rehydration session. On test days the session drinking fluid was 1.5% NaCl solution rather than water. One group was injected (SC) with the benzodiazepine antagonist Ro 15-1788 (2.5-10 mg/kg) and another group with the agonist agent midazolam (0.13-2.0 mg/kg) every 5-6 days at 10 and 15 min before a test session, respectively. Both Ro 15-1788 and midazolam increased 1.5% NaCl solution intake in a dose-related manner. In this study and in previous research, benzodiazepines and barbiturates were shown to increase the intake of hypertonic NaCl solutions. The present results reveal a similar effect for Ro 15-1788, indicating an agonistic dimension to the spectrum of action of this specific receptor antagonist.

Chronic Ingestion Techniques for the Production of Physical Dependence on Ethanol

The study of ethyl alcohol abuse by man would be aided if animals could be induced to abuse alcohol in a like fashion. The history of attempts over the last few decades to produce a set of conditions which results in the oral overindulgence of alcohol has been rather disappointing. Transient large or sustained moderate intake increases have been demonstrated. However, no chronic, oral overindulgence model has emerged in which animals maintain high blood ethanol levels leading to physical dependence indices unequivocally attributable to the elevated ethanol intake.

Midazolam-induced increase in NaCl solution ingestion: differential effect of the benzodiazepine antagonists Ro 15-1788 and CGS 8216.

After adaptation to a 23-hr water deprivation regimen, under which rats were allowed a daily 1-hr water rehydration session, they were injected (SC) with 1 or 2 drugs presession and given 1.5% NaCl solution to drink in place of water. Midazolam (0.5-1.0 mg/kg) increased the intake of 1.5% NaCl solution as did Ro 15-1788 (2.5-10.0 mg/kg). This confirmed a previously noted agonist effect of midazolam and partial agonist action of Ro 15-1788. When injected in combination with midazolam, Ro 15-1788 (2.5-10.0 mg/kg) antagonized the effect of midazolam. CGS 8216 (2.5-20.0 mg/kg) revealed no partial agonist action on the NaCl solution ingestion procedure nor did it block the effect of midazolam.

Amelioration of genetic (SHR) hypertension: A consequence of early handling☆

Abstract The blood pressures of genetically hypertensive, adult rats (SHR strain) were decreased significantly (30 mm Hg) by having been handled each day as preweanlings, while control animals (WKY strain) were not. The demonstration that early postpartum manipulation of SHR rats can result in a lowered adult level of blood pressure may have implications for the participation of early environmental conditions in the degree of development of this form of essential hypertension.

Simultaneous determination of flurazepam and five metabolites in serum by high-performance liquid chromatography and its application to pharmacokinetic studies in rats.

A reversed-phase high-performance liquid chromatographic method is described which allows the quantification of flurazepam and five of its metabolites with a single, isocratic determination. In addition, it has the advantage of possessing a low detection limit and high precision. A 2 mm I.D. column was used to minimize sample size (50 microliter), increase sensitivity and reduce solvent consumption. The method was used to demonstrate that N-1-desalkylflurazepam, the major metabolite, has a short half-life in the rat in contrast to its prolonged life in humans.

Sar1-Ala8 angiotensin II blocks renin-angiotensin but not beta-adrenergic dipsogenesis☆

Abstract Continuous, intravenous (IV) infusion (10 μg/min) of Sar 1 -Ala 8 angiotensin II (P-113), an angiotensin II blocking analog, into rats greatly attenuated water intake resulting from IV renin (4 U) and IV angiotensin II (80 μg). P-113 infusion did not attenuate the drinking induced by the subcutaneous (SC) administration of beta-adrenergic agents: isoproterenol (0.05 mg/kg), quinterenol (4 mg/kg), and diazoxide (40 mg/kg). P-113 also functioned as a weak agonist with respect to the drinking response. It was concluded that beta-adrenergic dipsogenesis in not attributable to renin release but does depend upon some unknown renal endocrine factor.

Diazepam-induced NaCl solution intake: independence from renal factors.

Rehydrating rats injected with diazepam (8 mg/kg, SC) increased their intake of 2.0% NaCl solution. Neither bilateral nephrectomy nor bilateral ureter ligation interfered with the increased NaCl solution ingestion produced by diazepam. It is concluded that the increased intake of the NaCl solution is not secondary to renal water-electrolyte losses nor dependent upon intact renal benzodiazepine receptors.

Schedule-induced cocaine drinking: Choice between cocaine and vehicle

Rats were exposed to daily 3-hr schedule-induced polydipsia sessions (fixed-time 1-min food-pellet delivery) with two drinking fluids available: cocaine solution and water. Fluid position was alternated daily. Polydipsia occurred mostly from a preferred-side spout (position preference) until cocaine solution concentration was increased to between 0.52 and 1.04 mg/ml and animals drank mostly water. Within a lower concentration range (0.28-0.6 mg/ml) maximum session cocaine intakes ranged from 54.3 to 120.1 mg/kg. Postsession serum cocaine levels were about 200 ng/ml. At individually chosen cocaine solution concentrations, the addition of saccharin to the solution did not increase cocaine intake, but a compound solution (saccharin plus glucose) did. With progressive dilution of the compound vehicle, an almost complete preference for cocaine solution was maintained. But with a return to water as the vehicle, animals reverted to a position preference after a few sessions, although one maintained a clear cocaine preference. Schedule-induced polydipsia produced chronic, oral self-administration of cocaine resulting in pharmacologically significant intakes and serum levels.

Ethanol dependence as a determinant of fluid preference.

Rats made dependent on ethanol by a schedule-induced polydipsia procedure preferred 5% ethanol to an increasing concentration of dextrose solution to a greater extent than animals on a non-dependent, non-polydipsic procedure which allowed an equivalent opportunity to drink ethanol, confirming a previous study. Two corresponding groups of animals drinking isotonic (0.9%) NaCl rather than 5% ethanol behaved similarly to the latter group, changing to a dextrose preference at a lower dextrose concentration than the ethanol polydipsic group. Therefore, neither the intermittent food regimen (polydipsia-generating procedure) in itself, nor a history of isotonic saline polydipsia biased fluid preference against dextrose solution choices. The enhanced preference for ethanol over dextrose solutions shown by the ethanol polydipsic group can be attributed to physical dependence rather than regiment produced artifacts.

Anxiolytic effect of caffeine and caffeine-clonazepam interaction: Evaluation by NaCl solution intake

The administration of drugs with anxiolytic action to rehydrating rats augments the intake of 1.5% NaCl solution. In order to clarify the status of caffeine as an anxiolytic agent and its possible interaction with a benzodiazepine having high potency and efficacy in this regard, caffeine (0.78-100 mg/kg) alone and caffeine (0.78-50 mg/kg) plus clonazepam (0.05 or 0.50 mg/kg) injections (IP) were administered to rehydrating rats prior to 1-hr sessions during which they drank 1.5% NaCl solution. When given alone, caffeine, within a particular dose range, and clonazepam at both doses, augmented NaCl solution intake, but when administered in combination, caffeine antagonized the effects of clonazepam.