A light and electron microscopic study of the CB1 cannabinoid receptor in the primate spinal cord

The distribution of cannabinoid receptors was studied in the monkey spinal cord by immunocytochemistry and electron microscopy, using an antibody to the CB1 brain cannabinoid receptor. Large numbers of labelled neurons were observed in all portions of the grey matter of the spinal cord. These included small diameter 9–16µm neurons in the dorsal horn, larger (40–60µm) neurons in the intermediate grey, and very large (60–100µm), motor neurons in the ventral horn. Reaction product was observed in dendrites postsynaptic to unlabelled axon terminals. Since cannabinoid receptor activation decreases neuronal excitability by several mechanisms, including inhibition of voltage dependent calcium channels, the dense staining of CB1 in dorsal horn neurons suggests that CB1 could reduce calcium influx through such channels in these neurons. This, in turn, could decrease calcium-dependent changes in synaptic transmission and decrease sensitisation to nociceptive stimuli in these neurons. Similarly, the dense staining of CB1 in ventral horn cells suggests that cannabinoid receptors could limit calcium influx through voltage dependent calcium channels in these neurons, and could be significant in terms of neuroprotection to these neurons.     

Electrophysiological actions of the dopamine agonist apomorphine in the paraventricular nucleus during penile erection

The ability to achieve and maintain penile erection is necessary for successful copulation. Studies have demonstrated that dopamine receptor stimulation in the paraventricular nucleus (PVN) of the hypothalamus induces penile erection in rodents, and the dopamine agonist apomorphine has been used to treat erectile dysfunction. The aim of this study was to determine the electrophysiological characteristics of PVN neuronal firing activity in anaesthetised rodents during apomorphine-induced erection. Our findings can be placed in two categories; those effects that occur immediately upon apomorphine administration and continue for up to several minutes prior to penile erection, deemed ‘pre-erectile’, and those effects that were only observed during penile erection and seminal emission. In the pre-erectile period, apomorphine acts on two different populations of PVN neurons to increase or decrease firing rates and increases alpha1 frequency band power in local field potentials. Decreased delta and increased theta frequency power in PVN local field potentials occur only during penile erection and seminal emission. These studies provide further understanding of the coordinated neuronal activity that occurs in the PVN during apomorphine-induced penile erection.     

Cannabinoid receptor, CB1, expression follows neuronal differentiation in the early chick embryo

The role of the CB1 cannabinoid receptor and endocannabinoid signalling has been widely studied in the adult nervous system. However, an emerging body of evidence suggests that the CB1 receptor may also play a role during development. Here we have scrutinized the expression profile of the CB1 receptor from the onset of neurogenesis in the chick embryo. We find that this gene exhibits a dynamic expression pattern that spatially and temporally follows neuronal differentiation in the early embryo.     

Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy

Status epilepticus (SE) is a major medical emergency associated with a significant morbidity and mortality. Little is known about the mechanisms that terminate seizure activity and prevent the development of status epilepticus. Cannabinoids possess anticonvulsant properties and the endocannabinoid system has been implicated in regulating seizure duration and frequency. Endocannabinoids regulate synaptic transmission and dampen seizure activity via activation of the presynaptic cannabinoid receptor 1 (CB1). This study was initiated to evaluate the role of CB1 receptor-dependent endocannabinoid synaptic transmission towards preventing the development of status epilepticus-like activity in the well-characterized hippocampal neuronal culture model of acquired epilepsy using patch clamp electrophysiology. Application of the CB1 receptor antagonists SR141716A (1 microM) or AM251 (1 microM) to "epileptic" neurons caused the development of continuous epileptiform activity, resembling electrographic status epilepticus. The induction of status epilepticus-like activity by CB1 receptor antagonists was reversible and could be overcome by maximal concentrations of CB1 agonists. Similar treatment of control neurons with CB1 receptor antagonists did not produce status epilepticus or hyperexcitability. These findings suggest that CB1 receptor-dependent endocannabinoid endogenous tone plays an important role in modulating seizure frequency and duration and preventing the development of status epilepticus-like activity in populations of epileptic neurons. The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges.     

