In previous studies, we found that THC and capsaicin can protect AF5 cells from NMDA-induced cell toxicity, an effect apparently related to antioxidant properties of these compounds (Chen J, et al., in preparation). We have investigated the signaling pathways involved in neuroprotection against NMDA-induced toxicity mediated by THC and capsaicin in AF5 cells. Gene expression profiles were studied using a mouse developmental cDNA microarray. Expression of the 14-3-3 transcript was altered after exposure to NMDA alone, NMDA plus cannabinoids, or capsaicin. The 14-3-3 transcript was decreased by 2.14-fold after exposure to 7.5 mM NMDA as compared to the untreated control condition, while THC increased 14-3-3 expression by 3.08 fold as compared to NMDA alone. Capsaicin also significantly increased the 14-3-3 transcript, but to a smaller degree than THC. WIN55,212 produced no significant change. Changes in 14-3-3 expression measured by Q-PCR were consistent with those obtained using microarrays. The 14-3-3 prot...

The biochemical substrates underlying rewarding effects of Δ9-tetrahydrocannabinol (THC) are poorly understood. We analyzed intracellular signaling pathways mediating immediate early gene expression (c-Fos and Zif 268) after acute administration of THC in striatal neurons. In male CD1 mouse brain, immunohistochemical detection of phosphorylated ERK/MAPK proteins showed a progressive but transient activation of this pathway in the striatum. Activation of ERK occurred in both striatal neurons and the neuropil surrounding these activated neurons, suggesting a pre- and post-synaptic activation of this signaling pathway. A systemic injection of a specific inhibitor of ERK/MAPK (SL 327) prevented THC-induced expression of c-Fos and Zif 268. As previous reports show that THC induces DA release in the striatum, we then analyzed whether DA transmission played a role in these molecular events. We found that injection of a selective antagonist of DA-D1 receptors (SCH 23390), prior to THC administration, prevented ERK...

The potential of repeated exposure to delta-9-tetrahydrocannabinol (THC) to produce long lasting changes in synaptic connections in a manner similar to other drugs of abuse was evaluated in Sprague-Dawley rats. For 14 days, rats received two intraperitoneal injections per day (8 hr apart) of vehicle, a low dose of THC (0.5 mg/kg) or escalating doses of THC (0.5 – 4.0 mg/kg). Thirty days later, they were evaluated for sensitized locomotor activity (during the night cycle) for 60 min on each of three trials. Using a within-groups design, rats were tested following an injection of vehicle, 0.5 mg/kg THC or 2.0 mg/kg. The rats showed no evidence of sensitized locomotor activity in any group. On Day 33, their brains were removed and then processed for Golgi-Cox staining. Prior exposure to THC (both the low dose and the escalating doses) increased the length of the dendrites as well as the number of dendritic branches in the shell of the nucleus accumbens and in the medial prefrontal cortex. There were no signif...

Increased eating is a common effect of systemically-administered cannabinoid drugs in both humans and rats. Microinjections of these drugs into the nucleus accumbens shell (NAc) and other brain areas can also increase feeding in rats. The psychological mechanism of these effects is as yet unknown, however. In particular, it is unknown whether cannabinoids actually increase palatability of tastes (‘liking’), beyond elevating food intake. The taste reactivity test is a useful way to assess changes in hedonic impact of taste palatability in rats. In these experiments, we tested whether intra-nucleus accumbens microinjections of anandamide altered positive hedonic reactions (e.g. tongue protrusions, paw licking) elicited by oral infusions of sucrose solution. We then compared these hedonic effects to effects of the same microinjections on food intake. These results provide insight into the involvement of NAc cannabinoid receptors in food ‘liking’ vs. ‘wanting.’.

To estimate the effects of Delta-9-THC on locomotion activities, we used multiple-channel, single unit recording technique to investigate the neuronal activity in the dorsal striatum, the globus pallidus, the subthalamic nucleus and the substantia nigra pars reticulata during freely moving and treadmill locomotion tasks in rats. Sixty-four stainless steel microwires were implanted in those brain areas and neuronal activity were recorded simultaneously with a 64 channel recording device. Six infrared beams were used to measure the locomotion activity in the open field condition. Delta-9-THC pre-treatment (0.05-2.0mg/kg, i.p.) caused a decrease in locomotion activity in a clear dose dependent manner. Delta-9-THC treatment resulted in significant inhibition in the neural activities across all four basal ganglia areas recorded in the freely moving conditions. A treadmill task was employed to test the actions of Delta-9-THC in different behavioral contexts. Each trial consists of 20 seconds walking followed by ...

