Effects of psychoactive drugs on short-term memory in rats and rhesus monkeys.

To examine the effects of drugs on short-term memory in animals, the delayed discrimination experiment in rats and the delayed matching to sample experiment in rhesus monkeys were conducted. Nicotine at 0.125 mg/kg, s.c. in rats and at 0.5 mg/kg, s.c. in monkeys increased the percentages of correct choices. Scopolamine at 0.06-0.12 mg/kg, s.c. in rats and at 0.015 mg/kg, s.c. in monkeys decreased the percentages of correct choices. However, supposedly memory-specific, delay-time-dependent disruptive effects by scopolamine were found only in monkeys. Diazepam at 0.5-2 mg/kg, s.c. did not change the correct choices in rats. However, diazepam at 1-4 mg/kg, i.g. decreased the correct choices in monkeys regardless of the delay time. Chlorpromazine at 0.25-1.5 mg/kg, s.c. showed inconsistent effects in rats. In monkeys, chlorpromazine at 0.25-0.5 mg/kg, s.c. had no effect. These results suggested that using both rats and monkeys would be useful for evaluating the effects of drugs on memory.     

Substitution of psychoactive drugs in pentobarbital-dependent rats

The substitution of either bromazepam, diazepam, methaqualone, mazindol, nortriptyline or bupropion for pentobarbital, in dependent rats, was assessed using a continuous drug infusion method. Male, Sprague-Dawley rats were made dependent on pentobarbital during 12 days of continuous, intraperitoneal, pentobarbital infusion. On Day 13, pentobarbital was replaced with either saline, vehicle, or one of the drugs of interest and rats were infused for 24 h. On Day 14, all rats were infused, for 24 h, with saline. Changes in both body weight and behavioral indices of withdrawal were assessed during Day 13 and 14. It was observed that bromazepam and methaqualone substituted for pentobarbital in a dose-dependent fashion. Diazepam also substituted in pentobarbital dependent rats but, inexplicably, the low dose of diazepam provided better substitution than did the higher dose. On the other hand, neither mazindol or nortriptyline substituted for pentobarbital and there was a tendency for exacerbation of the withdrawal signs. Finally, it was noted that the low dose of bupropion appeared to decrease the severity of the withdrawal symptoms. The data supports the view that the substitution of compounds for pentobarbital, in dependent rats, is limited to those compounds which, presumably, possess similar mechanisms of action in the CNS.     

Effects of various psychoactive drugs on the metabolism of Δ1-tetrahydrocannabinol by rats in vitro and in vivo

Metabolism of ¹⁴C-tetrahydrocannabinol (¹⁴C-THC) by rat liver microsomal preparations in vitro was studied in the absence and presence of other psychoactive drugs. Disappearance of ¹⁴C-THC, and changes in metabolite patterns as shown by thin layer chromatography, were studied. SKF 525-A, pentobarbital, phenobarbital and amphetamine all produced an apparently non-competitive inhibition of THC metabolism. The inhibition produced by meprobamate was at least partly competitive. Morphine and mescaline had no evident effect. SKF 525-A and the barbiturates markedly decreased the concentrations of all the major THC metabolites found in the incubation media.In contrast, none of the drugs tested in vivo, with the exception of SKF 525-A, had any effect on the biliary ¹⁴C-excretion or metabolite pattern, or on final tissue levels of ¹⁴C, when administered in doses comparable to those used for studies of interaction with THC in vivo. SKF 525-A, however, did markedly decrease the excretion of total ¹⁴C and alter the pattern of THC metabolites in the bile, and increased the final tissue ¹⁴C levels.It is concluded that in vivo interactions between THC and other psychoactive drugs are probably not explainable primarily on the basis of altered THC metabolism.     

Effects of psychoactive drugs on delta sleep-inducing peptide concentrations in rat brain

The concentration of delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) in rat brain regions was determined by radioimmunoassay following treatment with various psychoactive drugs or adrenalectomy. The antidepressant drugs imipramine and zimeldine, given orally twice daily for three weeks, reduced the concentrations of DSIP-LI in the hypothalamus, frontal cortex and cerebellum. The effects of zimeldine were similar but somewhat less pronounced than those of imipramine. The neuroleptic drug haloperidol, given i.p. once daily for two weeks, increased the concentration of DSIP-LI in the hypothalamus, but not in the frontal cortex. A single dose of haloperidol did not affect the concentration of DSIP-LI in either region. Like haloperidol, pentobarbital elevated the concentration of DSIP-LI in the hypothalamus; however, this effect of the barbiturate was seen after single but not after repeated administration. Cortical concentrations of DSIP-LI were unaffected following both single and repeated pentobarbital administration. Finally, adrenalectomy increased the concentration of DSIP-LI in the hypothalamus, but not in the other brain regions. In conclusion, the DSIP concentration in rat brain regions may be altered by a variety of interventions. The most profound and general alterations were observed following administration of antidepressant drugs.     

