Prolonged exposure to cigarette smoke blocks the neurotoxicity induced by kainic acid in rats

We examined the effects of cigarette smoke (CS) on three parameters associated with kainic acid (KA)-induced neurotoxicity: seizure activity, cell loss in the hippocampus, and increased Fos-related antigen (FRA) expression. Animals were exposed to the main stream of CS from 15 Kentucky 2R1F research cigarettes containing 28.6 mg tar and 1.74 mg nicotine per cigarette, for 10 min a day, 6 days per week, for 4 weeks, using an automatic smoking machine. KA administration (10 mg/kg, i.p.) produced robust behavioral convulsions lasting 4-5 h. Pre-exposure to CS significantly reduced the seizures, mortality, and severe loss of cells in regions CA1 and CA3 of the hippocampus after KA administration. Consistently, pre-exposure to CS significantly attenuated the KA-induced increased FRA immunoreactivity in the hippocampus. In contrast, pretreatment with central nicotinic antagonist, mecamylamine (2 or 10 mg/kg, i.p.) blocked the neuroprotective effects mediated by CS in a dose-dependent manner. These results indicate that CS exposure provides neuroprotection against the KA insult via nicotinic receptor activation.     

Prevention of kainic acid-induced changes in nitric oxide level and neuronal cell damage in the rat hippocampus by manganese complexes of curcumin and diacetylcurcumin

Curcumin is a natural antioxidant isolated from the medicinal plant Curcuma longa Linn. We previously reported that manganese complexes of curcumin (Cp-Mn) and diacetylcurcumin (DiAc-Cp-Mn) exhibited potent superoxide dismutase (SOD)-like activity in an in vitro assay. Nitric oxide (NO) is a free radial playing a multifaceted role in the brain and its excessive production is known to induce neurotoxicity. Here, we examined the in vivo effect of Cp-Mn and DiAc-Cp-Mn on NO levels enhanced by kainic acid (KA) and L-arginine (L-Arg) in the hippocampi of awake rats using a microdialysis technique. Injection of KA (10 mg/kg, i.p.) and L-Arg (1000 mg/kg, i.p.) significantly increased the concentration of NO and Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly reversed the effects of KA and L-Arg without affecting the basal NO concentration. Following KA-induced seizures, severe neuronal cell damage was observed in the CA1 and CA3 subfields of hippocampal 3 days after KA administration. Pretreatment with Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly attenuated KA-induced neuronal cell death in both CA1 and CA3 regions of rat hippocampus compared with vehicle control, and Cp-Mn and DiAc-Cp-Mn showed more potent neuroprotective effect than their parent compounds, curcumin and diacetylcurcumin. These results suggest that Cp-Mn and DiAc-Cp-Mn protect against KA-induced neuronal cell death by suppression of KA-induced increase in NO levels probably by their NO scavenging activity and antioxidative activity. Cp-Mn and DiAc-Cp-Mn have an advantage to be neuroprotective agents in the treatment of acute brain pathologies associated with NO-induced neurotoxicity and oxidative stress-induced neuronal damage such as epilepsy, stroke and traumatic brain injury.     

Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice

The effects of dextromethorphan (DM), and its major metabolite dextrorphan (DX) on kainic acid-induced seizures in mice were examined. Intracerebroventricular DM or DX (5 or 10 microg/0.5 microl) pretreatment significantly attenuated seizures induced by kainic acid (0.07 microg/0.07 microl) in a dose-related manner. DM or DX pretreatment significantly attenuated kainic acid-induced increases in AP-1 DNA-binding activity and fos-related antigen-immunoreactivity as well as neuronal loss in the hippocampus. DM appears to be a more potent neuroprotectant than DX. Since the high-affinity DM binding sites are recognized as being identical to the sigma-1 site, we examined the role of the sigma-1 receptor on the pharmacological action mediated by DM or DX. Pretreatment with the sigma-1 receptor antagonist BD1047 (2.5 or 5 mg/kg, i.p.) blocked the neuroprotection by DM in a dose-related manner. This effect of BD 1047 was more pronounced in the animals treated with DM than in those treated with DX. Combined, our results suggest that metabolism of DM to DX is not essential for DM to exert its effect. They also suggest that DM provides neuroprotection from kainic acid via sigma-1 receptor modulation.     

