Blockade of peripheral beta-adrenergic receptors fails to suppress the cerebral spread of an engram in mice

Using bitemporal injections of puromycin, we have reported observations interpreted to indicate that a systemic injection of (-)-propranolol (50 micrograms/kg) drastically suppressed the spread of an engram in mice from the hippocampalentorhinal area to widespread cerebral areas. The present experiments were made with a non-selective, irreversible beta-adrenergic receptor antagonist that fails to cross the blood-brain barrier in order to test the possibility that the propranolol-induced blockade of peripheral beta-receptors might contribute to its effect on engram spread. Prolonged blockade of peripheral receptors by the irreversible antagonist had no effect on engram spread, suggesting that propranolol's effect was centrally mediated.     

Studies on memory: The cerebral spread of an engram in mice as affected by inhibitors of dopamine β-hydroxylase

Bitemporal injections of puromycin that primarily affect the hippocampal-entorhinal areas consistently cause amnesia of maze-learning in mice for 3 days after training but become consistently ineffective if given 6 or more days after training. At these later times, additional puromycin injection sites covering widespread areas of the forebrain are necessary to induce amnesia. These observations are interpreted to indicate that the locus of the engram has become more widespread within the 6-day period. Treatment with inhibitors of dopamine β-hydroxylase for 3 days following training, retarded the spread of memory from a matter of days to a period of weeks. Repeated treatment with the inhibitors restricted engram spread for about 3 months; again spread was evident about a month after the last treatment. These observations imply that the mechanisms responsible for engram spread are capable of surviving for extraordinarily long periods of time.     

Puromycin's suppression of memory in mice as affected by caffeine.

It has previously been shown that expression of maze-learning in mice is blocked for long periods of time by puromycin injected intracerebrally one or more days after the training experience. Treatment with caffeine after training has now been found to reduce greatly the amnestic effects of puromycin. With a high dose of caffeine (200 mg/kg) this reduction is evident 6 days after treatment with puromycin. With a lower dose of caffeine (25 mg/kg) the effect becomes evident only after a more extended period of time. In view of control experiments, we suggest that caffeine modifies factors necessary for the expression of memory and that this alteration makes puromycin relatively ineffective in blocking memory.     

Evidence for adrenergic neurons in a memory access pathway

Injection of a beta-adrenergic blocker, propranolol, in rats within 5 min after training of a step-down passive avoidance response had no effect on performance either 2 or 6 hr later, however, when testing occurred 1, 3 or 7 days after training and injection a significant performance decrement was observed. If drug injection was postponed until 1 or 3 days after training and testing was conducted 2 hr later, again poor avoidance performance was obtained. No support for a state-dependency explanation [14] of the propranolol amnesia could be found. The amnesia that followed beta-adrenergic receptor block was identical to that previously reported when norepinephrine biosynthesis was reduced [9] and supports the hypothesis of a role for adrenergic neurons in memory formation and retrieval that is different from cholinergic neurons [4,10].     

Effects of concurrent subchronic treatments with desmethylimipramine and propranolol on beta-adrenergic and serotonin2 receptors in rat brain

The effects of seven consecutive daily injections of desmethylimipramine (DMI 20 mg/kg) and propranolol (PRO 10 mg/kg) on³H-dihydroalprenolol (³H-DHA) and³H-ketanserin (³H-KET) binding in rat brain were examined. Analyses of saturation binding data using the iterative, nonlinear curve-fitting program LIGAND revealed that PRO increased, while DMI reduced,³H-DHA binding site density in cerebral cortex without altering receptor affinity, as previously reported. DMI reduced³H-KET binding site density without changing affinity, and PRO produced the same effect. In cerebral cortex and probably in hippocampus and striatum, DMI and PRO administered together increased the density of³H-DHA binding sites (beta-adrenergic receptors) and reduced their affinity. This combination of drugs reduced the density of³H-KET binding sites (5-HT₂ receptors) in cerebral cortex, but did not change their affinity. These findings indicate a need for additional studies on the interactions of DMI and PRO and related drugs because of implications for the treatment of depressed patients with cardiovascular disorders.     

SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task

An endogenous cannabinoid system may play an important role in controlling memory processes. SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride), a selective cannabinoid CB(1) receptor antagonist, was studied in an eight-arm radial maze task in which either deficits or improvements in memory could be detected. This task required well-trained rats to recall after either a relatively short (3 h) or long (7 h) delay period where they had received rewards during an information phase in order to obtain the remaining rewards during a retention phase. SR141716A was administered intraperitoneally immediately after the information phase in order to determine the drug's effects on memory consolidation. Although SR141716A had no effect on the number of errors committed after a short interval, SR141716A significantly reduced the number of errors that occurred after 7 h. These results suggest that a cannabinoid CB(1) receptor antagonist can improve consolidation processes and thus may be useful in treating memory disorders.     

Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist,SR 141716

Social short-term memory in rodents is based on the recognition of a juvenile by an adult conspecific when the juvenile is presented on two successive occasions. Cannabimimetics are claimed to induce memory deficits in both humans and animals. In the brain, they mainly bind to CB1 receptors for which anandamide is a purported endogenous ligand. SR 141716, a specific antagonist of CB1 receptors, dose-dependently reverses biochemical and pharmacological effects of cannabimimetics. More particularly, it antagonizes the inhibition of hippocampal long-term potentiation induced by WIN 55,212-2 and anandamide, and it increases arousal when given alone. The present experiments study the ability of SR 141716 (from 0.03 to 3 mg/kg SC) to facilitate short-term olfactory memory in the social recognition test in rodents. SR 141716 improved social recognition in a long intertrial paradigm with a threshold dose of 0.1 mg/kg SC. At 1 mg/kg, it antagonized the memory disturbance elicited by retroactive inhibition. Scopolamine (0.06 mg/kg IP) partially reversed its memory-enhancing effect. Moreover, SR 141716 reduced memory deficit in aged rats (0.03–0.1 mg/kg) and mice (0.3–1 mg/kg). As SR 141716 is not known to exhibit any pharmacological activity which is not mediated by CB1 receptors, the results strongly support the concept that blockade of CB1 receptors plays an important role in consolidation of short-term memory in rodents and suggest there may be a role for an endogenous cannabinoid agonist tone (anandaminergic) in forgetting.     

A quantitative cerebral and whole body autoradiographic study of a intravenously administered benzodiazepine antagonist 3H-Ro 15-1788 in mice

³H-Ro 15-1788, a benzodiazepine receptor antagonist, was injected IV into male and pregnant mice. Autoradiograms were prepared from sagittal sections of animals killed after 30 s to 48 h. In the adult animal there was a rapid and high initial accumulation of radioactivity in the brain as compared to other organs and tissues. The highest accumulation was found in cortical brain areas, such as the olfactory bulb and the frontal cortex. Cerebellar cortex, globus pallidus, amygdala, substantia nigra, colliculus, hippocampus and pons followed in rank order. The rate of decline of radioactivity was highest in the pons and lowest in the olfactory bulb. The initial disappearance of radioactivity from the cerebellum was higher than from the other brain regions. Ro 15-1788 was rapidly eliminated; 4 h after drug administration there was an almost complete clearance of radioactivity from all tissues. After 24 h no trace of activity remained in the animal. The distribution of radioactivity at later time points indicates that metabolites of Ro 15-1788 are eliminated by fecal, urinary and nasal secretion. In the fetus also there was an early accumulation of radioactivity in the central nervous system. The radioactivity in fetal organs was lower than in the mother at all time intervals.     

The effects of clonidine, prazosin, and propranolol on short-term and long-term habituation of the acoustic startle response in rats

The unique effect of clonidine in facilitating habituation of the acoustic startle response [10] was replicated. However, clonidine had no effect on between-session habituation, showing a pharmacological dissociation between short- and long-term habituation. Systematic manipulation of ISI showed clonidine's habituation-facilitating effect to be most striking with longer within-session ISIs where habituation was relatively weak in controls. Comparing clonidine's effect to that of two other hypotensive agents, prazosin and propranolol, showed that the habituation-facilitating effect was not due to blood pressure effects. Prazosin, an alpha₁-adrenergic blocker, facilitated short-term habituation, but significantly less so than did clonidine, an alpha₂-agonist. Propranolol, a beta-adrenergic blocker, had no effect of short-term habituation. Both prazosin and propranolol impaired long-term habituation, but propranolol did so without suppressing initial response levels. The data suggest that a synapse with both alpha-₁- and alpha₂-adrenoceptors may be critically involved in habituation of the acoustic startle response. A beta-adrenergic involvement in long-term habituation is tentatively suggested.     

Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans

Effects of the novel competitiveN-methyl-d-aspartate (NMDA)-receptor antagonist SDZ EAA 494 were investigated on memory and attention in humans. SDZ EAA 494 was administered either as single doses at a dose range of 1–50 mg, or as multiple doses over the course of 1 week at doses of 25 mg once or twice daily. Selected cognitive functions were assessed at baseline, 2 and 4 h after single dose administration, and at baseline, 2, 4 and 8 h on days 1 and 7 of multiple dose administration. The assessments included simple and complex reaction time tests to assess attention, and verbal, non-verbal and spatial memory tests with immediate and late recall. Verbal and non-verbal memory test performance was significantly impaired at a dose level of 50 mg after single administration, and of 25 mg twice daily after multiple administration, without concomitant significant impairment of reaction time. Spatial memory test performance was not significantly affected. The maximum effect occurred 2 h postmedication and was more pronounced after repeated administration. These results suggest that the inhibition of NMDA-receptors in humans may impair memory processes.     