Effect of diuretics and calcium antagonists on circulatory parameters and plasma catecholamines during mental stress

In a model of mental stress the influence of nifedipine and hydrochlorothiazide on stress-induced changes in blood pressure, heart rate, and plasma catecholamines was studied in normal persons. The drugs were used to investigate whether substances with antihypertensive but no particular sympatholytic properties were capable of suppressing emotionally induced stress reactions. In all subjects blood pressure and heart rate increased significantly during mental stress, and this effect was not inhibited either by nifedipine or hydrochlorothiazide. In the hydrochlorothiazide group plasma noradrenaline levels were significantly higher than in controls in the resting state and during the stress reaction, whereas in the nifedipine group no difference was observed. It is concluded that nifedipine or hydrochlorothiazide do not inhibit emotional stress reactions in normotensive persons.     

Epigenetics of psychoactive drugs

Objectives Epigenetics refers to the heritable, but reversible regulation of various biological functions. Changes in DNA methylation and chromatin structure derived from histone modifications are involved in the brain development, pathogenesis and pharmacotherapy of brain disorders. Key findings Evidence suggests that epigenetic modulations play key roles in psychiatric diseases such as schizophrenia and bipolar disorder. The analysis of epigenetic aberrations in the mechanisms of psychoactive drugs helps to determine dysfunctional genes and pathways in the brain, to predict side effects of drugs on human genome and identify new pharmaceutical targets for treatment of psychiatric diseases. Summary Although numerous studies have concentrated on epigenetics of psychosis, the epigenetic studies of antipsychotics are limited. Here we present epigenetic mechanisms of various psychoactive drugs and review the current literature on psychiatric epigenomics. Furthermore, we discuss various epigenetic modulations in the pharmacology and toxicology of typical and atypical antipsychotics, methionine, lithium and valproic acid.     

Choline administration: Lack of effect on plasma catecholamines in rats

Choline chloride (35 or 70 mg/kg, IP) or saline was administered daily for 3 consecutive days to adult male Sprague-Dawley rats. Before and 30, 60 and 120 minutes after the third injection of choline chloride or saline, blood samples were collected from a chronic tail artery catheter and later analyzed for levels of norepinephrine (NE) and epinephrine (EPI). Plasma levels of both catecholamines did not differ between choline- and saline-injected rats at either of the four sampling points. When insulin (10 IU/kg, SC) was administered to stimulated the sympathetic-adrenal medullary system reflexy, plasma levels of NE and EPI increased significantly above basal values but were similar for choline- and saline-injected rats. These findings do not support a role for choline availability in the regulation of catecholamine secretion from the adrenal medulla.     

Effects of psychoactive agents on acquisition of conditioned pole jumping in rats

Summary Albino rats required progressively more trials to reach a 90 percent avoidance criterion and achieved less mean total percent avoidance learning than saline injected controls following administration of increasing doses of LSD-25, phencyclidine and amobarbital. The psychotomimetics were effective in depressing acquisition in dosages demonstrated by others to be ineffective in overtrained animals. In contrast d-amphetamine had a slight facilitating effect, but only in large doses.Support in part by grant MY-02653, USPHS.     

The effect of psychoactive drugs on plasma corticosterone levels and behavioural in the bulbectomised rat.

