The interaction between the cholinergic and dopaminergic system in learning and memory process in rats.

In normal rats, muscarinic acetylcholine receptors (mAChRs) have a facilitating role on both short-term and long-term memory tested by Y-maze task and multi-trial passive avoidance test, respectively, since scopolamine, a specific mAChRs antagonist, impairs both types of memory. A low dose of nicotine (0.3 mg/kg b.w., i.p.), a specific nicotinic acetylcholine receptors (nAChRs) agonist, administered once caused a significant facilitating effect on short-term memory. A higher dose of nicotine (3 mg/kg b.w., i.p.) administered 5 consecutively days had about the same facilitating effect on short- and long-term memory without affecting information acquisition. In rats, having mAChRs and nAChRs blocked by means of scopolamine and chlorisondamine respectively, a low dose of nicotine administered once caused a significant improvement of long-term memory deficits without affecting significantly short-term memory. A higher dose of nicotine administered 5 consecutive days in rats with a double blockade of cholinergic receptors had the same ameliorating effect on long-term memory deficits as low dose. Our data suggest that the antiamnesic effect of nicotine can result from an action at nicotinic receptors subtypes not blocked by chlorisondamine or at nonnicotinic receptors.     

The effect of dopaminergic nigrostriatal system on sleep deprivation in rats

The analysis of the electrophysiological features of sleep-wakefulness cycle in Wistar rats for 9h after a 6h sleep deprivation was carried out. The delay of sleep rebound (since 2.5-3 h after deprivation) was found in the form of moderate increasing of slow-wave sleep and fast-wave sleep phases. According to these sleep-wakefulness cycle changes, a quantitative immunohistochemical study of tyrosine hydroxylase: a key enzyme of dopamine synthesis--and D1 and D2 receptors in nigro-striatal projections has been performed. After sleep, an elevation of D1 receptors immunoreactivity in caudate nucleus and reduction of tyrosine hydroxylase immunoreactivity in compact part of substancia nigra was found. After postdeprivation sleep, a decrease of D1 receptors immunoreactivity and increase of D2 receptors immunoreactivity in caudate nucleus together some increase of tyrosine hydroxilase immunoreactivity in substancia nigra compacta has been observed. These data can testify about active role of dopaminergic nigrostriatal system which provide at the same time with another neurotransmitters of the central nervous system the telencephalo-diencephalic interaction in sleep-wakefulness-sleep cycle.     

Similar effect of caerulein on intracranial self-stimulation in vagotomized and non-vagotomized rats

Electrical stimulation eliciting self-stimulation behavior from postero-lateral hypothalamic implanted electrode was controlled by factors that control normal feeding. In this idea, lateral hypothalamic stimulation possessed an appetite whetting property and this is experienced as rewarding. The octapeptide cholecystokinin, a gut hormone, has been experimented upon to produce the complete behavioral sequence of satiety in rats. We observed that an i.p. injection of caerulein (an analog of cholecystokinin) did decrease, in a dose-related manner, the rate for brain self-stimulation. However, a similar effect on the rate of ICSS was measured after a bilateral cut of the vagus nerve at a subdiaphragmatic level. This result suggests that the decreasing effect on ICSS after an i.p. injection of caerulein is not strictly related to feeding. We interpret the decrease of reinforcement induced by caerulein as the action of a general satiety for any object presenting a rewarding value for behavior.     

