Dose-dependent Increase In Latency Research Articles

The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers.

Dopamine (DA) plays a key role in several central functions including cognition, motor activity, and wakefulness. Although efforts to develop dopamine receptor 1 (D1) agonists have been challenging, a positive allosteric modulator represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the dopamine receptor 1 positive allosteric modulator (D1PAM) mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al., 2021). Herein, we describe the effects of mevidalen on sleep and wakefulness in humanized dopamine receptor 1 (hD1) mice and in sleep-deprived healthy male volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent [3-100 mg/kg, orally (PO)] fashion when measured during the light (zeitgeber time 5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice after prior sleep deprivation and delayed sleep onset by 5.5- and 15.2-fold compared with vehicle-treated animals, after the 20 and 60 mg/kg PO doses, respectively, when compared with vehicle-treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, and 75 mg) separated from placebo at the first 2-hour postdose time point with a circadian effect at the 6-hour postdose time point. Sleep wakefulness should be considered a translational biomarker for the dopamine receptor 1 positive allosteric modulator mechanism. SIGNIFICANCE STATEMENT: This is the first translational study describing the effects of a selective dopamine receptor 1 positive allosteric modulator (D1PAM) on sleep and wakefulness in the human dopamine receptor 1 mouse and in sleep-deprived healthy male volunteers. In both species, drug exposure correlated with sleep latency, supporting the use of sleep-wake activity as a translational central biomarker for D1PAM. Wake-promoting effects of D1PAMs may offer therapeutic opportunities in several conditions, including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders.

Anticonvulsant activity of methanolic extract of Withania cogulans in mice

Mental and neurological diseases including depression, Parkinson's disease, dementia, epilepsy, anxiety disorders and bipolar disorders account for a considerable amount of the world's disease burden. Unfortunately, drugs used in the treatment of neurological diseases are expensive, symptomatic and they produce undesirable side effects. People from different cultures prefer to use medicinal plants for the treatment of various ailments ranging from plain to perplex disorders because they are most affordable, cost effective and easily accessible source of treatment in the primary healthcare system throughout the world. Withania coagulans, an erect grayish under-shrub belongs to family Solanaceae. It is common in Pakistan, East India, Iran and Afghanistan. The objective of this study was to analyze the anti-seizure activity of crude methanolic extract of Withania coagulans fruits (MeWc). For screening of this activity, maximal electroshock seizures model (MES) and chemically-induced seizures models were used. In maximal electroshock seizures test MeWc showed significant dose dependent percent protection against hind-limb tonic extension; significant and dose-dependent increase in latency to myoclonic jerks and tonic clonic convulsions and decrease in seizures duration were observed in PTZ-induced seizures. In strychnine-induced convulsions MeWc significantly increased latency to hind-limb tonic extension and percent protection from death in a dose-dependent manner. Thus, it was inferred from the experiments that extract of Withania coagulans showed anticonvulsant activity.

In Vivo Evaluation of Ethanol Extract of Forsythia Suspensa (Thunb.) Vahl (Fruit) in Anti-Inflammatory and Analgesic Activities

Objectives The dried fruit of Forsythia suspensa (Thunb.) Vahl (FSTV) is a typical heat-clearing and detoxicating herb according to traditional Chinese medicine theory. This study was undertaken to evaluate the anti-inflammatory and analgesic activities of 85% ethanol extract of FSTV (FSTV-ET) in vivo. Methods Conventional reflux extraction method was used to prepare FSTV-ET with a yield of 42.7%. The analgesic activity of FSTV-ET was evaluated using the hot plate test and acetic acid-induced abdominal writhing test, and the anti-inflammatory activity was evaluated by the xylene-induced ear oedema model in female Kunming (KM) mice. Lipid peroxidation product malondialdehyde (MDA) and inflammatory mediator prostaglandin (PG) E2 were both detected using methods reported in the literature. Results FSTV-ET exerted analgesic activity with a significant dose-dependent increase in latency in the hot plate test. The percentage inhibition suggested that FSTV-ET exhibited analgesic activity in the central nervous system. Meanwhile, FSTV-ET at 0.16, 0.32, and 0.64 g/kg strongly inhibited the acetic acid-induced writhing response. FSTV-ET also exerted analgesic activity in the peripheral nervous system. Moreover, FSTV-ET demonstrated a significant anti-inflammatory effect against xylene-induced oedema in a dose-dependent manner, and reduced MDA and PGE2 levels. Conclusions These findings indicate that FSTV-ET can produce anti-inflammatory and analgesic activities in vivo, and the mechanism is likely to be related to inhibiting lipid peroxidation and inflammation. Acknowledgements Supported by project grants from the National Natural Science Foundation of China (Grant No. 81503269), the Funding Scheme for Young Key Teachers of Colleges and Universities in Henan Province (Grant No. 2014GGJS-072), and the Science and Technology Project of Zhengzhou (Grant No. 20150309).