NO介质在大鼠红藻氨酸诱导癫痫发作中的作用

目的：进一步探讨脑内一氧化氮(NO)介质(NO或NO衍生物)在复杂部分性及全身强直阵挛性癫痫发作中的作用。方法：采用红藻氨酸(KA)诱导大鼠癫痫发作,以NO合酶抑制剂L-硝基精氨酸(L-NNA)或NO前体L-精氨酸(L-Arg)予以预处理,观察其癫痫发作行为及海马结构内NO含量(NO2^-/NO3^-)的变化。结果：给予大鼠惊厥剂量KA(10mg/kg),15min时出现湿狗样抖动(WDS),1～3h出现全身痉挛;经L-NNA(50mg/kg)或L-Arg(40mg/kg)预处理的大鼠,注射相同剂量的KA后,其癫痫行为发生明显变化,L-NNA预处理的大鼠癫痫发作行为明显加重,表现为全身痉挛的潜伏期缩短、时间延长、死亡率提高;L-Arg预处理的大鼠癫痫发作行为减弱,WDS和全身痉挛的潜伏期均延长,发作程度减轻、时间缩短,观察时间内无一例死亡。KA给药后30min海马结构内的NO2^-/NO3^-含量迅速增多,7d时仍持续增高;与NS预处理组相比,经L-Arg预处理的动物,KA给药后3h及3d,其NO2^-/NO3^-浓度升高明显。结论：兴奋诱导性癫痫发作过程中内源性NO介质的变化可能具有重要的抗发作作用。     

Neuroprotective effects of lactation against kainic acid treatment in the dorsal hippocampus of the rat

Marked hippocampal changes in response to excitatory amino acid agonists occur during pregnancy (e.g. decreased frequency in spontaneous recurrent seizures in rats with KA lesions of the hippocampus) and lactation (e.g. reduced c-Fos expression in response to N-methyl-d,l-aspartic acid but not to kainic acid). In this study, the possibility that lactation protects against the excitotoxic damage induced by KA in hippocampal areas was explored. We compared cell damage induced 24 h after a single systemic administration of KA (5 or 7.5 mg/kg bw) in regions CA1, CA3, and CA4 of the dorsal hippocampus of rats in the final week of lactation to that in diestrus phase. To determine cellular damage in a rostro-caudal segment of the dorsal hippocampus, we used NISSL and Fluorojade staining, immunohistochemistry for active caspase-3 and TUNEL, and we observed that the KA treatment provoked a significant loss of neurons in diestrus rats, principally in the pyramidal cells of CA1 region. In contrast, in lactating rats, pyramidal neurons from CA1, CA3, and CA4 in the dorsal hippocampus were significantly protected against KA-induced neuronal damage, indicating that lactation may be a natural model of neuroprotection.     

Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems

17beta-estradiol has been reported to possess antidepressant-like activity in animal models of depression, although the mechanism for its effect is not well understood. The present study is an effort in this direction to explore the mechanism of the antidepressant-like effect of 17beta-estradiol in a mouse model(s) of behavioral depression (despair behavior). Despair behavior, expressed as helplessness to escape from a situation (immobility period), as in a forced swim test in which the animals are forced to swim for a total of 6 min, was recorded. The antiimmobility effects (antidepressant-like) of 17beta-estradiol were compared with those of standard drugs like venlafaxine (16 mg/kg, i.p.). 17beta-estradiol produced a U-shaped effect in decreasing the immobility period. It had no effect on locomotor activity of the animal. The antidepressant-like effect was comparable to that of venlafaxine (16 mg/kg, i.p.). 17beta-estradiol also exhibited a similar profile of antidepressant action in the tail suspension test. When coadministered with other antidepressant drugs, 17beta-estradiol (5 microg/kg, i.p.) potentiated the antiimmobility effect of subeffective doses of fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.), or bupropion (10 mg/kg, i.p.), but not of desipramine (5 mg/kg, i.p.) or tranylcypromine (2 mg/kg, i.p.), in the forced swim test. The reduction in the immobility period elicited by 17beta-estradiol (20 microg/kg, i.p.) was reversed by haloperidol (0.5 mg/kg, i.p.; a D(2) dopamine receptor antagonist), SCH 23390 (0.5 mg/kg, i.p.; a D(1) dopamine receptor antagonist), and sulpiride (5 mg/kg, i.p.; a specific dopamine D(2) receptor antagonist). In mice pretreated with (+)-pentazocine (2.5 mg/kg, i.p.; a high-affinity sigma-1 receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced a synergistic effect. In contrast, pretreatment with progesterone (10 mg/kg, s.c.; a sigma-1 receptor antagonist neurosteroid), rimcazole (5 mg/kg, i.p.; another sigma-1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.     