Bilateral olfactory bulbectomy (OB) in the rat produces a rise in circulating 11-hydroxycorticosterone (11-OHCS) to intermediate levels (40–50 μg/100 ml plasma). Following footshock extreme corticosterone elevation occurs (65–80 μg/100 ml plasma). Bulbectomy also produces behavioural changes which include hyper-reactivity and an acquisition deficit in a step-down passive avoidance test. Treatment of the bulbectomised rat with amitriptyline (5 and 10 mg/kg), mianserin (5 and 10 mg/kg) and viloxazine (2 and 5 mg/kg) administered IP for at least 7 days corrected the acquisition deficit, reduced the hyper-reactivity and the elevated corticosterone levels in a reproducible manner. This reduction in 11-OHCS concentrations occurred in bulbectomised rats with and without footshock. In contrast, the antidepressant drugs did not produce these changes in sham-operated controls (SO). The central stimulant, amphetamine (1 and 3 mg/kg/day for 7 days, IP), increased 11-OHCS concentrations in unstressed OB and SO rats. There was no further elevation in the 11-OHCS concentrations of stressed rats of both OB and SO groups. This drug further impaired the acquisition of both OB and SO rats and increased the reactivity scoring of both groups. The major tranquillizer, chlorpromazine (1 and 3 mg/kg IP for 7 days), reduced plasma 11-OHCS levels and the hyperreactivity of both OB and SO groups. It did not reduce the acquisition deficit exhibited by the OB rats. Chlordiazepoxide (5 and 15 mg/kg IP for 7 days), had a profile similar to that of chlorpromazine except that it impaired acquisition in the SO group. Thus using the techniques described above it is possible to separate the antidepressants from other major classes of psychotropic drugs.     

Effects of psychoactive drugs in the Vogel conflict test in mice.

This study examined effects of various psychoactive drugs on the Vogel conflict test, where drinking behavior is punished by electric shocks, in ICR mice to clarify the pharmacological features of this method in mice. A benzodiazepine anxiolytic diazepam and a barbiturate pentobarbital produced significant anticonflict effects, which mean that these drugs increased the number of electric shocks mice received during 40-min test session. On the other hand, yohimbine (alpha2-receptor antagonist), caffeine (adenosine-receptor antagonist), scopolamine (muscarinic cholinergic antagonist), cyclazocine (sigma-receptor antagonist), cimetidine (H2-receptor antagonist), baclofen (GABA(B)-receptor agonist), MK-801 (NMDA-receptor antagonist), buspirone (5-HT1A-receptor agonist), chlorpromazine (dopamine-receptor antagonist) and haloperidol (dopamine-receptor and sigma-receptor antagonist) all did not produce anticonflict effects in this test using ICR mice. The results suggest that the Vogel conflict test is applicable to ICR mice and that this test in mice is appropriate as a screening method for drugs that have apparent anti-anxiety actions.     

Anaphylaxis-induced increase in plasma cyclic AMP dependent on endogenous catecholamines in rats

Plasma cyclic AMP levels during anaphylactic shock in rats was studied in 7 groups of animals: (1) control rats; (2) rats with adrenomedullectomy; (3) rats treated with propranolol; (4) rats with reserpinization; (5) rats with 6-hydroxydopamine-induced chemical sympathectomy; (6) rats treated with hexamethonium, and (7) rats treated with cocaine (catecholamine uptake inhibitor). All experiments were carried out in ovalbumin-sensitized rats. Plasma cyclic AMP showed a rapid increase during anaphylactic shock in control rats. Adrenomedullectomy abolished the anaphylaxis-induced increase in plasma cyclic AMP, while hexamethonium had no effect. Propranolol caused a dose-dependent abolition of the increase. The treatment of rats with reserpine, 6-hydroxydopamine or cocaine partially inhibited the increase in plasma cyclic AMP. The results show that the adrenal medulla is the major source of catecholamines during anaphylactic shock, and that catecholamines in the adrenergic neuronal terminals may be partly responsible for the anaphylaxis-induced increase in plasma cyclic AMP.     

Time course for plasma 11-hydroxycorticosteroid elevation in rats during stress

The time course of plasma 11-hydroxysteroid elevation was studied in two stress situations: regular unsignalled foot shock which produces an intermediate steroid elevation and irregular signalled foot shock with the possibility of escape, which produces an extreme steroid elevation. The initial time course for steroid elevation followed a similar pattern for both treatment groups with the exception that in the irregular signalled group the plasma steroid elevation was more pronounced and there was an indication of biphasic response. The results are discussed in terms of possible inhibitory feedback pathways.     

Abnormal sympatho-adrenal function and plasma catecholamines in obese Zucker rats

The functional integrity of the peripheral sympathetic nervous system and adrenal medulla was assessed in homozygous, lean and obese, 7–8 month old male Zucker rats by the changes in plasma catecholamines during cold and immobilization stresses. Five of eight obese, but no lean rats died during a 24 hr cold stress (4–7°C) from hypothermia. While both lean and obese rats had decreased rectal temperatures after 4 hr of cold stress, the obese had lower temperatures, relatively less of an increase of plasma norepinephrine (NE) and epinephrine (E) than the lean rats, and were unable to consistently maintain their temperatures even during intravenous NE infusions. Obese rats had lower rectal temperatures and higher plasma NE and dopamine levels at 21–22°C ambient temperature, a relative failure to increase plasma NE and E levels after 1 hr of immobilization, but normal or supranormal plasma catecholamine levels after decapitation compared to the lean rats. These results suggest that the obese Zucker rat has abnormalities of both peripheral sympatho-adrenal function and thermoregulation, which may play roles in the development and/or maintenance of many of the physiological and metabolic defects in this animal model of genetic obesity.     

The factors affecting plasma catecholamines concentration in rats and man

Rat and human plasma catecholamines were measured simultaneously by HPLC-THI, HPLC-ECD and REA, and the three methods were compared. An attempt was also made to determine the factors affecting the estimated value of plasma catecholamine concentration. Our study showed that: Sensitivity and reproducibility to norepinephrine and epinephrine were identical in all three methods. One advantage of the REA method is that comparatively smaller sample volumes are required to produce similar results. Plasma dopamine concentration in peripheral blood samples was determined by the HPLC-ECD rather than the HPLC-THI method. Withdrawal of 5 ml of blood produced a significant increase in norepinephrine, epinephrine and dopamine in rat plasma. The catecholamine concentration in these cases was determined by the REA method. Plasma norepinephrine concentration did not increase with age in Wistar Kyoto rats. However, plasma norepinephrine concentration increased significantly with age in stroke-prone spontaneously hypertensive rats (SHRSP). Plasma norepinephrine concentration in male SHRSP was greater than that in female SHRSP. SHRSP-plasma norepinephrine concentrations rose in parallel to increases in blood pressure. The plasma norepinephrine concentration in SHRSP with cerebral hemorrhage rose significantly as compared with the plasma norepinephrine levels in SHRSP without cerebral bleeding. Because each method of determination of plasma catecholamine concentration has both merits and demerits, selection should be determined by sample size and amount of catecholamines in the plasma samples. Factors affecting the estimated value of plasma catecholamine concentration should be taken into consideration.     

Licensing of psychoactive drugs in the Netherlands

The Dutch Board for the Evaluation of Medicines approves applications for a marketing authorization if on the basis of pharmaceutical, pharmacological--toxicological, and clinical data the benefit--risk balance is considered positive. In the Netherlands, almost 4000 drugs have a marketing authorization, 145 of these belonging to the psychotropic drugs. During the Board's existence the number of applications and the number of approvals for antipsychotics and antidepressants decreased, while an increasing amount of anxiolytics was applied for and approved. This phenomenon may reflect the prescribing behavior of doctors. The Board has on several occasions actively influenced the market situation of certain drugs, e.g., amphetamines have almost totally disappeared from the market since a strong restriction of the indications was imposed. A certain shift in the evaluation policy of the Board can be noticed in some respects, for instance, data on chronic use are no longer required for registration of hypnotics. The requirements for registration of antidepressants are less strict than in the past. The Board tries by its registration policy to be an objective interface between the drug-producing companies and the consumer, the patient, and seeks the highest standards possible in the drug market.     

Effects of depletion of brain catecholamines during the development of morphine dependence on precipitated withdrawal in rats

Summary The significance of long term depletion of brain catecholamines (CAs) for the development of morphine dependence and for the expression of morphine withdrawal was studied in rats which were implanted with morphine pellets for 10 days. CAs were depleted by inhibition of tyrosine-hydroxylase with alpha-methyl-tyrosine (AMT) or by destruction of catecholaminergic nerve terminals with 6-hydroxydopamine (6-OHDA). In the acute experiments these drugs were applied within 24 hrs before precipitation of withdrawal; in the chronic experiments drug administration was started before the first implantation and in the case of AMT, continued repeatedly thereafter.With either method, acute depletion of brain CAs resulted in reduced intensity of withdrawal. When CAs were kept low through the whole time of morphine exposure and also at the time of withdrawal, the intensity of withdrawal was normal in the case of 6-OHDA administration and only slightly decreased in the case of AMT. When AMT administration was discontinued 40 hrs before precipitation of withdrawal the withdrawal pattern occurred with unchanged intensity.Our experimental data are compatible with the assumption that long lasting depletion of brain CAs is compensated for by induction of neuronal supersensitivity for noradrenaline (NA) and dopamine (DA). While both CAs play an important role in the full expression of the withdrawal syndrome their possible involvement in mechanisms leading to dependence seems to be unlikely although final statements cannot be made by the presented experiments.