Anticonvulsant activity of methanolic extract from Kalanchoe pinnata (Lam.) stems and roots in mice: A comparison to diazepam

IntroductionIn ancient and current traditional medicine in Mexico, extracts from the leaves or whole plant of ‘life leaf’ (Kalanchoe pinnata [K. pinnata] Lam) have been used to treat an entity known locally as ‘yellow epilepsy’ (alferecía amarilla) when it is accompanied by seizures. However, the anticonvulsive activity of its stems and roots remains unexplored. MethodsThe anticonvulsant activity of the methanolic root extract (MER) or stem (MES) of K. pinnata Lam. was evaluated in a pentylenetetrazol-induced seizure model in BALB/c mice, and effects were compared to those of diazepam. The stem extract fractions that produced anticonvulsant activity were subsequently evaluated using the pentylenetetrazol-induced seizure model. ResultsWe observed increased latency of tonic–clonic seizures that was inversely proportional to the dose of MRE, with a similar impact on the lethal effects of pentylenetetrazol. Different doses of the MSE showed a dose-dependent increase in latency to myoclonus, clonus, and tonic–clonic seizures, acting similarly to diazepam and offering 100% protection against the lethal effects of pentylenetetrazol. Fractioning MSE decreased its effectiveness, but when fractions were mixed with fractions of chloroform and ethyl acetate, anticonvulsive activity was restored. The preliminary phytochemical analysis identified alkaloids and sterols in MRE, and sterols and terpenes in MSE. ConclusionsThe anticonvulsant activity of K. pinnata Lam. decreases with increased doses of MRE, whereas the effect of MSE is dose-dependent and preserved in the mixture chloroform and ethyl acetate. We suggest that the metabolites responsible for these effects are sterols in MRE, and sterols and terpenes in MSE.

In in vivo evaluation of the anti-inflammatory and analgesic activities of compound Muniziqi granule in experimental animal models.

BackgroundCompound Muniziqi granule (MNZQ), a traditional Uighur medicinal preparation, comprises 13 species of medicinal plants. MNZQ is traditionally used for regulating body immunity, modulating inflammation and pain, detoxification, and inhibiting tumor growth. This study aims to scientifically evaluate the anti-inflammatory and analgesic activities of MNZQ, support its clinical use and further research with scientific evidence.MethodsThe analgesic activity of MNZQ was evaluated using hot plate test and acetic acid-induced abdominal writhing test. Acute inflammation was evaluated using xylene-induced ear edema and carrageenan-induced paw edema models, while chronic inflammation was evaluated using cotton pellet-induced granuloma model.ResultsMNZQ exerted analgesic activities with a significant dose-dependent increase in latency in the hot plate test. The percentage inhibition suggested that MNZQ exhibited analgesic activities in the central nervous system. Meanwhile, MNZQ at 0.8, 2.4, and 7.2 g/kg strongly inhibited the acetic acid-induced writhing response by 25.22 % (p < 0.01), 44.60 % (p < 0.001), and 49.41 % (p < 0.001), respectively. MNZQ also exerted analgesic activities in the peripheral nervous system. Moreover, MNZQ was demonstrated a significant anti-inflammatory effect against xylene-induced edema in a dose-dependent manner. The percentage inhibition was 22.24 % (p < 0.01) at the highest dosage of 7.2 g/kg. MNZQ at 1.62 and 4.86 g/kg significantly reduced carrageenan-induced rat hind paw edema by 82.43 % and 84.32 % (p < 0.001), respectively, 1 h after injecting carrageenan, and the inhibitory effect lasted for 5 h. MNZQ also exerted a significant anti-inflammatory effect against cotton pellet-induced granuloma formation. MNZQ at 1.62 and 4.86 g/kg could inhibit granuloma formation by 17.07 % and 17.60 %, respectively, whereas the percentage inhibition of diclofenac was 33.12 %.ConclusionsThe results obtained suggest that MNZQ possesses potential anti-inflammatory and analgesic activities. This study provides a scientific basis for the use of MNZQ in alleviating pain and treating inflammatory disorders.