Acute and long-lasting effects of peripheral injection of caerulein and CCK-8 on the central GABAergic system in mice

Acute and long-lasting effects of peripheral injection of caerulein (CLN) and cholecystokinin octapeptide (CCK-8) on the gamma-aminobutylic acid (GABA) content and the GABA accumulation by aminooxyacetic acid (AOAA) in the discrete brain regions of mice were examined. The content and accumulation of GABA in the striatum, hypothalamus, and frontal cortex was measured with high performance liquid chromatography with electrochemical detection (HPLC-ECD). The GABA content slightly decreased in the striatum 60 min after CLN and CCK-8 were administered, whereas it slightly increased in the hypothalamus and frontal cortex. Moreover, with CLN and CCK-8, the GABA accumulation after AOAA treatment decreased in the striatum and hypothalamus 30 min after injection. Meanwhile, when administering CLN, the GABA content as well as the GABA accumulation after AOAA treatment increased in the striatum and frontal cortex 1 day after injection, and continued to increase the second and third day in the striatum. These results showed that peripheral injection of CLN and CCK-8 had effects on the central GABAergic system with local specific actions, and also the long-lasting and time-dependent biphasic effects of CLN.     

Gene expression profiling of the rewarding effect caused by methamphetamine in the mesolimbic dopamine system

Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.     

The role of the dopaminergic system and GABA-benzodiazepine- ionophore complex in the regulation of memory retrieval

The spontaneous forgetting model has been used to demonstrate the possibility of the memory forgetten trace extraction under the dopamine reuptake blockade by nomifensine and bupropion, increase of its quantity by amfonelic acid, activation of the postsynaptic dopaminergic receptors by (+)3-PPP, blockade of the latter by (-)3-PPP, and under the blockade of separate links of the GABA-benzodiazepine-ionophore complex by bicuculline, picrotoxin, flumazepil and R015-3505. Effectiveness of the neuropharmacological actions improving the memory forgotten trace retrieval is shown to depend upon the duration of the spontaneous forgetting process. The presynaptic receptors are involved in the retrieval process control--improvement of the conditioned habit performance after forgetting due to the activation of presynaptic dopaminergic receptors by specific agonist (-)3-PPP is clearly correlated with the initial retrieval level. The above facts underlie a hypothesis about the neurochemical forgetting mechanisms.     

Shortening the infectious period does not alter expansion of CD8 T cells but diminishes their capacity to differentiate into memory cells

Following a primary immune response, a portion of effector T cells gives rise to long-lived memory cells. Although primary expansion and differentiation of effector CD8 T cells is dictated by a brief exposure to Ag, it is unclear whether full memory differentiation is also programmed within the same short window. By carefully modulating the kinetics of Listeria monocytogenes infection, we analyzed the requirements for the programming of effector and memory T cell development in vivo. We find that although limiting the infectious period to the first 24-48 h does not impact the size of the primary CD8 response, the ensuing memory population is significantly diminished. This effect is particularly pronounced in the development of tissue-homing memory cells and is inversely proportional to the initial infectious dose. In contrast to CD8 responses, the differentiation of primary CD4 responses was highly dependent on the continued presence of the infection. Shortening the duration of the infection greatly reduced the development of CD4 effector responses in the spleen and prevented their trafficking to peripheral sites of infection. We propose that the stimulus received by CD8 T cells during the early stages of infection largely contribute to the differentiation of CD8 effector cells, whereas continued or distinct signals received at later stages influence their ability to differentiate into memory cells.     

Antagonism of caerulein, a CCK-8 receptor agonist, to the behavioral effects of ketamine in mice and rats

It has been established in experiments on male mice and rats that caerulein antagonized the behavioural effects of ketamine, an agonist of phencyclidine receptors. Caerulein (75-375 micrograms/kg) and haloperidol (0.1-1.5 mg/kg) suppressed the stereotyped behaviour and motor excitation induced by ketamine (30 mg/kg) in mice. Caerulein and haloperidol failed to affect ketamine-induced ataxia. Caerulein (10 micrograms/kg) and the opioid antagonist naloxone (5 mg/kg) completely blocked the amnestic action of ketamine (30 mg/kg) in passive avoidance experiments on rats. It seems likely that the suppression of the behavioural effects of ketamine by caerulein is related to its functional antagonism with dopamine and opioid receptors.     