Colocalization of CB1 receptors with L1 and GAP-43 in forebrain white matter regions during fetal rat brain development: evidence for a role of these receptors in axonal growth and guidance

There is recent evidence supporting the notion that the cannabinoid signaling system plays a modulatory role in the regulation of cell proliferation and migration, survival of neural progenitors, neuritic elongation and guidance, and synaptogenesis. This assumption is based on the fact that cannabinoid 1-type receptors (CB₁ receptors) and their ligands emerge early in brain development and are abundantly expressed in certain brain regions that play key roles in these processes. We have recently presented in vivo evidence showing that this modulatory action might be exerted through regulating the synthesis of the cell adhesion molecule L1 that is also a key element for those processes. To further explore this issue, we conducted here immunohistochemical studies aimed at determining the cellular substrates of CB₁ receptor–L1 interactions in the rat brain during late fetal development. In this period, we previously found that the activation of CB₁ receptors increased L1 synthesis in several forebrain white matter regions but not in gray matter areas. Using double labeling studies, we observed here colocalization of both proteins in fiber tracts including the corpus callosum, the adjacent subcortical white matter, the internal capsule and the anterior commissure. Experiments conducted with cultures of fetal rat cortical nerve cells revealed that L1 is present mainly in neurons but not in glial cells. This fact, together with the results obtained in the double labeling studies, would indicate that L1 and CB₁ receptors should possibly be present in axons elongating through these white matter tracts, or, alternatively, in migrating neurons. Further experiments confirmed the presence of CB₁ receptors in elongating axons, since these receptors colocalized with growth-associated protein 43 (GAP-43), a marker of growth cones, but not with synaptophysin, a marker of active synaptic terminals, in the same forebrain white matter regions. Lastly, using cultured fetal rat cortical neurons, we also observed that the activation of cannabinoid receptors increased the levels of the full-length L1 and altered those of some active proteolytic fragments of this protein whose generation has been associated with specific steps in the process of neuritic elongation in cultured neurons. In summary, we have demonstrated that the effects caused by cannabinoid agonists on L1 are facilitated by the colocalization of this cell adhesion molecule with CB₁ receptors in several forebrain white matter regions during fetal brain development. We have provided strong evidence that this phenomenon occurs in axons elongating through these white matter tracts, and we have explored in vitro how cannabinoid receptors influence L1 levels. Considering the role played by L1 in different events related to neural development, our observations support the occurrence of a physiological mechanism by which the cannabinoid system might regulate the process of axonal growth and guidance through regulating the synthesis and function of L1.     

Sub-chronic administration of AM251, CB1 receptor antagonist,within the nucleus accumbens induced sensitization to morphine in the rat

It seems that there is a cross-talk between the cannabinoid CB1 and opioid receptors in the process of sensitization to opiates. In present study, we tried to examine the effect of solely administration of AM251, a CB1 receptor antagonist, on conditioned place preference (CPP) by ineffective dose of morphine in the rat. 102 adult male albino Wistar rats were used in these experiments. Subcutaneous administration of morphine (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg) induced CPP only at the doses of ≥5 mg/kg. The dose of 0.5 mg/kg of morphine was selected as the appropriate (ineffective) dose for induction of CPP in animals which were previously received AM251 (5, 25 and 125 ng/0.5 μl per side) once daily for three days as a sub-chronic administration or those that received a single dose on the test day. Bilateral intra-accumbal sub-chronic but not single administration of AM251 dose-dependently produced sensitization to morphine and induced CPP by ineffective dose of morphine (0.5 mg/kg) in the rat. Bilateral intra-accumbal administration of neither saline nor DMSO (0.5 μl/side) had effects on sensitization to morphine. Our findings indicated that CB1 receptors within the nucleus accumbens are involved in the sensitization to morphine in rats.     

Temporal and Spatial Distribution of the Cannabinoid Receptors (CB1, CB2) and Fatty Acid Amide Hydroxylase in the Rat Ovary

