Influence of nootropic drugs on the learning- and memory-impairing effect of diethyldithiocarbamate in albino rats

The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on the impaired cognitive functions by the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDC) were investigated in albino rats. The changes in learning and memory were studied by the two-way active avoidance with punishment reinforcement (shuttle box). DDC injected intraperitoneally at a dose of 300 mg/kg in the course of the 5-day shuttle box training significantly impaired learning and retention. The 10-day treatment (5 days before and 5 days during training) with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the learning- and memory-impairing effect of DDC. The role of the NA-ergic neurotransmitter system for the DDC-induced disturbances in cognition as well as for the protective effects of nootropic drugs was discussed.     

Action of nootropic drugs on transcallosal responses in rats

The effects of nootropic drugs and related compounds on transcallosal responses were examined in urethane-anesthetized rats. The transcallosal response was recorded from the surface of the anterior neocortex following electrical stimulation of the contralateral corpus callosum. The transcallosal response consisted of a biphasic positive-negative waveform. Hopantenate increased the amplitude of the positive- and negative-waves, without affecting the latency. Aniracetam, idebenone, bifemelane hydrochloride, TRH and meclofenoxate increased the amplitude of the negative-wave, without affecting the latencies. Vinpocetine and eburunamonine had no effect on the transcallosal response. Muscimol, amino-oxyacetic acid, diazepam and pentobarbital increased the amplitude of the positive-wave and decreased the amplitude of the negative-wave, without affecting the latencies. Bicuculline and picrotoxin increased the amplitude of the negative-wave, without affecting the latencies. Physostigmine decreased the amplitude of the negative-wave, without affecting the latency. Atropine was without effect. The pharmacological nature of the transcallosal response is discussed, based on findings with 16 different pharmacological agents.     

Influence of testosterone on morphine analgesia in albino rats

Pain threshold for thermal stimulus after morphine, naloxone alone and naloxone in combination with morphine was studied in male rats before and after three days treatment with testosterone. It was also determined 15 days after gonadectomy and administration of testosterone in such rats. There was significant reduction in morphine analgesia after administration of testosterone and also after gonadectomy. Naloxone increased the pain threshold in gonadectomised rats and it enhanced morphine induced analgesia instead of antagonising it. Naloxone, however, had no effect on morphine analgesia in testosterone treated control rats and gonadectomised rats.     

Effects of nootropic drugs on dopaminergic systems in the CNS

The effect of 3 nootropic drugs, meclofenoxat (MEC), piracetam (PIR) and orotic acid (methylglucamine orotate, MGO), on locomotor activity and on rotational behavior after intracerebral injection of dopamine was tested in female Wistar rats. Whereas MGO-pretreatment increased the dopaminergic supersensitivity following repeated haloperidol in both behavioral tests, the other nootropics were without influence on intensity and duration of supersensitivity. Stimulating and sedative action of apomorphine on locomotion (following 2 mg/kg and 40 micrograms/kg apomorphine sc, respectively) was found to be unchanged after single doses of nootropics (300 mg/kg PIR or MEC, 225 mg/kg MGO, 30 min before apomorphine). Preceding systemic application of nootropics did not change the rotational behavior following application of dopamine (200 micrograms/2 microliters) into nucleus accumbens or nucleus caudatoputamen. The results show that nootropic drugs are without influence on spontaneous and dopaminergically stimulated locomotor activity but in contrast to PIR and MEC, MGO is able to facilitate the dopaminergic supersensitivity.     

Characterization of the transcallosal response in aged rats and its susceptibility to nootropic drugs.

The transcallosal response in aged rats was recorded and its susceptibility to certain nootropic drugs was compared with adult animals, under urethane-anesthesia. The transcallosal response in 24-month old rats was significantly reduced in the amplitude of both positive and negative waves, as compared with 5-month old animals. In adult rats, intravenous administration of 100 mg/kg of calcium hopantenate augmented the amplitude of both the positive and the negative waves. Intraperitoneal administration of 300 mg/kg of calcium hopantenate or 10-100 mg/kg of aniracetam increased the amplitude of the negative wave by 20-30% above the control level but had no effect on the positive one. In aged rats, these drugs, given intraperitoneally, also increased the negative wave without affecting the positive one and the degree of augmentation was more prominent; both drugs increased the amplitude of the negative wave by about 190% of the control. These results suggest that the susceptibility to the nootropic drugs became even more striking in older animals, the function in the brain of which are reduced by the natural ageing process.     