The effect of stimulation and blockade of the dopaminergic system on the choice of behavioral strategy by rats in the shuttle box]

Upon stimulation and blockade of dopaminergic system of rats in the shuttle box the correlation between the strategy of escape behavior and functional state of dopaminergic system has been found. The modulatory effect of these systems on the mechanism of the adequate choice is suggested.     

Participation of the dopaminergic system in the immune response-stimulating effect of muramyl dipeptide

It has been shown that administration of muramyl dipeptide (MDP) in a dose of 1 mg/kg simultaneously with SRBC (5 x 10(6) immunization resulted in a considerable increase of immune response. Stimulation of the immune response is prevented by preliminary blockade of dopamine receptors with haloperidol, that testifies to the activation of the dopaminergic system by certain MDP dosages.     

Effects of (8beta)-8-[methylthio)methyl]-6-propylergoline on dopaminergic function and brain dopamine turnover in rats.

(8β)-8-[(Methylthio)methyl]-6-propylergoline induced contralateral turning in rats with nigrostriatal lesions, lowered serum prolactin in reserpinized rats, and caused stereotyped hyperactivity. In addition to these functional effects typical of dopaminergic agonists, (8β)-8-[(methylthio)methyl]-6-propylergoline decreased dopamine turnover in rat brain. Decreased turnover was indicated by a diminished depletion of dopamine content after inhibition of its synthesis by α-methyltyrosine and by a decreased steady state concentration of the dopamine metabolite, 3, 4-dihydroxyphenylacetic acid (DOPAC). DOPAC concentration in whole brain was decreased after doses of (8β)-8-[(methylthio)methyl]-6-propylergoline as low as 0.003 mg/kg, and the lowering of DOPAC persisted for up to 16 hrs. after a 0.3 mg/kg dose. (8β)-8-[(Methylthio)-methyl]-6-propylergoline had less effect than a structurally-related compound, lergotrile, on 3-methoxy-4-hydroxy-phenyl-ethyleneglycol sulfate levels in whole brain and did not affect 5-hydroxy-indoleacetic acid levels over a dose range from .01–10 mg/kg. The behavioral and neuroendocrine effects of this new ergoline compound and its reduction of dopamine turnover in rat brain indicate that it is a potent dopamine receptor agonist $\text{in vivo}$.     

KA海马注射对大鼠学习和记忆的影响及雷公藤甲素的保护作用

目的:观察海人藻酸(Kainic acid,KA)海马内注射后大鼠学习记忆的变化及雷公藤甲素(TRP)对其的影响.方法:采用Morris水迷宫筛选空间学习记忆能力正常的SD雄性大鼠90只(200-220g).将实验动物分为:右侧海马注射生理盐水后生理盐水灌胃对照组(NS+NS)、右侧海马注射海人藻酸后生理盐水灌胃干预组(KA+NS)、右侧海马注射海人藻酸后雷公藤甲素灌胃干预组(KA+TRP).动物分别存活1天、3天、5天、7天、14天,用Morris水迷宫检测各组动物空间位置记忆能力:尼氏染色法观察海马CA1区神经元数目和形态.结果:与NS组(NS+NS)比较,KA组(KA+NS)大鼠逃避潜伏期延长(P<0.05).跨越原平台次数减少(P<0.05);CA1区的神经元出现胞体肿胀、排列散乱等形态改变及神经元的丢失(P<0.05);TRP组(TRP+KA)与KA组比较,大鼠的平均逃避潜伏期从第5天起缩短(P＜0.05),跨越原平台次数增多(P<0.05),神经元形态好转,数目增多.结论:KA 海马内注射,可以导致大鼠学习记忆功能障碍及神经元形态的改变;雷公藤甲素干预治疗,能够改善动物的学习和记忆能力,保护海马神经元.     