Although the effects of Δ⁹‐tetrahydrocannabinol (THC) on ovarian physiology have been known for many decades, its mechanism of action in the rat ovary remains poorly understood. The effects of THC and endocannabinoids on many cell types appear to be mediated through the G‐protein‐coupled CB₁ and CB₂ receptors. Evidence also suggests that the concentration of the endocannabinoid anandamide is regulated by cellular fatty acid amide hydrolase (FAAH). Therefore, we examined the rat ovary for the presence of CB₁ and CB₂ receptors and FAAH. The CB₁ receptor was present in the ovarian surface epithelium (OSE), the granulosa cells of antral follicles, and the luteal cells of functional corpus luteum (CL). The granulosa cells of small preantral follicles, however, did not express the CB₁ receptor. Western analysis also demonstrated the presence of a CB₁ receptor. In both preantral and antral follicles, the CB₂ receptor was detected only in the oocytes. In the functional CL, the CB₂ receptor was detected in the luteal cells. FAAH was codistributed with CB₂ receptor in both oocytes and luteal cells. FAAH was also present in the OSE, subepithelial cords of the tunica albuginea (TA) below the OSE, and in cells adjacent to developing preantral follicles. Western analysis also demonstrated the presence of FAAH in oocytes of both preantral and antral follicles. Our observations provide potential explanation for the effects of THC on steroidogenesis in the rat ovary observed by earlier investigators and a role for FAAH in the regulation of ovarian anandamide. Anat Rec 293:1425–1432, 2010. © 2010 Wiley‐Liss, Inc.     

Intra-accumbens rimonabant is rewarding but induces aversion to cocaine in cocaine-treated rats,as does in vivo accumbal cannabinoid CB1 receptor silencing: critical role for glutamate receptors

Reinforcing effects mediated by accumbal CB₁ receptors (CB₁R) are controversial, as well as their role in the rewarding effects of cocaine. Accumbal glutamate and glutamate receptors have been proposed to be involved in CB₁R-mediated effects on cocaine reward. Rewarding effects of cocaine can be evaluated with the conditioned place preference or CPP test. Rimonabant, a cannabinoid CB₁R ligand, lentiviruses aimed at silencing CB₁R, and selective glutamatergic ligands are good tools for studying the function of accumbal CB₁ and glutamate receptors. The objectives of the present study were (i) to discern the CPP effects of in vivo gene silencing of accumbal CB₁ receptors by means of lentiviruses containing siRNAs; (ii) to discern the CPP effects of intra-accumbens infusions of the cannabinoid CB₁R ligand rimonabant, and to evaluate whether effects are due to receptor blockade or inverse agonism; (iii) to discern the role of CB₁R located within the nucleus accumbens shell in the rewarding effects of cocaine, by means of local infusions of rimonabant, and (iv) to discern the role of glutamate receptors (AMPAR, NMDAR, mGluR2/3) in rimonabant-induced effects on CPP in cocaine-treated rats. The findings revealed that in vivo silencing of accumbal CB₁ receptors with Lenti-CB₁R-siRNAs induced place aversion to cocaine, but intra-acumbal rimonabant induced place preference in its own right, indicating that this compound seems to act as inverse agonist on the CPP. Glutamate receptors participate in rimonabant-mediated place preference because it was abolished after blocking AMPA glutamate receptors, but not NMDAR or mGluR2/3. Finally, in cocaine-treated rats, local rimonabant induced place aversion to the drug (not place preference), and this effect was mediated by glutamate neurotransmission because it was abolished after blockade of AMPA, NMDA or mGlu2/3 receptors, even though only the blockade of mGlu2/3 autoreceptors restored the emergence of place preference to cocaine.     

小鼠室旁核内雌激素受体与催产素、加压素表达的免疫组化研究

目的研究雌激素的核受体ER-α和ER-β以及催产素、加压素在成年雌性小鼠下丘脑室旁核内的表达。方法采用硫酸镍铵增强显色的免疫组化SP法检测ER-α、ER-β、催产素和加压素在室旁核内的表达。结果雌激素的两种核受体在室旁核内都有表达,但是以ER-β为主（P〈0.001）,其免疫阳性产物均在细胞核内,未见核外免疫阳性反应。催产素的免疫阳性产物主要在细胞核周围的胞浆即核周质内,而加压素的免疫阳性物质除了在核周质内有很强的反应外,在突起内也可见很强的免疫反应。ER-α的免疫阳性胞体主要在大细胞部内侧,而ER-β、催产素和加压素的免疫阳性胞体主要在背侧帽部或大细胞部的外侧。结论室旁核内两种雌激素受体可能都参与了对催产素和加压素的调节,但ER-β可能发挥了主要的调节作用。     

The role of oxytocin and the paraventricular nucleus in the sexual behaviour of male mammals