Influence of dietary fats on weight gain in albino rats

Carbon-chain length and degree of saturation of dietary fat may influence weight gain. To examine this hypothesis we randomly allotted 100 male, 30-day old, albino rats to each of four groups. Each group was fed, ad libitum, a diet containing, as the only source of fat, either lard (L) or safflower oil (SO) (representing saturated and polyunsaturated fat respectively) or groundnut oil (GO) or coconut oil (CO) (representing long-chain and medium-chain triglycerides respectively). At the end of 90 days it was found that rats fed SO consumed more food than those fed L enriched diet (P < 0.001) but the weight gain was similar in the two groups. Similarly rats fed GO-containing diet ate more than those fed diet containing CO (P < 0.001), yet weight gain was similar. Thus it appears that carbon-chain length and degree of saturation of dietary fat does not influence weight gain in rats fed an ad libitum diet.     

Antitesticular effect of copper chloride in albino rats

Copper chloride treatment adversely affects testicular activity in albino rats. To investigate its antitesticular effects mature (120 days) Wistar strain albino rats were treated intraperitoneally (i.p.) with copper chloride at doses of 1000, 2000 and 3000 micrograms/kg body weight/day for 26 days. Significant reduction of testicular and accessory sex organs (seminal vesicle, ventral prostate) weight, along with inhibition of testicular delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity and reduction in plasma testosterone level, were observed at the doses of 2000 and 3000 micrograms/kg body weight/day. The degree of inhibition in all the parameters were increased with the increase of dosage. But no significant change was observed in the above parameters when the animals were treated with 1000 micrograms/kg body weight/day dose. This suggests that copper produces a suppressive influence on male reproductive activity, mainly on testicular weight and steroidogenesis and accessory sex organ weight in a dose-dependent manner.     

Platelet hyperreactivity and antiaggregatory properties of nootropic drugs under conditions of alloxan-induced diabetes in rats

The effects of nootropic drugs (noopept, pentoxifylline, piracetam, pramiracetam, Ginkgo biloba extract, entrop, cerebrocurin and citicoline) on platelet aggregation in rats with experimental diabetes have been studied. It is established that all these drugs exhibit an inhibitory action of various degrees against platelet hyperreactivity under conditions of chronic hyperglycemia. The maximum universality of the antiaggregatory action is characteristic of pramiracetam, entrop and Ginkgo biloba extract.     

Studying specific effects of nootropic drugs on glutamate receptors in the rat brain

The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.     

The effect of clonidine on gastric acid secretion in rats and dogs

Summary The effect of clonidine on gastric acid secretion was investigated using rats and dogs. In the stomach lumen perfused rat basal gastric acid secretion was increased by clonidine in the anaesthetized rat but inhibited in the conscious animal. Clonidine also reduced the basal gastric acid secretion in rats with chronic gastric fistula, (ED₅₀ 12 g/kg p.o.). In addition, gastric secretion stimulated by insulin hypoglycaemia was inhibited by clonidine in anaesthetized stomach lumen perfused rats and in conscious dogs with gastric fistula. In the rat gastric secretion stimulated by electrical vagus stimulation was inhibited as well. However, clonidine had no effect on the gastric acid secretion stimulated by carbachol in stomach lumen perfused rats and in dogs with denervated fundic pouch.These results suggest that the inhibition of gastric acid secretion by clonidine probably is due to an inhibition of acetylcholine release at the vagus nerve endings. Additional central gastric antisecretory effects can, however, not be excluded by this study.     

Effects of neuroleptic drugs,clonidine and lithium on the expression of conditioned behavioral excitation in rats

Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 g/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.     