Circadian phase modulates the enhancing effect of the Egyptian Moringa peregrina extract on learning and memory in mice

One of the most important issues nowadays is memory disorders. The exact circadian modulation of learning and memory is still under investigation. The present study was carried out to evaluate the probable enhancing and neuroprotective effects of the Egyptian Moringa peregrina; administered at two different Zeitgeber times (ZT), on learning and memory in mice. M. peregrina dried leaves were aqueously extracted and intranasally (IN) administered at four doses (viz. 12.5, 25, 50, and 100 mg/kg). Twenty animal groups (n = 8/group) were treated with M. peregrina at ZT 3:00 vs. 15:00 representing the rest (day) vs. active (night) phases, respectively. Additionally, sub-chronic effect of daily IN administration of the 25 mg/kg dose for two weeks was examined at ZT 3:00 vs. 15:00. Memory performance was assessed after 1, 2 weeks of treatment and a 3rd recovery week. Memory test was performed at ZT 17:00 by measuring the percentage of time spent in novel arm of Y-maze. Dose-response curve revealed that both 25 and 50 mg/kg doses administered at ZT 3:00 significantly improved memory efficiency. Rest phase administration significantly enhanced memory functions after 1, 2 weeks as well as after the recovery week. Moreover, IN pretreatment with M. peregrina (25 mg/kg) revealed a protective effect against scopolamine-induced amnesia. In conclusion, these findings clearly indicated that M. peregrina possesses valuable enhancing and protective effects on learning and memory processes in mice which is circadian-phase dependent.     

Effect of centrally administrated substance P on the brain mesolimbic system activity in rats as measured by microdialysis

Action of substance P on the contents of dopamine, dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens of rats was investigated with microdialysis procedure. During 3 days, each animal daily received i.v. the saline (the 1st day), 0.1 mcg of substance P (the 2nd day), 1 mcg of substance P (the 3rd day). Elevation of accumbal dopamine was observed amounting up to 41% and 71% for 0.1 mcg and 1 mcg of substance P, resp. Rates and duration of these changes also depended on neuropeptide concentration. 1 mcg of substance P produced the dopamine elevation with a peak by the 50th min. Moreover, in 75 min. after infusion of the neuropeptide, the levels of dopamine still remained increased. Response of metabolites also proved to be dose-related. With 1 mcg of substance P, the contents of dihydroxyphenylacetic acid increased by 28%, while with 0.1 mcg of substance P, this parameter did not change. Contents of homovanillie acid was unaffected by central substance P at the above doses. The data obtained corroborate the assumption of influence of the substance P on the reward system arising from its dopaminergic properties and provide a possible explanation of the neuropeptide effects observed in the conditioned place preference paradigm.     

Coexistence of zinc and iron augmented oxidative injuries in the nigrostriatal dopaminergic system of SD rats

Clinical studies have demonstrated an excess of transition metals, including zinc and iron, in the substantia nigra (SN) of Parkinson's patients. In the present study, the neurotoxic effect of zinc was investigated using iron as a positive control. Addition of zinc or iron to brain homogenates increased lipid peroxidation. Zinc was less potent than iron in inducing lipid peroxidation. Coincubation with desferrioxamine prevented zinc- and iron-induced lipid peroxidation. Furthermore, glutathione (GSH), S-nitroso-N-acetylpenicillamine, or melatonin inhibited zinc-induced lipid peroxidation. The oxidative effect of zinc was further investigated in anesthetized rats. Seven days after intranigral infusion of zinc, lipid peroxidation was elevated in the infused SN, and dopamine content and tyrosine hydroxylase-positive axons were decreased in the ipsilateral striatum. Zinc was less potent than iron in inducing neurodegeneration in vivo. L-Buthionine-[S,R]-sulfoximine pretreatment (i.c.v.), which depletes cellular GSH levels, enhanced zinc-induced oxidative injuries in the nigrostriatal dopaminergic system. Moreover, simultaneous infusion of zinc and iron appeared to augment oxidative injuries in rat brain. Taken together, our results demonstrate that intranigral infusion of zinc caused degeneration of the nigrostriatal dopaminergic system in rat brain. Furthermore, coexistence of zinc and iron augmented oxidative injuries in rat brain. These findings indicate that both zinc and iron contribute to the etiology of Parkinsonism.     