Effects of MK-801 and CNQX on various neurotoxic responses induced by kainic acid in mice

Effects of MK-801 (a NMDA receptor blocker) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; a non-NMDA receptor blocker) on several neurotoxic responses induced by kainic acid (KA) were examined in ICR mice. In a lethality test, intracerebroventricular (i.c.v.) pretreatment of MK-801 (1 microg), but not CNQX (0.5 microg), attenuated the time to lethality induced by KA (0.5 microg) administered i.c.v. In the memory test (a passive avoidance test), MK-801, but not CNQX, prevented the memory loss induced by KA (0.1 microg). The damage induced by KA (0.1 microg) administered i.c.v. in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. Both MK-801 and CNQX blocked the pyramidal cell death in CA3 hippocampal region induced by KA. In the immunocytochemical study, KA dramatically increased the phosphorylated ERK (p-ERK) and decreased the phosphorylated CREB (p-CREB) in the hippocmapus. Both MK-801 and CNQX attenuated, in part, the increased p-ERK and the decreased p-CREB induced by KA. In addition, both MK-801 and CNQX partially reduced the increased c-Fos and c-Jun protein expression in hippocampus induced by KA. Our results suggest that both NMDA and non-NMDA receptors are involved in supraspinally administered KA-induced pyramidal cell death in CA3 region of hippocampus in the mouse and the p-ERK and the dephosphorylation of CREB protein may play an important role in CA3 region cell death of the hippocampus induced by KA administered supraspinally. Furthermore, c-Fos and c-Jun proteins may serve as third messengers responsible for CA3 pyramidal cell death induced by supraspinally administered KA.     

海马mu型阿片肽受体介导大鼠癫痫发作敏感性形成

为探讨海马mu型阿片肽受体介导癫痫发作敏感性形成的作用,实验采用微渗透泵技术,观察大鼠腹侧海马注射mu型阿片肽受体激动剂PL017(2.09、2.59、3.29μg/μ1)、拮抗剂β-funaltrexamine hydrochloride(β-FNA、0.88、1.10、1.35μg/μl)对红藻氨酸(kainic acid,KA)诱导癫痫发作的干预作用.PL017能够明显缩短癫痫发作潜伏期、增加癫痫发作级别(P＜0.05),β-FNA则可显著延长癫痫发作潜伏期、降低发作级别(P＜0.01);PL017和β-FNA的干预作用均表现出剂量依赖效应.结果表明,海马mu型阿片肽受体具有促进KA诱导的癫痫发作敏感性形成作用.     

Resveratrol Protects Against Neurotoxicity Induced by Kainic Acid

Increased oxidative stress has been implicated in the mechanisms of excitotoxicity in hippocampus induced by kainic acid (KA), an excitatory glutamate receptor agonist. Resveratrol, a polyphenolic antioxidant compound enriched in grape, is regarded as an important ingredient in red wine to offer cardiovascular and neural protective effects. This study was designed to investigate whether resveratrol treatment may ameliorate neuronal death after KA administration. Adult Sprague Dawley male rats were treated with KA (8 mg/kg) daily for 5 days and another group was treated similarly with KA plus resveratrol (30 mg/kg/day). Three hr after the last treatment protocol, animals were sacrificed, and brain sections were obtained for histochemical and immunohistochemical identification of neurons, astrocytes and microglial cells. After KA administration, significant neuronal death and activation of astrocytes and microglial cells were observed in the hippocampal CA1, CA3 and polymorphic layer (hilar) of the dentate gyrus (DG) (P < 0.001). The KA-induced hippocampal neuronal damage was significantly attenuated by treatment with resveratrol (P < 0.001). Resveratrol also suppressed KA-induced activation of astrocytes and microglial cells. Since increased oxidative stress is a key factor for KA-induced neurotoxicity, this study demonstrated the ability of resveratrol to act as free radical scavenger to protect against neuronal damage caused by excitotoxic insults.Special issue dedicated to Dr. Lawrence F. Eng.     

