One of the more valid animal models of abuse potential and addictive liability of drugs is self-administration. Research employing the self-administration paradigm has yielded advancements in our understanding of both general neural reward mechanisms and more specific effects of cocaine, heroin, nicotine, alcohol, and other common drugs of abuse. However, despite the widespread use and abuse of marijuana in the general public for thousands of years, reliable self-administration of the active chemical, Δ-9-tetrahydrocannibinol (THC), has been achieved only recently and only in a single animal species, namely squirrel monkeys. We present the results of two attempts to train Sprague-Dawley rats to self-administer the drug through chronic indwelling jugular catheters. In the first experiment, rats were trained to self-administer cocaine and then tested daily at various doses of THC dissolved in a solution of saline, Tween-80, and ethanol. In the second experiment, rats were trained to lever press for a sucrose...

Numerous clinical trials have shown that Δ 9-THC and its synthetic analogs (nabilone and levonantradol) are useful antiemetics in patients receiving chemotherapy. However, the receptor mechanism(s) by which cannabinoids prevent chemotherapy-induced emesis remains unknown. Recently, we have shown that the selective CB1 receptor antagonist SR 141716A can produce emesis in the least shrew in a dose-dependent manner when administered either intraperitoneally (ED50 = 5.5 ± 1.2 mg/kg) or subcutaneously (ED50 = 20.2 ± 1, mg/kg). The latter effect was blocked by Δ9-THC. The purpose of the present study was to investigate: 1) if Δ9-THC can prevent cisplatin-induced emesis in the least shrew, and ii) whether the latter antiemetic effect can be prevented by nonemetic doses of SR 141716A. At 0 time, different groups of shrews received varying doses of Δ9-THC (0, 1, 2.5, 5 and 10 mg/kg, i.p.) and an emetic dose of cisplatin (20 mg/kg, i.p.). The frequency of emesis was recorded for the next 60 min. Administration of Δ9...

We aimed to establish the pathogenic basis of the association of the tau gene, MAPT, H1 haplotype with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). EM analysis of HapMap SNP data for MAPT, showed considerable diversity of the H1 clade with 21 rare (<5%) and 3 common (>10%) haplotypes. Only one of the latter represents H2. We then typed a set of 6 haplotype-tagging SNPs (htSNPs) capturing most of this diversity, in large PSP and CBD case-control cohorts of UK and US origin. We confirmed the strong association with PSP of the H1 haplotype (UK PSP: p=1.14x10-5; US PSP: p=4.02x10-8). In PSP we identified differences in association of the H1H1 genotype between Richardson’s syndrome, RS (OR 13.2; 95%CI 3.0-57.2; p<0.001) and PSP-parkinsonism, PSP-P (OR 4.5; 95%CI 1.3-16.0; p=0.018)1. The H2 haplotype is negatively associated, ie is protective (UK PSP: p=1.1x10-5; US PSP: p=4.02x10-8). The H1-specific htSNPs, rs242557 and rs2471738, are highly associated with PSP and CBD (UK PSP: p=0....

Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic eff...

The active principle of marijuana, delta-9-tetrahydrocannabinol (Δ9-THC), exerts its pharmacological effects throught selective cannabinoid receptors. The cannabinoid receptor CB1 is expressed in the nervous system and is densely located in basal ganglia, a group of brain nuclei that includes substantia nigra compacta and subthalamic nucleus and is involved in motor activity. The present study sought to determine the role of subthalamic nucleus in the Δ9-THC effect on nigral dopamine neuron activity by extracellular recording techniques in anaesthetized rats. Systemic administration of Δ9-THC (0.25-2 mg/kg) stimulated substantia nigra compacta neurons (by a 33.54 ± 8.63% n= 8). This stimulatory effect was completely abolished by previous blockage of excitatory amino acid receptors after kynurenic acid application (0.5 µM, i.c.v.; n=5). Similarly, destruction of the ipsilateral subthalamic nucleus by chemical lesion with ibotenic acid (10 µg/ml, 5 µl) completely blocked Δ9-THC effect (n=5). Neither kynureni...

Δ9-Tetrahydrocannabinol (THC), the psychoactive ingredient of cannabis, induces apoptosis in cultured cortical neurons prepared from neonatal rats1. However there is no evidence to suggest that THC is toxic to adult neurons2. This study was aimed at determining if post-natal development of the rat cortex influenced the ability of THC to activate components of the THC-induced apoptotic cascade in the rat cortex in vivo. Neonatal (4 day-old) and adult (3 month-old) male Wistar rats were anaesthetized by intraperitoneal injection of urethane (1.5g/kg). The THC group received subcutaneous injections of 10mg/kg THC in vehicle and the control group received injections of vehicle only (5% absolute alcohol, 5% Cremophor EL and 90% saline). Three hours later rats were killed humanely, half the cortex dissected and cortical slices prepared, and the other half brain frozen and prepared for cryostat sections. JNK activity was assessed by immunocytochemistry. Caspase-3 activity was measured using a fluorogenic assay an...

Using the rat conditioned gaping model of nausea, the interoceptive insular cortex (IIC) has been identified as a critical site for the regulation of lithium chloride (LiCl)-induced nausea. Indirect evidence supports a model where serotonin (5-HT) acts on postsynaptic 5-HT3 receptors and its release is suppressed by elevating 2-arachidonylglycerol (2-AG) by monoacylglycerol lipase (MAGL) inhibition to suppress nausea. Here, we directly test the hypothesis that systemic LiCl elevates 5-HT in the IIC, and this is prevented by pretreatments that reduce 5-HT release. Using male Sprague Dawley rats, LiCl (but not saline), elevated 5-HT selectively in the IIC, for 20 min after LiCl administration (127.2 mg/kg, i.p.). Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the LiCl-induced elevation of 5-HT in the IIC. Systemic cannabidiol (CBD), which reduces LiCl-induced nausea by acting at 5-HT1A somatodendritic autoreceptors, also prevented LiCl-induced elevation of 5-HT in the IIC. Since 5-HT3 recep...

Recent research has suggested that marijuana use is associated with volumetric and shape differences in subcortical structures, including the nucleus accumbens and amygdala, in a dose-dependent fashion. Replication of such results in well controlled studies is essential to clarify the effects of marijuana. To that end, this retrospective study examined brain morphology in a sample of adult daily marijuana users ( n = 29) versus nonusers ( n = 29) and a sample of adolescent daily users ( n = 50) versus nonusers ( n = 50). Groups were matched on a critical confounding variable, alcohol use, to a far greater degree than in previously published studies. We acquired high-resolution MRI scans, and investigated group differences in gray matter using voxel-based morphometry, surface-based morphometry, and shape analysis in structures suggested to be associated with marijuana use, as follows: the nucleus accumbens, amygdala, hippocampus, and cerebellum. No statistically significant differences were found between da...

Cannabinoid receptors are abundant in the frontal cortex and hippocampus, areas crucial for attentional control, working memory (WM), and the creation of more lasting memories. Although knowledge of marijuana's neurobiological effects has proliferated, research on marijuana's impact on human cognitive brain function has not progressed as quickly. To examine marijuana’s effects on neurophysiological measures of working and recent memory, a double-blind, counterbalanced study was performed in which 40-channel EEG recordings were obtained from N=10 casual marijuana users before and after smoking active (3.45% THC) or placebo (0.006% THC) marijuana. A spatial N-back task was used to measure WM ability. Intermediate-term memory over a period of 5-10 minutes was measured with a word recognition task. Objective and subjective measures of intoxication increased after smoking marijuana, but alertness and motivation were unchanged. After smoking marijuana reaction time in the WM task increased, as did EEG alpha (8-1...

The present study investigated the potential of various doses of delta-9-tetrahydrocannabinol (THC), Ondansetron (5-HT3 receptor antagonist, OND) and a combined pretreatment of OND and THC to suppress cisplatin-induced emesis in the Suncus murinus. OND and THC both dose-dependently suppressed cisplatin-induced vomiting and retching. Furthermore, a combined pretreatment of doses of the two drugs that were ineffective alone (0.02 mg/kg OND and 1.25 mg/kg THC) completely suppressed vomiting and retching. This suggests that a combination of lower doses of these agents may be an effective alternative treatment for vomiting that may have fewer side effects than higher doses of either agent alone.