Actividad anticonvulsivante del extracto metanólico de tallo y raíz de Kalanchoe pinnata Lam. en ratones: Comparación con diazepam

IntroductionIn ancient and current traditional medicine in México, extracts from the leaves or whole plant of ‘life leaf’ (Kalanchoe pinnata [K. pinnata]Lam) have been used to treat an entity known locally as ‘yellow epilepsy’ (alferecía amarilla) when it is accompanied by seizures. However, the anticonvulsive activity of its stems and roots remains unexplored MethodsThe anticonvulsant activity of the methanolic root extract (MER) or stem (MES) of K. pinnata Lam. was evaluated in a pentylenetetrazol-induced seizure model in Balb/C mice, and effects were compared to those of diazepam. The stem extract fractions that produced anticonvulsant activity were subsequently evaluated using the pentylenetetrazol -induced seizure model. ResultsWe observed increased latency of tonic-clonic seizures that was inversely proportional to the dose of MRE, with a similar impact on the lethal effects of pentylenetetrazol. Different doses of the MSE showed a dose-dependent increase in latency to myoclonus, clonus, and tonic-clonic seizures, acting similarly to diazepam and offering 100% protection against the lethal effects of pentylenetetrazol. Fractioning MSE decreased its effectiveness, but when fractions were mixed with fractions of chloroform and ethyl acetate, anticonvulsive activity was restored. The preliminary phytochemical analysis identified alkaloids and sterols in MRE, and sterols and terpenes in MSE ConclusionsThe anticonvulsant activity of K. pinnata Lam. decreases with increased doses of MRE, whereas the effect of MSE is dose-dependent and preserved in the mixture chloroform and ethyl acetate. We suggest that the metabolites responsible for these effects are sterols in MRE, and sterols and terpenes in MSE

Evaluation of anticonvulsant, sedative, anxiolytic, and phytochemical profile of the methanol extract from the aerial parts of Swertia corymbosa (Griseb.) wight ex C.B. Clarke.

The objective of the present study was to evaluate the anxiolytic, antidepressant, and anticonvulsant activity of the methanolic extract of Swertia corymbosa (SCMeOH). After acute toxicity test, oral treatment with SCMeOH at doses of 125, 250, and 500 mg/kg behavioral models of open field, elevated-plus-maze, actophotometer, rotarod, pentylenetetrazole, isoniazid, and maximal electroshock induced seizure models were utilized. In open field test, SCMeOH (125, 250, and 500 mg/kg) (P < 0.01, P < 0.001) increased the number of rearings. However, the number of central motor and ambulation (P < 0.01, P < 0.001) were reduced. Likewise, the number of entries and the time spent in open arm were increased while the number of locomotion was decreased (P < 0.001) in elevated-plus-maze and actophotometer test, respectively. SCMeOH (125–500 mg/kg) protected the mice against the pentylenetetrazole and isoniazid induced convulsions; it causes significant (P < 0.01 and P < 0.001) dose dependent increase in latency of convulsion. Treatment with SCMeOH reduced the duration of the tonic hind limb extension induced by electroshock. Two major compounds such as gentiopicroside and swertianin were analyzed by HPLC system.

Evaluation of &amp;lt;i&amp;gt;Abelmoschus moschatus&amp;lt;/i&amp;gt; seed extract in psychiatric and neurological disorders

Background: Abelmoschus moschatus is an aromatic and medicinal plant, used as traditional medicine in the Thirunelveli district and distributed in many parts of Asia, including India. The present study was aimed to evaluate central nervous system (CNS) activities of ethanolic seed extract of A. moschatus (AEAM). Methods: Oral administration of AEAM at doses of 200 and 400 mg/kg on various behavioral models forced swim, tail suspension, light-dark box, hole-board, elevated-plus-maze, locomotor, strychnine, maximal electroshock induced seizure, pentylenetetrazole (PTZ), rotarod, climbing an inclined screen models were utilized. Results: In the open field test, AEAM (200 and 400 mg/kg) increased the numbers of rearing. However, the number of central motor and ambulation were reduced. The number of entries and the time spent in the open arm were increased, whereas the number of locomotion was decreased (p&lt;0.001) in elevated-plus-maze and actophotometer test, respectively. AEAM (200 and 400 mg/kg) protected the mice against the PTZ and strychnine-induced convulsions; it causes significant dose-dependent increase in latency of convulsion. Treatment with AEAM reduced the duration of the tonic hind limb extension, increased the hypnotics time and decreased motor co-ordination of experimental animals. Conclusion: This study concludes A. moschatus is an alternative source for CNS drug development.