The paraventricular nucleus of the hypothalamus contains the cell bodies of a group of oxytocinergic neurons projecting to extrahypothalamic brain areas and to the spinal cord, which are involved in the control of erectile function and copulation. In male rats, these neurons can be activated by dopamine, excitatory amino acids, nitric oxide (NO), hexarelin analogue peptides and oxytocin itself to induce penile erection and facilitate copulation, while their inhibition by gamma-aminobutyric acid (GABA) and GABA agonists and by opioid peptides and opiate-like drugs inhibits sexual responses. The activation of paraventricular oxytocinergic neurons by dopamine, oxytocin, excitatory amino acids and hexarelin analogue peptides is apparently mediated by the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as yet unidentified, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Paraventricular oxytocinergic neurons and mechanisms similar to those reported above are also involved in the expression of penile erection in physiological contexts, namely, when penile erection is induced in the male by the presence of an inaccessible receptive female, which is considered a model for psychogenic impotence in man, as well as during copulation. These findings show that paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas and to the spinal cord and the paraventricular nucleus play an important role in the control of erectile function and male sexual behaviour in mammals.     

Opposite action of hippocampal CB1 receptors in memory reconsolidation and extinction

Retrieval of a consolidated memory triggers a number of processes which depend, among other factors, on the duration of the reactivation session: reconsolidation requires a brief reactivation session, and extinction, a prolonged one. The scope of this study is to explore the potential role of the hippocampal endocannabinoid system on reconsolidation and extinction processes. Bilateral infusion of the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) into the CA1 region of the dorsal hippocampus of Wistar rats after memory reactivation facilitated the reconsolidation of the contextual fear conditioning memory. The inhibition of protein synthesis with DRB in the same brain region blocked memory reconsolidation. Both effects were persistent, lasting up to 7 days after the first retrieval experience. In contrast, the local infusion of anandamide blocked memory reconsolidation, an effect that was antagonized by the combined administration of anandamide with a subthreshold dose of a CB1 antagonist, supporting a CB1-mediated role of the hippocampal endocannabinoid system in the modulation of the memory reconsolidation. Local infusion of AM251 into CA1 blocked memory extinction whereas the administration of anandamide facilitated it; however, when combined with a subthreshold concentration of the CB1 antagonist, anandamide did not affect the extinction process. The clear-cut, opposite effects observed in each situation suggest a possible role of the hippocampal endocannabinoid system as a switching mechanism deciding which processes will take place, either maintaining the original memory (reconsolidation) or promoting a new learning (extinction).     

大麻素CB_1受体活化对神经病理性疼痛大鼠脊髓背角嘌呤能P2X_2受体表达的抑制作用

目的:观察脊髓背角大麻素CB_1受体(CB_1R)在坐骨神经缩窄性损伤(CCI)所致的神经病理性疼痛中的作用及其对嘌呤能P2X_2受体表达的调节。方法:7~8周龄SD大鼠分为4组:(1)sham组;(2)CCI组;(3)CP55940+CCI组;(4)AM251+CP55940+CCI组。分别于CCI术前1 d,术后1、3、5、7、10、14 d测定热缩足反射潜伏期(TWL);免疫印迹技术检测各组大鼠损伤侧L_4~L_6段脊髓背角P2X_2受体表达。结果:CCI术后大鼠出现热痛敏,TWL明显缩短;鞘内给予非选择性大麻素受体激动剂CP55940可明显延长CCI大鼠TWL(P0.05);预先鞘内注射CB_1R拮抗剂AM251(0.05 mg/kg)可显著降低CP55940的镇痛效果(P0.05)。免疫印迹实验结果显示:CCI大鼠脊髓背角P2X_2受体在术后7、14 d表达明显增加(P0.05);鞘内给予CP55940可显著降低P2X_2受体表达(P0.05),而预先给予AM251可降低CP55940抑制P2X_2受体表达的效应(P0.05)。结论:脊髓背角CB_1受体激活对CCI所致的神经病理性疼痛具有良好的镇痛作用,其镇痛效应可能与抑制CCI大鼠嘌呤能P2X_2受体表达有关。     

Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease

Huntington's disease (HD) is an inherited neurodegenerative disease characterised by cell dysfunction and death in the basal ganglia and cortex. Currently there are no effective pharmacological treatments available. Loss of cannabinoid CB1 receptor ligand binding in key brain regions is detected early in HD in human postmortem tissue [Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience 97:505–519]. In HD transgenic mice environmental enrichment upregulates the CB1 receptors and slows disease progression [Glass M, van Dellen A, Blakemore C, Hannan AJ, Faull RL (2004) Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 123:207–212]. These findings, combined with data from lesion studies have led to the suggestion that activation of cannabinoid receptors may be protective. However, studies suggest that CB1 mRNA may be decreased early in the disease progression in HD mice, making this a poor drug target. We have therefore performed a detailed analysis of CB1 receptor ligand binding, protein, gene expression and levels of endocannabinoids just prior to motor symptom onset (12 weeks of age) in R6/1 transgenic mice. We demonstrate that R6/1 mice exhibit a 27% decrease in CB1 mRNA in the striatum compared to wild type (WT). Total protein levels, determined by immunohistochemistry, are not significantly different to WT in the striatum or globus pallidus, but are significantly decreased by 19% in the substantia nigra. CB1 receptor ligand binding demonstrates significant but small decreases (<20%) in all basal ganglia regions evaluated. The levels of the endocannabinoid 2-arachidonoyl glycerol are significantly increased in the cortex (147%) while anandamide is significantly decreased in the hippocampus to 67% of WT. Decreases are also apparent in the ligand binding of neuronal D1 and D2 dopamine receptors co-located with CB1, while there is no change in GABA_A receptor ligand binding. These results suggest that in this R6/1 mouse colony at 12 weeks there are only very small changes in CB1 protein and receptors and thus this would be an appropriate time point to evaluate therapeutic interventions.     

Time-course of SKF-81297-induced increase in glutamic acid decarboxylase 65 and 67 mRNA levels in striatonigral neurons and decrease in GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, in adult rats with a unilateral 6-hydroxydopamine lesion

Striatal projection neurons use GABA as their neurotransmitter and express the rate-limiting synthesizing enzyme glutamic acid decarboxylase (GAD) and the vesicular GABA transporter vGAT. The chronic systemic administration of an agonist of dopamine D1/D5-preferring receptors is known to alter GAD mRNA levels in striatonigral neurons in intact and dopamine-depleted rats. In the present study, the effects of a single or subchronic systemic administration of the dopamine D1/D5-preferring receptor agonist SKF-81297 on GAD65, GAD67, PPD and vGAT mRNA levels in the striatum and GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, were measured in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion. After a single injection of SKF-81297, striatal GAD65 mRNA levels were significantly increased at 3 but not 72 h. In contrast, striatal GAD67 mRNA levels were increased and nigral alpha1 mRNA levels were decreased at 72 but not 3 h. Single cell analysis on double-labeled sections indicated that increased GAD or vGAT mRNA levels after acute SKF-81297 occurred in striatonigral neurons identified by their lack of preproenkephalin expression. Subchronic SKF-81297 induced significant increases in striatal GAD67, GAD65, preprodynorphin and vGAT mRNA levels and decreases in nigral alpha1 mRNA levels. In the striatum contralateral to the 6-OHDA lesion, subchronic but not acute SKF-81297 induced a significant increase in GAD65 mRNA levels. The other mRNA levels were not significantly altered. Finally, striatal GAD67 mRNA levels were negatively correlated with nigral alpha1 mRNA levels in the dopamine-depleted but not dopamine-intact side. The results suggest that different signaling pathways are involved in the modulation by dopamine D1/D5 receptors of GAD65 and GAD67 mRNA levels in striatonigral neurons. They also suggest that the down-regulation of nigral GABA(A) receptors is linked to the increase in striatal GAD67 mRNA levels in the dopamine-depleted striatum.     

Activation of gamma-aminobutyric acid(A) receptors in the paraventricular nucleus of the hypothalamus reduces apomorphine-, N-methyl-D-aspartic acid- and oxytocin-induced penile erection and yawning in male rats

The effect of muscimol and baclofen injected into the paraventricular nucleus of the hypothalamus on penile erection and yawning induced by apomorphine, oxytocin and N-methyl-D-aspartic acid (NMDA) was studied in male rats. Muscimol (20-200 ng), but not baclofen (200 ng), injected into the paraventricular nucleus of the hypothalamus 10 min before apomorphine (50 ng), oxytocin (10 ng) or NMDA (50 ng) reduced penile erection and yawning induced by the above compounds given into the paraventricular nucleus. Bicuculline (250 ng) injected into the paraventricular nucleus 5 min before muscimol (100 ng) prevented the inhibitory effect of muscimol on penile erection and yawning induced by apomorphine, oxytocin and NMDA. The present results show that gamma-aminobutyric acid (GABA) inhibits penile erection and yawning by acting on GABA(A) receptors in the paraventricular nucleus of the hypothalamus.     

