We have previously demonstrated that estrogen replacement in ovariectomized rats attenuates behavioral deficits produced by the cannabinoid receptor agonist, Δ9-THC, on a task of learning and memory. In the present experiment we determined if a similar regimen of estrogen replacement would affect levels of cannabinoid receptor binding in the hippocampus. Female rats, age 75 days, were ovariectomized and received subcutaneous implants of 5-mm Silastic capsules containing 100% cholesterol (n = 10) or 25% estradiol diluted in cholesterol (n = 10). Ten days after receiving the capsules, animals were sacrificed and frozen coronal sections (20 µm) were taken through the hippocampus. Sections were incubated with [3H]CP55,940 (10 nM) in order to selectively label CB1 receptors and were exposed to storage phosphor screens for 3 days. Quantitative autoradiography using phosphorimaging technology revealed a significant estrogen-induced downregulation of CB1 cannabinoid receptor density in the CA1 region of the hippoc...

Type 1 cannabinoid receptors (CB1) bind Delta(9)–tetrahydrocannabinol and endogenously released n-acylethanolamines in various regions of the brain, including the brainstem. Cannabinoids have been shown to modify autonomic functions, including feeding behavior, but the central mechanisms underlying of these effects have not been adequately described. Immunoblots using antibodies that recognize the CB1 receptor revealed a major band of ~63 kd in both brainstem and dorsal vagal complex (DVC) tissue microdissected from brainstem slices. To determine if cannibinoids affect synaptic regulation in the caudal dorsal motor nucleus of the vagus (DMV), the effects of a cannabinoid receptor agonist on synaptic input to putative preganglionic DMV neurons were examined using whole-cell voltage-clamp recordings in brainstem slices. WIN-55,212-2 (2-10 uM), decreased spontaneous EPSC (n=14) and IPSC frequency (n=10) and attenuated synaptic responses evoked by glutamate microstimulation of nucleus tractus solitarius (NTS)....

The antinociceptive effects of the cannabinoid agonist delta-9-tetrahydrocannabinol are inhibited by spinal administration of an α²-noradrenergic receptor antagonist (Lichtman & Martin, Brain Res. 559: 309-314, 1991). In the present study, the antinociceptive effects of the cannabinoid agonist WIN55,212-2 were assessed in rats depleted of spinal norepinephrine. The neurotoxin 6-hydroxydopamine (6-OHDA; 20 µg) was administered intrathecally (i.t.) to deplete spinal norepinephrine. Sham-operated rats were treated identically but received the vehicle (10 µl i.t.). After establishing stable baseline responses to thermal stimulation of the tail on the test day, WIN55,212-2 (5 or 10 mg/kg) or vehicle was administered and post-injection tail-flick latencies were recorded. The antinociceptive effects of the cannabinoid agonist were attenuated in rats whose norepinephrine levels were depleted by i.t. administration of 6-OHDA. High performance liquid chromatography was used to quantify monoamine levels in lesioned a...

Cannabinoid receptors have been characterized as two subtypes in mammalian species: CB1 (neuronal) and CB2 (immune). Using an antibody against the N-terminal 14 amino acid domain of the rat/human CB1 receptor, Western blots of Drosophila melanogaster heads revealed a CB1 receptor-like immunoreactive band at 105 kDa. Immunoreactive neurons were identified in the third instar larval and adult brains. The CB receptor agonist radioligand [3H]CP55940 quantitated specific binding in membranes to be 3-fold greater density in heads than in bodies. Heterologous displacement defined potency ratios as: CP55940 > desacetyllevonantradol, Δ9-tetrahydrocannabinol > arachidonylethanolamide. No displacement of [3H]CP55940 by aminoalkylindoles WIN55212-2 or WIN58000, or by aryl pyrazoles SR141716A or SR144528 was observed. Desacetyllevonantradol stimulated [35S]GTPγS binding to G proteins in head membranes under defined ionic conditions; however, this was not antagonized by SR141716A or SR144528. Thus, the recognition...