CNS depressant and anticonvulsant activities of the alcoholic extract of leaves of Ziziyphus nummularia

Ethnopharmacological relevanceZiziyphus nummularia (family: Rhamnaceae) is a xerophyte, grows in the grazing lands of the Thar Desert of Rajasthan. Ziziyphus nummularia (ZN) is used as sedative in ethnomedicine. The objective of this study is to investigate the anticonvulsant, anxiolytic and sedative activities of the alcoholic extract of leaves of Ziziyphus nummularia (EZN). Materials and methodsThe anticonvulsant effect of the EZN (100, 200 and 300mg/kg) was evaluated in mice using the pentylenetetrazole and maximal electroshock induced seizure models. Its anxiolytic activity was evaluated using the elevated plus maze, hole board and open field models board methods, while the pentobarbital induced sleep was used to evaluate the sedative activity. The acute toxicity and effect on motor coordination were also assessed. ResultsEZN (100–300mg/kg) protected the mice against the pentylenetetrazole induced convulsions; it causes a significant (P<0.05) dose dependent increase in latency of convulsion. Treatment with EZN reduced the duration of the tonic hind limb extension induced by electroshock. Mice treated with EZN preferred the open arm of the plus maze and were found to be devoid of open-arm avoidance. EZN potentiation the barbiturate induce sleep in mice, it causes a decrease in the sleep latency and increases the duration of sleep. ConclusionThe results obtained from the experiments indicate that the EZN has CNS depressant and anticonvulsant activities.

CB1 RECEPTOR ACTIVATION IN THE BASOLATERAL AMYGDALA PRODUCES ANTINOCICEPTION IN ANIMAL MODELS OF ACUTE AND TONIC NOCICEPTION

1. Recent studies have suggested that the basolateral nucleus of the amygdala (BLA) participates in the processing of pain information, especially noxious somatic information. Cannabinoid receptors or CB1 mRNA are expressed more in the BLA than in other nuclei of the amygdala. Thus, the aim of the present study was to examine whether CB1 receptors in the BLA may be involved in modulating acute and/or tonic nociceptive processing. 2. Adult rats were exposed to intra-BLA microinjection of the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo [1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN 55,212-2 (1, 2.5, 5 or 10 microg/side)] and subjected to the tail flick and formalin tests. 3. The rats demonstrated a dose-dependent increase in latency to withdraw from a thermal noxious stimulus in the tail flick test and a decrease in formalin-induced pain behaviours. The antinociceptive effects of the CB1 receptor agonist WIN 55,212-2 (10 microg/side) in both tests were attenuated in the presence of the selective CB1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide (AM251; 0.55 ng/side). Administration of the CB1 receptor antagonist AM251 (0.55, 5.5, or 55.5 ng/side) alone did not alter the nociceptive thresholds in either test. Bilateral microinjection of the selective CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 1 microg/side) had no effect on the antinociception produced by WIN 55,212-2, suggesting that the antinociceptive actions of WIN 55,212-2 are mediated by CB1 receptors. 4. The findings suggest the existence of a CB1-mediated inhibitory system in the BLA that, when activated, can diminish responsivity to acute and tonic noxious stimuli, but that normally has no tonic effect on the response threshold of these stimuli.

Pharmacologic and physiologic influences affecting sensory evoked potentials: implications for perioperative monitoring.

Pharmacologic and physiologic influences affecting sensory evoked potentials: implications for perioperative monitoring.

