Effects of beta-CCE on retention of aversively- and appetitively-motivated tasks in rats.

Beta-carboline-3-carboxylic acid ethyl ester (beta-CCE; 1.0 or 5.0 mg/kg, i.p.) or vehicle control was administered to male Sprague-Dawley rats immediately after training in an aversively- or appetitively-motivated task. Aversively-motivated training consisted of a one-trial step-though inhibitory (passive) avoidance task with a 0.6 mA, 1.0 s foot shock. Retention was tested 21 days after training. The 5.0 mg/kg dose of beta-CCE significantly enhanced retention performance in the inhibitory avoidance task compared to the vehicle control. For appetitive training, the animals learned a T-maze for water reward. Retention was tested 48 h later, and neither dose of beta-CCE was found to affect retention performance. These results suggest that beta-CCE, when administered immediately after training, may alter retention performance of an aversively-motivated task but not an appetitive task.

Possible involvement of an endogenous benzodiazepine receptor ligand of the inverse agonist type in the regulation of rapid-eye movement (REM) sleep: an hypothesis.

1. Rapid-eye movement (REM) sleep is a complex behavioral state characterized by desynchronized electroencephalographic (EEG) activity, postural atonia, rapid, saccadic movements of the eyes, and vivid dreaming. 2. A recently developed class of drugs, the inverse agonist beta-carboline-3-carboxylates, elicits a number of effects similar to the properties of REM sleep, such as desynchronized cortical EEG and penile erections. 3. The hypothesis is put forth that an endogenous beta-carboline-3-carboxylate exists which may initiate many aspects of REM sleep. 4. Clinical relevance of this hypothesis is discussed with regard to REM anxiety dreams, night terrors, narcolepsy, and depression.

Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): biphasic dose-response curves.

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased Bmax for sulpiride-inhibitable [3H]spiroperidol binding) of striatal and limbic D2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D2-DAr binding assays showed 1) that CLG-induced changes in Bmax parallel these behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower Bmax. CLG also reversed an already established D2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal of HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D2 DAr upregulation/supersensitivity in animal models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e.g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia).

Long-lasting dopamine receptor up-regulation in amphetamine-treated rats following amphetamine neurotoxicity.

Amphetamine (A) (9.2 mg/kg, IP), in combination with iprindole (I) (10.0 mg/kg, IP), caused long-lasting dopamine (DA) depletions in striatum (-49%, 4 weeks) but not in nucleus accumbens following one A/I injection. Striatal DA had recovered by 4 months. DA receptors (DAr) were up-regulated: 1) behavioral responses to a DA receptor agonist (apomorphine) were significantly elevated. These included apomorphine-induced locomotor activity (+103% and +160%, on weeks 3 and 10) and apomorphine-induced stereotypy (day 10). 2) Bmax for [3H]spiroperidol binding to striatal D2 DAr (12 weeks) increased (+53%, week 12). Injection of the DAr neuromodulator cyclo(leucyl-glycyl) (8 mg/kg/day x 4 days, SC) reversed the Bmax increase. Thus toxicity (DA depletion) following high-dose amphetamine appears to induce compensatory changes in DAr. This DAr upregulation may explain the lack of abnormal movements despite enduring DA depletion. Additionally, the A/I paradigm as an animal model of long-lasting DAr up-regulation, could be used to screen neuromodulatory agents, like CLG, that might treat disorders (e.g., tardive dyskinesia and schizophrenia) thought to involve up-regulated DAr.

Neurochemical basis for the absence of overt "stereotyped" behaviors in rats with up-regulated striatal D2 dopamine receptors.

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.

The effects of cyclo(leucyl-glycyl) on nigrostriatal dopaminergic supersensitivity--inhibition of apomorphine-induced climbing.

In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.

Effects of amnesic doses of reserpine or syrosingopine on mouse brain acetylcholine levels.

The effects of reserpine and syrosingopine on mouse whole brain acetylcholine levels were examined. At 2 or 24 hr following injection, the brains were removed and analyzed by mass spectrometry. No differences were found between drug-treated and control mice in the acetylcholine content of the brain at either time interval. The results suggest that whole brain acetylcholine levels do not predict the amnesic effects of either reserpine or syrosingopine.

Clinical-pharmacokinetic investigations of acetylsalicylic acid in cases of imminent premature delivery.

The pharmacokinetics of acetylsalicylic acid have been examined in a dose of 3.6 g per day (0.9 g every 6 h) for 4 days, and the effect of the drug in 25 gravidae, threatened by premature delivery, has also been studied. Salicylate in maternal blood was higher than in amniotic fluid, umbilical cord and foetus at birth. It is concluded that 9 h after a dose of 3.6 g acetylsalicylic acid, the salicylate level in maternal blood was sufficient to reduce the number of uterine spasms in most patients. No effect of the drug on blood coagulation in mother or child was observed.

Correlation between serum concentration and hypoglycemic effect of chlorpropamide in man.

The relationship between the serum concentration and some of pharmacokinetic parameters of chlorpropamide and the hypoglycemic effect of this drug was studied. Studies were carried out in a group of 18 patients in whom the concentrations of drug and sugar in blood were determined simultaneously. Close correlation between the concentration and some pharmacokinetic parameters of chlorpropamide and the intensity of decrease of the blood glucose level as well as the time of its occurrence has been found.

Biopharmaceutical evaluation of ferrous salts in form of oral long-acting tablets.

We determined the relative bioavailability in men of two preparations containing ferrous salts in the form of long-action tablets in relation to analogous conventional preparations in the from of drops and tablets. The comparison of the bioavailability of preparations slowly and quickly releasing the active substance did not show any prolonged effect and greater absorption of drugs slowly releasing the active substance along the alimentary tract.

Correlation between the total cholesterol serum concentration data and carbamazepine steady-state blood levels in humans.

The purpose of this study was to investigate the pharmacokinetics of carbamazepine at steady state, after multiple doses in patients with elevated serum cholesterol levels. Twelve patients participated in the investigation; patients were divided into two groups according to their total serum cholesterol levels. Each patient received multiple doses of carbamazepine 600 mg po once per day. Blood samples were collected and analyzed for carbamazepine by gas-liquid chromatography. The clearance concept was used to describe the pharmacokinetic behavior of carbamazepine in high and low cholesterol patients. The area under the plasma concentration-time curve was determined by the trapezoidal rule method. This value was used to determine the oral dose clearance. In this study, the authors found that the elevated serum cholesterol and elevated total lipids cause a decrease in drug concentration. The significantly higher values of the total body clearance of carbamazepine, obtained in patients with elevated serum cholesterol levels, may have significance in clinical practice.

The effect of reserpine, syrosingopine, and guanethidine on the retention of discriminated escape reversal: peripherally administered catecholamines cannot reverse the reserpine amnesia in this situation.

In a series of experiments, the effects of reserpine, syrosingopine, and guanethidine on retention of a discriminated escape reversal training were investigated in mice. The peripherally and centrally acting reserpine produced amnesia while the primarily peripherally acting compounds, syrosingopine or guanethidine, did not produce amnesia even when given in high dosages or when training was given with low footshock. Unlike in the passive avoidance situation, peripherally administered norepinephrine or dopamine was not able to attenuate the reserpine-induced amnesia. The results were discussed in terms of the role of biogenic amines in memory formation.