大鼠丘脑前核神经元内γ-氨基丁酸及其受体的表达

目的:探讨大鼠丘脑前核内γ-氨基丁酸(GABA)及其GABAA受体(GABAARα1和β2subunits)的表达,从形态学角度为系统研究丘脑前核的功能提供依据。方法:分别采用包埋后胶体金免疫电镜技术和原位杂交检测丘脑前核内GABA及GABAARα1和β2mRNA的表达。结果:(1)在丘脑前核,GABAARα1和GABAARβ2阳性神经元分布较密集,细胞形态较一致。空白对照切片为阴性,未见GABAARα1和GABAARβ2mRNA表达阳性神经元。(2)GABA胶体金免疫反应切片上,GABA胶体金颗粒浓重标记GrayⅡ型轴突终末,而树突、神经元、胶质细胞及背景标记极少。GABA能阳性轴突终末与中小型树突形成对称性轴-树突触,也与神经元胞体形成对称性轴-体突触。结论:提示在丘脑前核能够合成GABAARα1和GABAARβ2,且GABA能轴突终末与神经元的树突或胞体形成对称性突触。     

Increased vulnerability to 6-hydroxydopamine lesion and reduced development of dyskinesias in mice lacking CB1 cannabinoid receptors

Motor impairment, dopamine (DA) neuronal activity and proenkephalin (PENK) gene expression in the caudate-putamen (CPu) were measured in 6-OHDA-lesioned and treated (l-DOPA + benserazide) CB1 KO and WT mice.A lesion induced by 6-OHDA produced more severe motor deterioration in CB1 KO mice accompanied by more loss of DA neurons and increased PENK gene expression in the CPu. Oxidative/nitrosative and neuroinflammatory parameters were estimated in the CPu and cingulate cortex (Cg). CB1 KO mice exhibited higher MDA levels and iNOS protein expression in the CPu and Cg compared to WT mice.Treatment with l-DOPA + benserazide (12 weeks) resulted in less severe dyskinesias in CB1 KO than in WT mice.The results revealed that the lack of cannabinoid CB1 receptors increased the severity of motor impairment and DA lesion, and reduced l-DOPA-induced dyskinesias. These results suggest that activation of CB1 receptors offers neuroprotection against dopaminergic lesion and the development of l-DOPA-induced dyskinesias.     

Post-training CB1 cannabinoid receptor agonist activation disrupts long-term consolidation of spatial memories in the hippocampus

Cannabinoids have long been associated with mnemonic deficits. However, existing evidence has generally focused on the effect of cannabinoids when they are delivered prior to task-training, and such findings are confounded by possible drug effects on sensory, motor, and/or motivational systems that support the acquisition and the expression of learning. The present study investigated the effects of the CB1-receptor agonist WIN 55,212-2 (WIN) on memory consolidation in the Morris water maze. In experiment 1, systemic injections of either WIN or DMSO vehicle were given daily following each training day (post-training), and rats were probe-tested 1 week or 4 weeks later. Rats injected with 1 mg/kg and 3 mg/kg of WIN spent significantly less time in the target quadrant compared with controls 4 weeks later, while no difference was observed at 1-week retention. In experiment 2, intrahippocampal injections of WIN were administered to the dorsal hippocampus following each training day and rats were again probe-tested 1 week or 4 weeks later. Rats bilaterally infused with WIN at 2.5 microg and 5 microg (per side) during training spent significantly less time in the target quadrant than vehicle controls on probe trial 4 weeks later, while no difference was seen at 1-week retention. Taken together, our results showed that post-training activation of CB1 receptors in the hippocampus disrupts long-term memory consolidation but has no effect on acquisition and short-term retention. Plausible pharmacological interactions between cannabinoids and other neurotransmitter systems and associated plasticity mechanisms are discussed.