Haloperidol and chlorpheniramine interaction in inhibitory avoidance in goldfish

The purpose of this study was to investigate a possible interaction between histaminergic and dopaminergic systems in learning and memory processes, in an inhibitory avoidance test in goldfish. Haloperidol, a dopaminergic antagonist, was administrated pre-training and the chlorpheniramine (CPA), a histaminergic antagonist, post-training. The inhibitory avoidance procedure was performed in 3 days, using a rectangular aquarium divided into two compartments (black and white), with a central door. On the first day, the animals were habituated for 10 min. On the second day, they were injected with 2 mg/kg of haloperidol or dimethyl sufoxide (DMSO) 20 min before training. Then, the animals were placed in the white compartment, the central door was opened and the time spent for crossing between compartments was recorded. After the fish crossed the line between compartments a 45 g weight was dropped. This procedure was done five times in a row. Immediately after the fifth trial, the fish were injected intraperitoneally (i.p.) with either saline or CPA (0.4, 1.0, 4.0, 8.0 or 16 mg/kg). On the next day (test) the time to cross was recorded again. On the training trials, the animals treated with DMSO or haloperidol presented a significant increase in the latencies indicating learning (Friedman P=0.0062 and 0.0001). The latencies in the test day showed that groups pre-treated with haloperidol and treated with CPA presented a dose-dependent increase in latencies, and those treated with the 16 mg/kg CPA group showed a significant increase (ANOVA two-way followed by Student–Newman–Keuls (SNK) P<0.01). Thus, it can be suggested that the facilitatory action occurs due to an additive interaction between both systems, in a dose-dependent way.

The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception.

N-methyl-D-aspartate receptor antagonism probably accounts for most of ketamine's anesthetic effects; its analgesic properties are mediated partly via N-methyl-D-aspartate and partly via opioid receptors. We assessed the involvement of the mu-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 mu-opioid receptor knockout mice (MOR(-/-)) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO(2) was measured with whole body plethysmography. Two antinociceptive assays were used: the tail-immersion test and the hotplate test. S(+) ketamine (0, 10, 100, and 200 mg/kg intraperitoneally) caused a dose-dependent respiratory depression in both genotypes, with greater depression observed in WT relative to MOR(-/-) mice. At 200 mg/kg, S(+) ketamine reduced the slope of the hypercapnic ventilatory response by 93% +/- 15% and 49% +/- 6% in WT and MOR(-/-) mice, respectively (P < 0.001). In both genotypes, S(+) ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in MOR(-/-) mice smaller compared with those in WT animals (P < 0.05). In contrast to WT mice, MOR(-/-) mice displayed no ketamine-induced antinociception in the tail-immersion test. These results indicate that at supraspinal sites S(+) ketamine interacts with the mu-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception. The involvement of the mu-opioid receptor system in S(+) ketamine-induced respiratory depression and spinal and supraspinal analgesia was demonstrated by performing experiments in mice lacking the mu-opioid receptor and in mice with intact mu-opioid receptors.

Effects of central administration of arginine-vasopressin on aversive memory retrieval

This study examined whether arginine-vasopressin (A-VP), given before the test would produce an improved retrieval of aversive memory, in the same way as pre-exposure to inescapable footshocks, in rats. For this purpose animals conditioned in a T-maze with appetitive (10% sucrose) and aversive (2.0 mA footshock) events were administered (intracerebroventricular) a single dose of 2.5, 5, 10 or 20 ng/rat of A-VP, 20-min before testing. In the retention test conducted with the same training apparatus 72 h after conditioning, the peptide treated rats showed a dose-dependent increase in latencies to enter the previously shocked goalarm, with the absence of such a difference in responding to the non-shocked goalarm. This differential response was not observed in saline treated rats. This effect of peptide on memory retrieval was similar to that seen following inescapable footshock in rats. These results suggest the possible involvement of central vasopressinergic mechanisms in the differential enhancement of memory of helplessness condition.

Role of 5-HT 1A and 5-HT 2 receptors in the aversion induced by electrical stimulation of inferior colliculus

In addition to being a relay station for auditory pathways in the brainstem, the inferior colliculus may also be part of a brain system commanding defensive behavior. In the present work, we present evidence for the serotonergic modulation of the neural substrate of aversion in this structure. Rats implanted with an electrode-cannula in the inferior colliculus were placed inside a shuttle-box and submitted to a switch-off paradigm. Microinjections of zimelidine, a 5-HT uptake blocker, caused dose-dependent increases in latency and reductions in the frequency of switch-off responses to the inferior colliculus electrical stimulation. The 8-OH-DPAT, a classical 5-HT 1A agonist, and α-methyl-5-hydroxytryptamine, a highly selective 5-HT 2 agonist, injected directly into the inferior colliculus also produced clear antiaversive effects in a dose-dependent manner. The antiaversive effect produced by α-methyl-5-hydroxytryptamine was attenuated by the systemic administration of ketanserin, a preferential 5-HT 2 receptor antagonist. These results suggest that serotonergic mechanisms modulate the neural substrates commanding defensive behavior in the inferior colliculus, probably through a cooperative mechanism with the activation of 5-HT 1A and 5-HT 2 receptors.

