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They are divided into three generations, according to the time of their synthesis, properties and side effects for therapeutic purposes. The objective of this research was to investigate the effects of antihistamines chlorpheniramine 1st generation , Loratadine 2nd generation and Levocetirizine 3rd generation applied i.

Materials and Methods: A passive avoidance task step through was used as a test for learning and memory. Results: Chlorpheniramine 1st generation applied i. The i.

Comparing the effects of antihistamines after i. Conclusion: These findings suggest that the impaired learning and memory effect of antihistamines might be connected with inhibition of brain H1 receptors. Histamine [2- 4-imidazole -ethylamine] is an endogenous short acting biogenic amine formed by decarboxylation of the amino acid L-histidine in a reaction catalysed by the enzyme histidine decarboxylase 1.

It possesses a wide spectrum of activities, including its function in neurotransmission 2.


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As a neurotransmitter, histamine is involved in the regulation of sleep and wakefulness, water intake, motor activity, nociception, learning and memory and energy and endocrine homeostasis 3 , 4 , 5. It also modulates the release of several neurotransmitters through presynaptic receptors located on histaminergic and non-histaminergic neurons of the central and peripheral nervous system. Histamine exerts its effects through four distinct subtypes of G-protein-coupled receptors, designated H1, H2, H3 and H4 that are differentially expressed in various cell types.

H1 and H2 receptors are widely distributed, H3 receptors are mainly presynaptic and H4 receptors are mainly haematopoietic 6. Histamine H1 receptor antagonists as known as antihistamines, are widely used drugs to treat allergy symptoms by blocking the peripheral histamine H1 receptor.

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The antihistamines H1 receptor blockers are divided into three generations, according to the time of their synthesis, properties and side effects for therapeutic purposes 7. The H1-receptor antagonists or H1 antihistamines include the older-type, sedating, multipotent blockers or the so-called first-generation H1 antihistamines, including chlorpheniramine, dexchlorpheniramine, promethazine and cyclizine and the newer non-sedating, selective H1-receptor blockers or the so-called second-generation H1 antihistamines and more recent improvements, generally in the form of active metabolites, so-called third-generation antihistamines 7.

It is well known that the first-generation antihistamines are hydrophilic molecules that can easily go across the blood brain barrier and affect the Central Nervous System CNS 8. Some literatures have reported that the disturbance of central histaminergic receptors by the first-generation antihistamines may underlie their neuronal toxic effects on the neuronal system 9 , The drugs belonging to the second and third generation have a very limited ability to do so or none at all.

These antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the CNS, having fewer sedative effects as a result 7. Most currently known antihistamines have been reclassified as inverse agonists and the term histamine antagonists is only reserved for those compounds that function as true antagonists.

H1-antihistamines are not receptor antagonists but are inverse agonists in that they produce the opposite effect on the receptor to histamine Antihistamines have been shown to impair learning and memory 12 , For example, diphenhydramine, promethazine, chlorpheniramine and triprolidine have been reported to impair spatial memory in rats, with alteration of the theta rhythm It was found that diphenhydramine-first generation antihistamine which easily crosses the blood-brain barrier 15 impaired the consolidation and expression of conditioned fear, whereas the second generation anti-histamines levocetirizine 16 and olopatadine 17 which have poor brain penetration 18 , 19 had no effect on fear, memory consolidation and expression The aim of the present study was to compare the effects of antihistamines first, second and third generation administered intraperitoneally i.


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Animals: The experiments were carried out on male Wistar 3-months aged rats g at the beginning of the experiments. The behavior experiments were carried out between am and pm. The experiments were performed according to the "Rules for care and experiments on laboratory animals" of the Ethics Committee of the Institute of Neurobiology, Bulgarian Academy of Sciences. Stereotaxic implantation and drug injection into ventriculus ventrolateralis dextra: After anaesthesia Calypsol 50 mg kg -1 i.

After surgery, the animals were allowed for seven days to recover before the behavioral test. During the recovery period, the rats were handled daily.

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One-way passive avoidance test step through : In the passive avoidance task, the rat must learn to remain in a brightly lit compartment and not enter the preferred dark compartment to avoid a mild foot shock. One training trial and two retention tests were conducted according to the method of Buresovaand Bures The training trial was started by placing the rat in the light compartment. Once the rat had entered the dark compartment, the guillotine door was closed and an electrical shock 0.

Each rat underwent one trial.

Retention tests no shocks were performed 3 and 24 h after the acquisition trial. At that time, the animals were returned to the light compartment and step-through latency was estimated by measuring the length of time latent time for the rat to move to the dark compartment. A maximum latency of sec was used as a criterion for learning. The step through passive avoidance task was performed on rats divided in two main groups: A Treated i.

The tested drugs were applied in two doses: 10 and 20 mg i. Training started 60 min after i. ANOVA data were further analyzed by post hoc t-test. GraphPad Prism statistical software was used. Effects of antihistamines applied i. CLPH injected i.

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In recent years, the effects of antihistamines in cognitive function has been investigated intensively. Most studies performed in animals show that a decrease in histamine neurotransmission results in impaired performance. However, some studies have shown stimulating effects of decreased histamine neurotransmission, induced by the administration of H1-antagonists 23 , In the present study, the effects on learning and memory of three generations of antihistamines Chlorpheniramine, Loratadine and Levocetirizine applied in different way in rats have been studied.

These results demonstrated that Chlorpheniramine 1st generation applied i. The effect was expressed as a decrease of the latent time on 3rd and 24th h of the retention test and a decrease of the rats that reached the learning criteria. No correlation between lower and higher dose of any antihistamine drugs was found. Some results correlate with the findings of the earlier research study as reviewed herein.

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Clinical Pharmacology of Learning and Memory | W.B. Essman | Springer

It has been reviewed in experimental as well as in clinical studies The first generation antihistamines are associated with CNS side effects like sedation and the secondary effects like psychomotor impairment. Although second and third generation H1 antihistamines claim to be "non-sedating", some agents still cause CNS side effects, though findings are conflicting with one and another The effects of antihistamines on CNS are determined by their capability to cross blood brain barrier and capacity to bind with H1 receptor.

Capability of drugs to cross blood brain barrier depends on the lipophilic nature of drug entity and its affinity towards P glycoprotein Second and third generation drugs are highly specific for histamine receptors. They penetrate poorly into the CNS due to their lipophilic nature, relatively high molecular weight or recognition by the P glycoprotein reflux pump expressed on the luminal surfaces of endothelial cells in the cerebral vasculature Therefore, the administration of antihistamines in the ventricular system is a more convenient way to study their role in the CNS than peripheral administration, since some ligands might be more prone to cross the blood-brain barrier and there is less potential for peripheral side effects.

To assess the involvement of H1 receptors in learning and memory processes, the antihistamines 1st, 2nd and 3rd generation have been applied by i.

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The results showed that i. As compared the effects of anti-histamines after i. It has been supposed that this discrepancy of the effects of antihistamines from different generations might be due to the difference in administration routes. This suggests that Chlorpheniramine 1st generation easily cross the blood-brain barrier, while Loratadine 2nd generation and Levocetirizine 3 rd generation did not penetrate into the CNS. From these findings, it can be assumed that the inhibitory effect of antihistamines on the avoidance response may be exerted through the H1-receptor.

Ben-Yakov, A. Memory retrieval in mice and men. Cold Spring Harb. Izquierdo, I. Different molecular cascades in different sites of the brain control memory consolidation. Millan, M. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Drug Discov. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


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