Memory deficits produced by marijuana are thought to arise, in part, via the interaction of the psychoactive component, Δ9-THC, with cannabinoid (CB) receptors located in the hippocampus. Whereas CBs acutely disrupt synaptic transmission and hippocampal long-term potentiation (LTP), a putative synaptic correlate of memory, the consequences of prolonged exposure to Δ9-THC on hippocampal function are less well understood. Sprague Dawley (SD) rats were treated once daily for 7 days with either a vehicle control solution or Δ9-THC (10 mg/kg). Hippocampal brain slices were prepared approximately 24 hours following the final treatment, and electrophysiological recordings were performed in the CA1 region. Relative to vehicle-treated controls, repeated Δ9-THC treatment completely blocked the LTP generated by both high-frequency stimulation(HFS, 100 Hz) and by a theta-burst stimulation protocol. Tolerance to the inhibitory effects of the CB agonist WIN55,212-2 was observed at GABAergic, but not glutamatergic, synap...

Recent evidence suggests that toxin-induced taste avoidance in the non-emetic rat is not mediated by conditioned sickness. However, it is possible that toxin-induced taste avoidance in an emetic species is mediated by conditioned sickness. The present experiments evaluated the potential of the anti-emetic agents, ondansetron (OND) and delta-9-tetrahydrocannabinol (THC) to interfere with lithium (LiCl)-induced taste avoidance in the house musk shrew (Suncus murinus). In Experiment 1, shrews were pretreated with OND (1.5 mg/kg) or Saline 30 min prior to drinking 0.1% saccharin solution then they were injected with LiCl (390 mg/kg) or saline. When assessed by a two-bottle test over a 12 hr period, but not a one bottle test, the shrews displayed a LiCl-induced saccharin avoidance that was prevented by pretreatment with OND. The relatively weak effects may have been due to floor effects in consumption of saccharin solution; therefore a highly preferred 32% sucrose solution was used in another experiment. In Exp...

Marijuana is the most widely used illicit substance in the USA, and there is no effective medication available to treat marijuana abuse. Delta-9-tetrahydrocannabinol (THC), the active constituent in marijuana, significantly stimulates the brain mesolimbic dopamine (DA) system and enhances brain stimulation reward. We have previously shown that blockade of brain DA D3 receptors by SB-277011A significantly attenuates cocaine- or nicotine-enhanced brain reward, cocaine self-administration, cocaine- or heroin-conditioned place preference, and cocaine- or nicotine-induced reinstatement of drug-seeking behavior (Heidbreder, et al, 2005). In the present study, we investigated whether SB-277011A inhibits THC-enhanced brain stimulation reward and THC-induced increase in DA in the nucleus accumbens. THC (0.25 mg/kg i.p.) reliably shifted brain-reward stimulation curves to the left, lowering stimulation thresholds by around 15% in male Lewis rats. SB-277011A (3-12 mg/kg i.p., 1 hour prior to THC) dose-dependently blo...

5-HT3 receptor agonists produce vomiting in the least shrew whereas 5-HT2A agonists induce the head-twitch response (HTR) in this species. Both behaviors were induced by the 5-HT precursor 5-hydroxytryptophan (5-HTP) in the absence and presence of a peripheral decarboxylase inhibitor, carbidopa (10 mg/kg). The aim of this study was to investigate: 1) whether Δ9-THC can prevent the induced behaviors, and 2) if the inhibitory effects are CB1 receptor-mediated. 5-HTP (0, 10, 50 and 100 mg/kg, i.p.) increased the frequencies of vomiting and HTR in shrews in a dose-dependent manner both in the absence and presence of carbidopa. However, in the presence of carbidopa the number of HTRs produced were 2-6.5 fold greater whereas the frequency of observed vomiting tended to be less. Two doses of 5-HTP (50 and 100 mg/kg) were chosen to determine the inhibitory action of Δ9-THC (1, 2.5, 5, 10 and 20 mg/kg) on the induced behaviors in the absence and presence of carbidopa. Lower doses of Δ9-THC were required to signific...