Influence of nitric oxide synthetase inhibitor on the blood pressure action of clonidine in rats

We are investigating the influence of NO synthetase inhibitor on the clonidine-induced cardiovascular actions in urethane-anesthetized rats. The systemic blood pressure was measured from right femoral artery, heart rate from the pressure pulse under inhalation of O2. Nw-nitro-L-arginine-methylester (L-NAME, 5 mg/kg), NO synthetase inhibitor, administered intravenously increased blood pressure slightly, although decreased heart rate. The responses to L-NAME were stable about 10 min after the injection. Clonidine (5 mg/kg) administered intravenously indicated the transient increase blood pressure and following continuous decrease of blood pressure. The early transient hypertension of clonidine was potentiated by pretreatment with L-NAME and later continuous hypotension was markedly inhibited. While, the early transient hypertension of clonidine was inhibited by pretreatment with L-arginine and later continuous hypotension was potentiated. The hypertension and tachycardia of intravenous tyramine was enhanced by L-NAME. Clonidine administered into the cerebroventricle did not indicate the early transient hypertension, though produced the later continuous hypotension. These results suggest that L-NAME modifies the cardiovascular responses to clonidine and NO may participate in the modulation.     

Mechanisms of the inhibitory effect of clonidine on the reproductive system of female rats

It has been demonstrated in experiments on puberal and infantile female rats that a single subcutaneous injection of clonidine (0.03 mg/kg) disturbed whereas in a dose of 1 mg/kg completely inhibited spontaneous or induced ovulation as well as sexual receptivity. When injected in a daily dose of 0.03 mg/kg to puberal rats for 8 days clonidine potentiated the total gonadotropic activity of the pituitaries. When injected in a daily dose of 0.5 mg/kg for 10 days the drug induced the disorders of the estrous cycle during diestrus.     

Influence of central pretreatment with 6-hydroxydopamine on the hypotensive effect of clonidine

Intracisternal (i.ci.) pretreatment of rabbits with 6-hydroxydopamine (6-OH-DA) (3 times 0.5 mg/kg) reduced the norepinephrine content of the brainstem significantly by 52% but did not diminish the hypotensive and bradycardiac action of 2-(2,6-dichloroanilino)-2-imidazoline (clonidine; Catapresan; Catapres) (doses 10, 30 and 100 microgram/kg i.v. and 1 microgram/kg i.ci.) in anaesthetized animals. Pretreatment with 6-OH-DA did not abolish the enhancement by clonidine (100 microgram/kg i.v.) of reflex bradycardia elicited by angiotensin 0.2 microgram/kg i.v. The conclusion is drawn that clonidine acts directly on central alpha-adrenergic receptors independent of storage and synthesis of endogenous catacholamines in the central adrenergic neurons.     

Influence of 6-hydroxydopamine on the behavioral effects induced by apomorphine or clonidine in rats

The aim of this paper is to examine if central chemical sympathectomy induced by two injections of 6-hydroxydopamine (6-OHDA) in a dose of 250 g intracerebroventricularly (k.c.v.) affects behavioral phenomena elicited by apomorphine (AP) (1 or 1.2 mg/kg i.p.) or clonidine (CL) (0.1 mg/kg, 5 or 1 g/kg i.p.).Experiments were carried out on male Wistar rats. The time of duration of several components of behavior and the degree of irritability of rats were measured. Moreover, open field and hole test were performed. The lower dose of AP did not affected behavior of rats. The higher dose increased the locomotor and exploratory activity of animals. 6-OHDA potentiated these effects of AP. CL (0.1 mg/kg) had a depressive effect on the rats' behavior, which was potentiated by 6-OHDA. CL (5 g/kg) had no effect on the rats' behavior, but in a dose of 1 g/kg caused excitatory behavior. This type of behavior was abolished by 6-OHDA. In conclusion, central chemical sympathectomy caused increased sensitivity of the central nervous system on AP. Excitatory behavioral effects of CL in low dosage may be connected with stimulation of central adrenergic receptors. Depressive behavioral effect of CL in high dosage is unspecific. Central chemical sympathectomy affects by different methods the reactivity of dopaminergic and noradrenergic neurons.