Alzheimer's disease (AD) is most common neurodegenerative disorder associated with aging, manifest as progressive dementia with extensive cortical atrophy, extracellular amyloid deposits that contain Aβ peptide, and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau. While much progress has been made in clarifying the biology of the Aβ peptide, the regulation of tau processing is less well understood. A recent report suggested that NFT in AD might result from increased activation of CDK5-mediated phosphorylation of tau, a consequence of constitutive activation of the kinase by its regulatory component p25. The present study examines the levels of p25, its precursor p35, and CDK5 in brains of patients with AD, familial AD (FAD), and other neurodegenerative disorders which display NFT such as Down's syndrome (DS), Parkinson's disease (PD), Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). While CDK5 levels we...

Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2′,3′-cyclic nucleotide 3′-phosphodiesterase promoter. Filamentous OLG tau inclusions developed in these Tg mice as a result of human tau expression in OLGs, especially those expressing the FTDP-17 human P301L mutant tau. Notably, structural disruption of myelin and axons preceded the emergence of thioflavin-S positive tau inclusions in OLGs, but impairments in axonal transport occurred even earlier, whereas motor deficits developed subsequently, especially in Tg mice with the highest tau expression levels. These data s...

˝Non-organic failure-to-thrive˝ (NOFTT) afflicts 2-4% of infants and is characterized by low body weight and height for age, without known organic cause. A “biological vulnerability” leading to hypotonia, deficient oral-motor function and impaired suckling has been postulated. Administration of the CB1 receptor antagonist rimonabant caused severe growth failure and death in newborn mice, reversible with Д9-tetrahydrocannabinol (Fride et al., Eur J. Pharmacol. 419:207-14 2001, 461:27-34 2003). Here, we investigated whether neonatal rimonabant may serve as an animal model for NOFTT. One-day-old mouse pups were injected with rimonabant. Nursing-related behaviors were recorded throughout the first 10 days of life. Exp. 1 Motivation to suckle, oral-motor performance and general motor behavior were recorded. The results indicated that motivation was normal, but general and oral-motor performance were significantly impaired. Exp. 2 Some pups were placed at the nipple, thus circumventng the general hypotonia cause...

Two well-characterized cannabinoid receptors (CBrs), CB1 and CB2 mediate the effects of cannabinoids and marijuana use. CB1 receptors are expressed primarily in the brain and in peripheral tissues. Several laboratories have not been able to detect CB2 in brain that are intensely expressed in peripheral and immune tissues and has traditionally been referred to as peripheral CB2 CBrs. In mice the effects of direct CB2 antisense olignucleotide injection into the brain and i.p treatment with JWH015 in motor function and plus-maze tests were evaluated. We also used RT-PCR, immunoblotting, immunohistochemistry, and hippocampal cultures to determine the expression of CB2 CBrs in rat brain and in mice brain exposed to chronic mild stress (CMS) or those treated with cocaine or heroin. JWH015 a CB2 receptor agonist reduced mouse locomotor activities while direct CB2 antisense oligonucleotide microinjection induced anxiolysis. In the CMS animals the expression of CB2 CBrs was enhanced and was modified in the brains o...

Curc and its metabolite, tetrahydrocurcumin (THC) are both anti-inflammatory phenolic antioxidants, which confer significant neuroprotection, for example, in models of neurodegeneration including AD. We examined the bioavailability, anti-inflammatory and anti-amyloidgenic effects of curc and its metabolite with different routes of administration: (chronic oral, COR; gavage, Gav; intra-muscular, IM; or intra-peritoneal, IP) with or without LPS. The low concentration of IP and IM-injected curc and its metabolite resulted in their elevation in plasma and brain by HPLC detection, and significantly reduced (p< 0.05) CNS iNOS production, nitrotyrosine, carbonyls and interleukin-1 β (IL-1 β). QPCR studies showed curc and its metabolite decreased significantly (p< 0.001) LPS induced iNOS mRNA expression and other inflammatory related genes. Higher (1.3 μmoles) Gav doses of curc were required to detect levels in plasma by HPLC, but low doses of curc or its metabolite by Gav still (p< 0.01) reduced iNOS mRNA. Anothe...

### Introduction It is well established that children, adults, and nonhuman animals share a basic ability to perceive and compare nonsymbolic quantities of items, commonly referred to as “numerosity.” Symbolic numerical representations build on these basic abilities to enable human children and