Opposing acute and chronic behavioural effects of a beta-blocker,propranolol, in the rat

Rats were trained over 40 days to lever-press for food reward under a schedule of differential reinforcement of low rates of response with a 20-s criterion (DRL 20), following seven sessions of continuous reinforcement. The effect of injecting a beta-adrenergic blocker, propranolol (5 mg/kg IP), before and at two different delays after each daily session of DRL were investigated. In Experiment I, rats drugged 5–8 min before every session earned fewer reinforcements compared to controls, and showed impaired temporal discrimination. In Experiment II, this result was not replicated, but similar effects were clear in animals drugged pre-session from the 15th day of acquisition. By contrast, an improved temporal discrimination, and increased number of reinforcements were seen in rats drugged 5–8 min after every session. In Experiment III, the postsession effects were replicated and found also in rats drugged 4–5.5 h after each session. These results suggest that propranolol has an acute effect on DRL responding which resembles that of anxiolytics, and a chronic effect which opposes the acute one.     

白三烯受体拮抗剂ONO-1078对内皮素-1诱导的大鼠局灶性脑缺血的保护作用

目的观察白三烯受体拮抗剂ONO-1078对内皮素-1诱导的大鼠局灶性脑缺血的保护作用。方法向大脑中动脉附近微量缓慢注射内皮素-1(120 pmol,6 μL,>6 min),诱导大鼠局灶性脑缺血模型,在注射内皮素-1前1 h ip ONO-1078(0.1 mg·kg^-1)。观察神经症状、脑水肿程度、脑梗死体积、纹状体和皮层的存活神经元数的变化。结果 脑内微量注射内皮素-1引起动物出现明显神经症状、脑梗死、脑水肿及皮层和纹状体的存活神经元减少。预先ip ONO-1078显著抑制脑水肿,减小脑梗死体积,增加纹状体和皮层的存活神经元数,可减轻神经症状,但无显著意义。结论ONO-1078对内皮素-1诱导的脑缺血损伤有保护作用,白三烯参与了脑缺血后的组织损伤过程。     

The selective 5-HT3 receptor antagonist,WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system

The effects of three doses (0.003, 0.03 and 1.0 mg/kg sc) of the 5-HT₃ receptor antagonist, WAY 100289, on spatial learning and memory in the water maze were examined in rats before and after ibotenate lesions to the nucleus basalis and medial septal brain regions at the source of cholinergic projections to cortex and hippocampus. The representative cholinergic nicotinic and muscarinic receptor agonists nicotine (0.1 mg/kg) and arecoline (1.0 mg/kg) were also tested for comparison. Both arecoline and nicotine improved initial acquisition in rats before lesioning, in terms of latency to find a hidden platform and accuracy of search strategy. WAY100289 did not affect the performance of normal rats significantly, apart from some non-significant trends towards improvement with the highest dose. However, in animals showing transient navigational deficits in retention and relearning after lesioning, WAY100289 improved performance at all three doses, though ameliorative effects of nicotine and arecoline were more marked also in lesioned rats. These results show that WAY100289 improved spatial learning in animals impaired after lesions to cholinergic projection nuclei, which may reflect an interaction with cholinergic transmission to enhance cognitive function. However, in the present study, WAY100289 appeared to be less effective than direct cholinergic agonists.     

Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats

Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB₁ receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB₁ receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5 mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0 mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0 mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0 mg/kg) and saline. Rimonabant at a dose of 3.0 mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB₁ receptors play a role in nicotine reward memory, suggesting that CB₁ receptor antagonists may be a potential target for managing nicotine addiction.     

内皮素受体拮抗剂BQ—123对全脑缺血再灌流后脑组织损伤的保护作用

目的 观察内皮素拮抗剂 ＢＱ－１２３对缺血再灌流后脑神经元损伤的保护作用。方法 采用Ｐｕｓｉｎｅｌｌｉ的四血管阻断法（４ＶＯ）制作大鼠全脑缺血再灌流动物模型。在再灌流后 ３０分钟给予ＢＱ－１２３（５０μｇ／１μｌ，ｉｃｖ）。结果 ＢＱ－１２３能增加缺血后海马ＣＡ１区神经元的存活数，行为实验表明 ＢＱ－１２３治疗后大鼠的学习了己忆能力有提高。结论 内皮素受休拮抗剂 ＢＱ－１２３对全脑缺血再灌流引起海马区神经元损伤有部分保护作用。     

The effect of age on diurnal variation in the pharmacokinetics of propranolol in hypertensive subjects

Summary There is diurnal variation in the absorption rate of propranolol in younger subjects. This study was undertaken to examine the effect of age on the chronopharmacokinetics of propranolol.We gave 20 mg of propranolol orally to 13 younger and 11 older hypertensive subjects at 09.00 h (day study) or 21.00 h (night study) in a cross-over design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 h after dosage. In the younger subjects the absorption rate constant (k_a) of propranolol and its maximum plasma concentration (C_max) were significantly higher and the time to maximum concentration (t_max) was significantly shorter in the day than at night. There were similar time-variant changes in C_max and t_max for 4-hydroxypropranolol and naphthoxylactic acid. In contrast, there were no time-variant changes in k_a, C_max and t_max of propranolol and its metabolites in the older subjects.These results suggest that propranolol is absorbed more rapidly after morning dosing than after night-time dosing in younger but not in older subjects. Based on these findings, we speculate that the time-variance in the absorption rate or first-pass elimination, or both, of propranolol diminish with age.     

Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans

Rationale Beta-adrenergic receptors are involved in the consolidation of emotional memories. Yet, a number of studies using Pavlovian cued fear conditioning have been unable to demonstrate an effect of beta-adrenergic blockade on acquisition or retention of fear conditioning. Evidence for the involvement of beta-adrenergic receptors in emotional memories comes mostly from studies using fear inhibitory avoidance in rodents. It is possible that fear inhibitory avoidance is more akin to contextual conditioning than to cued fear conditioning, suggesting that context conditioning may be disrupted by beta-adrenergic blockade.Objective This study investigated the effects of the beta-adrenergic blocker propranolol on cued and contextual fear conditioning in humans.Methods Subjects were given either placebo (n=15) or 40 mg propranolol (n=15) prior to differential cued conditioning. A week later, they were tested for retention of context and cued fear conditioning using physiological (startle reflex and electrodermal activity) and subjective measures of emotional arousal.Results The results were consistent with the hypothesis. The skin conductance level (SCL) and the subjective measure of arousal suggested reduced emotional arousal upon returning to the conditioning context in the propranolol group, compared to the placebo group. The acquisition and retention of cued fear conditioning were not affected by propranolol.Conclusions These results suggest that beta-adrenergic receptors are involved in contextual fear conditioning.     

Biliary excretion and enterohepatic circulation of two beta-adrenergic blocking drugs,exaprolol and propranolol in rats

Plasma levels and excretion of two beta-adrenoceptor blocking drugs ³H-exaprolol and ³H-propranolol wereobserved up to 96 h after a single i.v. administration to rats. Terminal half-lives of 26·8 ± 9·1 h and 51·3 ± 7·5 h were found for exaprolol and propranolol, respectively. The recovery of ³H radioactivity in feces following i.v. administration of the drus (34·2 ± 0·8 per cent and 12·0 ± 1·3 per cent ³H of exaprolol and propranolol, respectively) is of biliary origin, as 30·7 ± 3.5 per cent and 13·4 ± 3.6 per cent ³H of exaprolol and propranolol, respectively, was excreted in the bile after i.v. administration. Enterohepatic circulation of the drugs was studied using the donor-recipient rat method. After intraduodenal administration of donor bile to the recipient rat approximately 50 per cent and 40 per cent of the biliary ³H activity of exaprolol and propranolol, respectively, was re-excreted following absorption. A formula for calculating the amount of the substance together with its metabolites excreted in the bile, urine or feces as a result of enterohepatic circulation has been proposed.     

Effect of two inhibitors of dopamine β-hydroxylase on maturation of memory in mice

Bitemporal injections of puromycin that primarily affect the hippocampal-entorhinal cortical areas suppress memory of maze-learning in mice for 3 days after training but are ineffective 6 or more days after training. At these later times, injections affecting widespread areas of the brain in addition to the hippocampal-entorhinal area are necessary for amnesia. These observations are interpreted to indicate that the locus of the memory trace has enlarged at 6 days to include other parts of the central nervous system in addition to the hippocampal-entorhinal area. To produce an imbalance of neurotransmitters and so to test their importance in enlargement of the memory trace's locus, we treated mice for 7 days after training with inhibitors of dopamine β-hydroxylase. These mice, unlike untreated controls, developed amnesia after bitemporal injections of puromycin. In view of additional control experiments, we interpret these results to suggest that an imbalance of suppresses the normal enlargement of the locus of the memory trace.     

The effect of administration of propranolol on the pharmacokinetics of isoxicam

In order to examine a potential interaction between isoxicam and propranolol, single 200 mg doses of isoxicam were administered to ten healthy male volunteers before and during treatment with propranolol, gradually attaining a dose of 80 mg t.i.d. for 11 days. The pharmacokinetic profiles of the isoxicam plasma concentration/time data obtained over 96 h following the doses of isoxicam before and during propranolol administration were compared. No significant change was found in any of the pharmacokinetic parameters determined. These results suggest that propranolol has no effect on the metabolic disposition of isoxicam.