Spatial working memory in rats: the effect of the dipeptide gamma-L-glutamyl-taurine and haloperidol

To assess the possible involvement of the dipeptide gamma-L-glutamyl-taurine (Litoralon) and some of its analogues in the maintenance of spatial working memory, rats were treated with the dipeptides immediately or 2 hours after completing the first four choices in an 8 arm radial maze, or 3 hours before the test to exclude proactive effects of the compounds. Treatment with Litoralon, SZJ 3381 and 3361 at doses of 100 and 500 micrograms/kg (i.p.) did not impair spatial memory in rats, regardless of when these substances were injected during the session. By contrast, haloperidol (500 micrograms/kg, i.p.) treatment resulted in a dramatic decrease of performance.     

Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats

The α7 nicotinic acetylcholine receptor (nAChR) is a potential target for the treatment of cognitive deficits in patients with schizophrenia, ADHD and Alzheimer's disease. Here we test the hypothesis that upregulation of α7 nAChR levels underlies the enhanced and sustained procognitive effect of repeated administration of α7 nAChR agonists. We further compare the effect of agonists to that of α7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the α7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the α7 nAChR agonist A-582941 improves short-term memory immediately after repeated (7× daily), but not a single administration. The α7 nAChR PAMs PNU-120596 and AVL-3288 do not affect short-term memory immediately after a single or repeated administration. This demonstrates a fundamental difference in the behavioral effects of agonists and PAMs that may be relevant for clinical development. Importantly, A-582941 and AVL-3288 increase short-term memory 24 hrs after repeated, but not a single, administration, suggesting that repeated administration of both agonists and PAMs may produce sustained effects on cognitive performance. Subsequent [(125)I]-bungarotoxin autoradiography revealed no direct correlation between α7 nAChR levels in frontal cortical or hippocampal brain regions and short-term memory with either compound. Additionally, repeated treatment with A-582941 did not affect mRNA expression of RIC-3 or the lynx-like gene products lynx1, lynx2, PSCA, or Ly6H, which are known to affect nAChR function. In conclusion, both α7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the α7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect.     

Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat

Rasagiline [N-propargyl-l(R)-aminoindan] is a selective irreversible MAO-B inhibitor as is (-)deprenyl. The effect of the drug on antioxidant enzyme activities on dopaminergic tissue was examined in male F-344 rats (8.5-months-old). Two experimental groups were infused subcutaneously with rasagiline saline solutions by means of osmotic minipumps implanted subcutaneously in the back of the rats. Control animals were also similarly implanted with saline filled mini-pumps. Three-and-one-half weeks later, animals were sacrificed and selected tissue samples removed from brain, kidney and heart. Two doses of rasagiline (0.5 mg/kg/day, 1.0 mg/kg/day, both for 3.5 weeks) significantly increased catalase activities about 2-fold in substantia nigra and striatum but not in hippocampus. Interestingly, in both renal cortex and medulla. catalase (CAT) activities were significantly increased. Both Mn- and Cu,Zn-superoxide dismutase (SOD) activities were increased 2 to 4 fold in substantia nigra, striatum and renal cortex and heart. Several groups, including our own have reported an extension of survival of deprenyl-treated animals of different species. Although the mechanism(s) of the life extension by deprenyl remains unresolved, it would be interesting to investigate the effect of rasagiline on the survival of animals, since deprenyl also was shown to increase antioxidant enzyme activities in brain dopaminergic regions.     

Neurotoxic action of 6-hydroxydopamine on the nigrostriatal dopaminergic pathway in rats sensitized with D-amphetamine.

To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 microg in 10 microl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA.