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.

We have recently shown that large doses of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A induces emesis which can be reversed by Δ9-THC and synthetic cannabinoids. Furthermore, low nonemetic doses of SR 141716A block the antiemetic effect of Δ9-THC against cisplatin-induced vomiting. These studies implicate a role for endogenous cannabinoids in emetic circuits in the least shrew (Cryptotis parva). We investigated the role of 2-arachidonoylglycerol (2-AG), anandamide and methanandamide in causing emesis. 2-AG (0.25 - 10 mg/kg, i.p.) caused a dose-dependent increase in both vomiting frequency (ED50 = 1.13±1.1 mg/kg) and percent of shrews vomiting (ED50 = 0.48±3.48 mg/kg) in the 30 min observation period. Both anandamide (2.5 - 20 mg/kg) and methanandamide (5-10 mg/kg) failed to produce a dose-dependent emetic effect. The possible antiemetic action of psychoactive [Δ9-THC (1-5 mg/kg), WIN 55, 212-2 (0.25 - 5 mg/kg) and CP55, 940 (0.025 - 0.1 mg/kg)] and a nonpsychoactive cannabinoid (cann...

The potential of Δ-9-THC to interfere with place conditioning in rats was evaluated in three experiments. Experiment 1 was designed to evaluate the potential of a low dose of THC (0.5 mg/kg, ip) to interfere with the establishment and/or the expression of lithium-induced place avoidance. Since lithium produces nausea, this experiment aimed to evaluate the potential of THC to interfere with unconditioned or conditioned nausea in rats. As measured by resistance to extinction across test trial cycles, pretreatment with THC interfered with (but did not eliminate) lithium-induced place aversion learning without producing place conditioning on its own. In Experiment 2, THC eliminated a weaker lithium-induced place aversion produced by a single conditioning trial cycle. Experiment 3 evaluated whether the interference with place aversion learning was the result of interference with nausea or interference with learning. Rats were pretreated with THC prior to place preference conditioning with amphetamine. Indeed, T...

BACKGROUND AND PURPOSE: Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice. METHODS: Male MCA occluded mice were treated with cannabidiol, abnormal cannabidiol, anandamide, methanandamide, cannabidiol plus capsazepine, and cannabidiol plus WAY100135 before and 3 hours after MCA occlusion. The infarct size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Cerebral blood flow (CBF) was measured at, before and 1, 2, 3, and 4 hours after MCA occlusion. RESULTS: Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume. Moreover, the neuroprotective effect of cannabidiol was inhibited by WAY100135, a serotonin 5-hydroxytriptamine1A (5-HT1A) receptor antagonist but not c...

Chemotherapy patients report not only acute nausea and vomiting during the treatment itself, but also report anticipatory nausea and vomiting upon re-exposure to the cues associated with the treatment. We present a model of anticipatory nausea based on the emetic reactions of the Suncus murinus (musk shrew). Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with each of the principal cannabinoids found in marijuana, δ9-tetrahydrocannabinol or cannabidiol, at a dose that did not suppress general activity. On the other hand, pretreatment with a dose of ondansetron (a 5-HT3 antagonist) that interferes with acute vomiting in this species, did not suppress the expression of conditioned retching during re-exposure to the lithium-paired context. These re...

Cannabis use has been associated with deficits in prefrontal- cortex dependent cognitive processes in humans. We have previously shown that acute administration of Δ9-tetrahydrocannabinol (THC) produces deficits in reversal learning (REV) and the ability to shift attention within a perceptual dimension (intradimensional shift, IDS) in an attentional set shifting task (ASST) (Egerton et al., Program No. 110.15 2003 Abstract viewer/Itinerary Planner. Washington, DC: Society for Neuroscience). However, the human literature suggests that cannabis-induced cognitive deficits are more apparent following chronic use. We therefore employed the ASST to test the hypothesis that a chronic intermittent THC treatment regime would lead to deficits in executive function that were different from those induced by acute treatment. Long Evans hooded rats were administered THC (1mg/kg i.p.) or vehicle once per week for 4 weeks and tested in the ASST 30 minutes after the last dose of THC or vehicle. Chronic intermittent THC pro...

Numerous CNS processes, including neurotransmitter synthesis, gene expression, and cellular proliferation are controlled by neurotransmitters acting through second messenger systems that phosphorylate the transcription factor cyclic AMP response element-binding protein (CREB). Several converging lines of evidence indicate that drug of abuse may exert their profound long-term effects on the CNS by modulating signaling pathways controlling gene expression. Cannabinoids produce locomotor effects that include hypolocomotion, ataxia and catalepsy mediated by CB1 cannabinoids receptors located in motor control regions and cognitive impairment. Since there is evidence that cerebellum have a role not only in motor function but also in cognition, the purpose of the present study was to examine the effect of the Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive component of marijuana, on the phosphorylation of CREB in rat cerebellum, which present an high density of cannabinoids CB1 receptors and to deter...

The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ9-tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ9-tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictiv...

Ventilatory (VE) responses to NaCN injections in the descending aorta of CBD piglets demonstrate plasticity in peripheral chemosensitivity (J.Appl.Physiol. 87:2128-2135, 1999). Further, immunostaining shows an increase in serotonin (5-HT) in the subendothelial and adventitia layers of the same aortic areas after CBD (FASEB J. 15(4):A422, 2001). The present study assesses whether the peripheral chemosensitivity after CBD in the aorta requires 5-HT and if chemosensitivity remains after combined aortic and carotid body denervation (AOD+CBD). In 25 piglets, peripheral chemosensitivity (VE responses) was assessed 3 weeks after carotid and/or aortic, or sham denervation by injections of 6.3 mM NaCN (0.05mg.kg-1) into the jugular vein, common carotid arteries and descending aorta, before (control) and after the IV administration of the 5-HT blockers, metoclopramide (MCP), and methiothepin (MTN). Venous NaCN VE responses did not differ among all groups (p = 0.531) whereas carotid responses were present in SHAM and...

Male rats (n = 9) were trained on the accuracy task (Kubie, et al, Abstracts, Society for Neuroscience, 2003), where rat was rewarded when visiting a target location: a 9 cm diameter unmarked circle in a cylindrical enclosure that had 2 cue-cards (black and white) separated by 90 degrees on the walls. Within 5 min sessions, rats must stand still for 1 sec in the target location in order to receive a reward. We examined the effects of tetrahydrocannabinol (THC) or methylphenidate (MPD) pretreatment on this choice response. Drugs were administered ip in increasing doses 1, 3 and 9 mg/kg/day alternating with saline and each rat received either MPD or THC. Different characteristics were registered – the number of correct choices, number of the rewards, speed and number of walking bouts during the session, median distance to choice center and goal, ratio of events in correct and false goals and others. It was found that methylphenidate slightly improved the accuracy of entering the target location since there w...