A Prosaposin-Derived Peptide Alleviates Kainic Acid-Induced Brain Injury

Four sphingolipid activator proteins (i.e., saposins A–D) are synthesized from a single precursor protein, prosaposin (PS), which exerts exogenous neurotrophic effects in vivo and in vitro. Kainic acid (KA) injection in rodents is a good model in which to study neurotrophic factor elevation; PS and its mRNA are increased in neurons and the choroid plexus in this animal model. An 18-mer peptide (LSELIINNATEELLIKGL; PS18) derived from the PS neurotrophic region prevents neuronal damage after ischemia, and PS18 is a potent candidate molecule for use in alleviating ischemia-induced learning disabilities and neuronal loss. KA is a glutamate analog that stimulates excitatory neurotransmitter release and induces ischemia-like neuronal degeneration; it has been used to define mechanisms involved in neurodegeneration and neuroprotection. In the present study, we demonstrate that a subcutaneous injection of 0.2 and 2.0 mg/kg PS18 significantly improved behavioral deficits of Wistar rats (n = 6 per group), and enhanced the survival of hippocampal and cortical neurons against neurotoxicity induced by 12 mg/kg KA compared with control animals. PS18 significantly protected hippocampal synapses against KA-induced destruction. To evaluate the extent of PS18- and KA-induced effects in these hippocampal regions, we performed histological evaluations using semithin sections stained with toluidine blue, as well as ordinal sections stained with hematoxylin and eosin. We revealed a distinctive feature of KA-induced brain injury, which reportedly mimics ischemia, but affects a much wider area than ischemia-induced injury: KA induced neuronal degeneration not only in the CA1 region, where neurons degenerate following ischemia, but also in the CA2, CA3, and CA4 hippocampal regions.     

In vivo neuroprotective role of NMDA receptors against kainate-induced excitotoxicity in murine hippocampal pyramidal neurons

Activation of NMDA receptors has been shown to induce either neuronal cell death or neuroprotection against excitotoxicity in cultured cerebellar granule neurons in vitro. We have investigated the effects of pretreatment with NMDA on kainate-induced neuronal cell death in mouse hippocampus in vivo. The systemic administration of kainate (30 mg/kg), but not NMDA (100 mg/kg), induced severe damage in pyramidal neurons of the hippocampal CA1 and CA3 subfields 3-7 days later, without affecting granule neurons in the dentate gyrus. An immunohistochemical study using an anti-single-stranded DNA antibody and TdT-mediated dUTP nick end labeling analysis both revealed that kainate, but not NMDA, induced DNA fragmentation in the CA1 and CA3 pyramidal neurons 1-3 days after administration. Kainate-induced neuronal loss was completely prevented by the systemic administration of NMDA (100 mg/kg) 1 h to 1 day previously. No pyramidal neuron was seen with fragmented DNA in the hippocampus of animals injected with kainate 1 day after NMDA treatment. The neuroprotection mediated by NMDA was prevented by the non-competitive NMDA receptor antagonist MK-801. Taken together these results indicate that in vivo activation of NMDA receptors is capable of protecting against kainate-induced neuronal damage through blockade of DNA fragmentation in murine hippocampus.     

Role of α-CGRP in the regulation of neurotoxic responses induced by kainic acid in mice

Kainic acid (KA) is an excitatory and neurotoxic substance. The role of α-calcitonin gene-related peptide (α-CGRP) in the regulation of KA-induced hippocampal neuronal cell death was investigated in the present study. The intracerebroventricular (i.c.v.) administration with KA (0.07 μg) increased hippocampal α-CGRP mRNA level in ICR mice. The α-CGRP mRNA level began to increase at 1 h, reached at maximal level at 6 and 12 h, and returned to the control level by 24 h after i.c.v. administration with KA. In addition, KA-induced hippocampal CA3 neuronal death in C57BL6 (wild type) group was more pronounced compared to KA-induced hippocampal CA3 pyramidal cell death in α-CGRP knock-out (KO) group. Furthermore, sumatriptan, a CGRP releasing inhibitor, significantly protected the pyramidal cell death in CA3 hippocampal region induced by KA administered i.c.v. in ICR mice. Our results suggest that α-CGRP may play an important role in the regulation of KA-induced pyramidal cell death in CA3 region of the hippocampus.     

Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice

Dehydroepiandrosterone (DHEA) is one of the most abundant neurosteroids synthesized de novo in the CNS. We here found that sigma-1 receptor stimulation by DHEA improves cognitive function through phosphorylation of synaptic proteins in olfactory bulbectomized (OBX) mouse hippocampus. We have previously reported that calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) were impaired in OBX mouse hippocampus. OBX mice were administered once a day for 7-8 days with DHEA (30 or 60 mg/kg p.o.) 10 days after operation. The spatial, cognitive and conditioned fear memories in OBX mice were significantly improved as assessed by Y-maze, novel object recognition and passive avoidance task, respectively. DHEA also improved impaired hippocampal long-term potentiation in OBX mice. Notably, DHEA treatment restored PKCα (Ser-657) autophosphorylation and NR1 (Ser-896) and myristoylated alanine-rich protein kinase C substrate (Ser-152/156) phosphorylation to the control levels in the hippocampal CA1 region. Likewise, DHEA treatment improved CaMKIIα (Thr-286) autophosphorylation and GluR1 (Ser-831) phosphorylation to the control levels in the CA1 region. Furthermore, DHEA treatment improved ERK and cAMP-responsive element-binding protein (Ser-133) phosphorylation to the control levels. Finally, NE-100, sigma-1 receptor antagonist, significantly inhibited the DHEA-induced improvement of memory-related behaviors and CaMKII, PKC and ERK phosphorylation in CA1 region. Taken together, sigma-1 receptor stimulation by DHEA ameliorates OBX-induced impairment in memory-related behaviors and long-term potentiation in the hippocampal CA1 region through activation of CaMKII, PKC and ERK.     

Temporal expression of hippocampal lysophosphatidic acid receptors and their roles in kainic acid-induced neurotoxicity

In this investigation, the role of hippocampal lysophosphatidic acid (LPA) receptors in the regulation of kainic acid (KA)-induced neurotoxicity was investigated. KA (0.07 μg) intracerebroventricular (i.c.v.) administration increased hippocampal Lpar1, 2, 3, and 5 mRNA levels. In the immunohistochemical study, alteration of LPA₁ or LPA₃ immunoreactivity was different depending on the hippocampal regions, such as CA1, CA2, CA3, and dentate gyrus. In addition, the i.c.v. pretreatment with LPA₁ and LPA₃ antagonists, such as VPC12249 (0.05 μg) and VPC32183 (0.05 μg) attenuated KA-induced neuronal cell death in the hippocampal CA3 region. However, the i.c.v. 18:1 LPA (0.05 μg) pretreatment aggravated KA-induced neuronal cell death in the hippocampal CA3 region. Our results suggest that LPA receptors, such as LPA₁ and LPA₃ activation might play an important role in the regulation of KA-induced neuronal cell death in the hippocampal CA3 region.     

Effect of piperine,the active ingredient of black pepper,on intestinal secretion in mice

We have investigated the effect piperine on castor oil-stimulated fluid accumulation in the mouse small intestine. Piperine (2.5-20 mg/kg, i.p.) dose-dependently reduced castor oil-induced intestinal fluid accumulation. The inhibitory effect of piperine (10 mg/kg i.p.) was strongly attenuated in capsaicin (75 mg/kg in total, s.c.)-treated mice but it was not modified by the vanilloid receptor antagonist capsazepine (30 mg/kg i.p.). Pretreatment of mice with hexamethonium (1 mg/kg i.p.), naloxone (2 mg/kg i.p.), yohimbine (1 mg/kg i.p.) or the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg/kg i.p.) did not modify the inhibitory effect of piperine (10 mg/kg i.p.). These results suggest that piperine reduces castor oil-induced fluid secretion with a mechanism involving capsaicin-sensitive neurons, but not capsazepine-sensitive vanilloid receptors.     

Altered expression of sphingosine kinase 1 and sphingosine-1-phosphate receptor 1 in mouse hippocampus after kainic acid treatment

Kainic acid (KA) induces hippocampal cell death and astrocyte proliferation. There are reports that sphingosine kinase (SPHK)1 and sphingosine-1- phosphate (S1P) receptor 1 (S1P₁) signaling axis controls astrocyte proliferation. Here we examined the temporal changes of SPHK1/S1P₁ in mouse hippocampus during KA-induced hippocampal cell death. Mice were killed at 2, 6, 24, or 48 h after KA (30 mg/kg) injection. There was an increase in Fluoro-Jade B-positive cells in the hippocampus of KA-treated mice with temporal changes of glial fibrillary acidic protein (GFAP) expression. The lowest level of SPHK1 protein expression was found 2 h after KA treatment. Six hours after KA treatment, the expression of SPHK1 and S1P₁ proteins steadily increased in the hippocampus. In immunohistochemical analysis, SPHK1 and S1P₁ are more immunoreactive in astrocytes within the hippocampus of KA-treated mice than in hippocampus of control mice. These results indicate that SPHK1/S1P₁ signaling axis may play an important role in astrocytes proliferation during KA-induced excitotoxicity.     