Effects of ACTH and ACTH 4-10 on aversive memory retrieval in rats.

The aim of the study was to examine whether ACTH and ACTH-fragment 4-10, given before the test would produce a selectively enhanced retrieval of aversive memories, in the same way as preexposure to inescapable footshocks, in rats. For this purpose animals conditioned in a T-maze with appetitive (10% sucrose) and aversive (2.0 mA footshock) events were administered (s.c.) a single dose of 10, 20 or 40 ug/rat of ACTH or 5, 10 or 20 ug/rat of ACTH-fragment 4-10, 20-min before testing. The retention test conducted in the same training apparatus 72-hrs after conditioning showed a dose-dependent increase in latencies to enter the previously shocked goalarm with the absence of such a difference in responding to the nonshocked goalarm, in ACTH and ACTH 4-10 treated groups. This differential response was not observed in saline treated rats. This effect of peptides on memory retrieval was similar to that seen following inescapable footshock in rats. The results suggest the possible involvement of ACTH in the differential enhancement of memory of helplessness condition.

Scopolamine does not differentially affect Morris maze performance in adult rats exposed prenatally to alcohol

Rats exposed prenatally to alcohol have shown deficits in spatial learning in radial-arm and Morris mazes. Prenatal exposure to alcohol in rats has also been shown to alter central nervous system (CNS) cholinergic function. Since cholinergic dysfunction disrupts spatial learning in normal rats, the present experiment assessed the role of putative prenatal alcohol-induced cholinergic dysfunction in spatial learning in rats. Pregnant rats were fed alcohol via liquid diet from gestation day 6 to 20. Control dams were pair-fed liquid diet without alcohol or fed ad lib lab chow and water. Group housed adult male and female offspring (postnatal days 110 to 135) were given scopolamine-HCl (o, 0.5, or 1.0 mg/kg/day) and tested in a Morris maze, with four trials per day for four days. A 15-s probe trial preceded testing on days 2–4. On day 5, the rats were given four trials to learn a new platform location. Scopolamine produced dose-dependent increases in latency to find the platform for all groups. There were no significant differences among prenatal treatment groups in scopolamine-induced shifts in performance. The results did not support the hypothesis that prenatal alcohol-induced CNS cholinergic dysfunction is related to spatial learning performance in these rats.

Enhancement of Memory Retrieval and Attenuation of Scopolamine‐Induced Amnesia Following Administration of 5‐HT3 Antagonist ICS 205‐930

Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT3-receptor antagonist (ICS 205-930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205-930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205-930 (1, 10 & 100 micrograms/kg) produced a dose-dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205-930 (10 micrograms/kg). These results suggest that memory deficits may be susceptible to attenuation with non-cholinergic treatments.

The effects of chloralose on the brainstem auditory evoked potential of the rat

The effects of alpha-chloralose were examined on the brainstem auditory evoked potential of the rat. Subjects were given one of four different doses of chloralose. These were a sedative dose (50 mg/kg), an anaesthetic dose (100 mg/kg), a usually fatal dose (150 mg/kg) or an invariably fatal dose (200 mg/kg). Recordings were made 60 min later. There was no evidence of any dose-dependent increase or decrease in the amplitudes of the four principal components (waves I, II, III and IV) of the brainstem auditory potential. There were only minor dose-dependent increases in latency. These were less than 0.1 msec for waves I, II and III and just over 0.1 msec for wave IV. Wave IV was the component which was most sensitive to chloralose, although this was apparent only at a large dose. In general, the latencies showed little or no difference from those recorded previously from awake animals. The results are discussed in relation to a series of experiments, where animals were initially immobilized with chloralose in order to study the effects of a variety of pharmacological agents on the brainstem auditory potential.

Attenuation of febrile seizures in epileptic chicks by N-methyl-D-aspartate receptor antagonists

Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(+/- )2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-alpha-aminoadipic acid (AAA), and DL-alpha, epsilon-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5, 10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH greater than APV much greater than AAA greater than DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.