Capsaicin prevents kainic acid-induced epileptogenesis in mice

Epilepsy is a neurodegenerative disease with periodic occurrences of spontaneous seizures as the main symptom. The aim of this study was to investigate the neuroprotective effects of capsaicin, the major ingredient of hot peppers, in a kainic acid (KA)-induced status epilepticus model. After intraperitoneal injections of KA (30mg/kg) in 8-week-old male ICR mice, the animals were treated subcutaneously with capsaicin (0.33mg/kg or 1mg/kg) and then examined for any anti-ictogenic, hypothermic, antioxidative, anti-inflammatory, and anti-apoptotic effects of the capsaicin treatment 3 days after KA treatment. KA injections significantly enhanced neurodegenerative conditions but co-injection with capsaicin reduced the detrimental effects of KA in a dose-dependent manner in mice. The co-administered group that received KA and 1mg/kg of capsaicin showed significantly decreased behavioral seizure activity and body temperature for 3h and also remarkably blocked intense and high-frequency seizure discharges in the parietal cortex for 3 days compared with those that received KA alone. Capsaicin treatment significantly diminished the levels of oxidant activity and malondialdehyde concentration and increased the antioxidant activity in the blood and brain of KA-treated mice. In addition, capsaicin significantly lowered the KA-induced increase in the concentration of the cytokines IL-1β and TNF-α in the brain. Furthermore, co-treatment of KA and capsaicin (1mg/kg) resulted in considerably decreased apoptotic cell death in the cornu ammonis sections of the hippocampus compared with that seen in the KA-alone group. These findings indicate that capsaicin is preventative for the epileptogenesis induced by KA in mice.     

Effects of alpha-MSH on kainic acid induced changes in core temperature in rats

The effects of intraperitoneal (i.p.) administration of kainic acid (KA) and alpha-melanocyte-stimulating hormone (alpha-MSH) alone or in combination, on core temperature of freely moving rats were examined. KA or saline was administered once (10 mg/kg) and alpha-MSH or saline was given repeatedly i.e. 10 min before and 10, 30 and 60 min after the administration of saline or KA. Two doses of alpha-MSH were used: 0.5 and 2.5 mg/kg. KA alone produced a biphasic effect on core temperature, i.e. an initial short-lasting hypothermia followed by hyperthermia that lasted about 6 h. The higher dose of alpha-MSH had a potentiating effect on KA-induced hypothermia, while the lower dose of alpha-MSH increased the hyperthermia produced by KA. alpha-MSH administered alone produced a late (3 h), dose-dependent increase in core temperature. It is conceivable that repeated administration of alpha-MSH in the doses used in our study may cause a cumulative effect in raising body temperature for a limited period of time.The previously described interactions between KA and alpha-MSH, respectively, with dopaminergic and serotoninergic systems may account for the effects on core temperature in rats observed in our study.     

Cannabinoids, hippocampal function and memory.

Prior studies from this laboratory have shown that the psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), interferes with short-term memory (1-3) in both delayed match and nonmatch to sample tasks (DMS/DNMS). Recent experiments have shown that other cannabinoids such as the potent CB1 receptor agonist, WIN 55,212-2 produces a delay-dependent deficit in the DNMS task at a dose range (0.10-0.50 mg/kg) well below that of delta9-THC which was blocked by the CB11 receptor antagonist SR141716A (Sanofi Inc). The effects of WIN 55,212-2 at low doses were similar to those of isolated lesions of the hippocampus, whereas high doses (0.50 mg/kg, i.p.) produced effects similar to lesions of both hippocampus and surrounding retrohippocampal areas. The low dose effect was delay-dependent while the high dose introduced an additional deficit at short delays that was sensitive to both SR141716A and the GABA(B) receptor antagonist, phaclofen. Comparison of lesion vs. cannabinoid effects on DNMS performance suggests that CB1 receptors on hippocampal neurons interfere with the processing of DNMS task-specific information within a trial. CB1 receptors on hippocampal GABAergic interneurons and in retrohippocampal areas appear to influence the ability to maintain segregation of information between trials in the task.