The effect of the cannabinoid, Δ9-THC, on conditioned and unconditioned sickness was evaluated in the Suncus murinus, an emetic species. Experiment 1 demonstrated that, at the doses tested, THC did not suppress unconditioned vomiting elicited by lithium chloride. In a drug-free test of conditioned sickness, Experiment 2 revealed that shrews displayed conditioned gaping (a precursor to vomiting) when subsequently exposed to the lithium-paired chamber. THC suppressed conditioned gaping. These results support anecdotal suggestions that THC may reduce conditioned nausea in humans.

CB1 cannabinoid receptors are G-protein-coupled receptors that primarily activate Gi/Go. CB1 receptors are abundant in the CNS, where they mediate the effects of psychoactive cannabinoids such as Δ9-tetrahydrocannabinol (THC) and endocannabinoid lipid messengers. Our previous studies have shown that chronic THC administration in mice produces widespread desensitization and downregulation of CB1 receptors in the CNS, with hippocampus exhibiting profound CB1 receptor adaptation. The present study examined the mechanism of CB1 receptor downregulation in brain. THC was administered by subcutaneous injection twice daily using an escalating dosage paradigm in which the dose was ramped from 10 to 160 mg/kg over 15 days. Results showed that CB1 receptor-mediated G-protein activation was reduced by approximately 50% in THC-treated mice compared to control, as determined by agonist-stimulated [35S]GTPγS binding in hippocampal or striatal membranes. CB1 receptor binding sites measured with the antagonist [3H]SR141716...

There remains debate regarding the impact of cannabis on neuropsychiatric disorders. Here, we examined the effects of cannabidiol (CBD), a nonpsychoactive constituent of cannabis, on heroin self-administration and drug-seeking behavior using an experimental rat model. CBD (5–20 mg/kg) did not alter stable intake of heroin self-administration, extinction behavior, or drug seeking induced by a heroin prime injection. Instead, it specifically attenuated heroin-seeking behavior reinstated by exposure to a conditioned stimulus cue. CBD had a protracted effect with significance evident after 24 h and even 2 weeks after administration. The behavioral effects were paralleled by neurobiological alterations in the glutamatergic and endocannabinoid systems. Discrete disturbances of AMPA GluR1 and cannabinoid type-1 receptor expression observed in the nucleus accumbens associated with stimulus cue-induced heroin seeking were normalized by CBD treatment. The findings highlight the unique contributions of distinct canna...

Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined with in vivo single-unit neuronal electrophysiology recordings in the ventral teg...

Marijuana is one of the most widely abused illicit drugs and is known to cause significant cognitive impairments. It has been hypothesized that marijuana may preferentially target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana’s more subtle effects on neural mechanisms subserving cognitive functions. To this end, we examined the effects of different doses and treatment regimens (both acute and chronic) of delta-9-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the mouse dentate gyrus (DG), using the bromodeoxyuridine method (BrdU; 200 mg/kg, i.p; 2 h survival time). Administration of THC produced marked dose- and time-dependent behavioral sedation and catalepsy. The number of BrdU labeled cells was not significantly changed from vehicle contr...

Evidences suggest that both single and repeated exposure to addictive drugs can alter synaptic plasticity in the brain reward pathway. Despite its widespread use, the effects of cannabis derivatives on synaptic transmission and plasticity remain poorly understood. We evaluated the consequences of single and repeated in-vivo exposure to Δ9-Tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis, in the nucleus accumbens (NAc), a key structure of the brain reward pathway where we have previously described an endocannabinoid mediated long-term depression (eCB-LTD) induced by sustained cortical activation (10 min @ 13Hz) (Robbe et al., 2002). First, we found that a single exposure of mice to a non-aversive dose of THC (3mg/kg) abolished the retrograde signalling responsible for eCB-LTD one day after in-vivo treatment. This effect was reversed within three days and associated with a marked functional desensitization of cannabinoid CB1 receptors (Mato et al., 2004). Second, we found that af...

Delta-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of marijuana and is thought to be responsible for acute and long-term behavioral effects seen in humans potentially through a dysfunction of the frontal cortex. In the rat, acute exposure to THC increases cortical dopamine (DA) turnover and disrupts short-term memory (Neuropsychopharm 16:426-432, 1997). In this current study, we examined the effects of a single dose of THC on midbrain DA neurons in non-human primates using the immediate-early gene, c-fos, as an indicator of the initiation of long-term adaptation brought on by acute activation. Twelve male, adult African green monkeys of St Kitts origin (Cercopithecus aethiops sabaeus) were given a single injection of vehicle or THC, 1.25 mg/kg or 2.5 mg/kg. After 1 hour, the monkeys were overdosed on pentobarbital, perfused with saline, and the brains were placed in 4% formalin for 24 hours. The midbrains were cut into 50 μm sections and stained for Fos-immunoreactivity (Fos-ir) and t...

Although Δ9-tetrahydrocannabinol (THC) produces analgesia, its effects on nociceptive primary afferents are unknown. These neurons participate not only in pain signaling but also in the local response to tissue injury. Here, we show that THC and cannabinol induce a CB1/CB2 cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves. Other psychotropic cannabinoids cannot mimic this action. The vanilloid receptor antagonist ruthenium red abolishes the responses to THC and cannabinol. However, the effect of THC on sensory nerves is intact in vanilloid receptor subtype 1 gene knock-out mice. The THC response depends on extracellular calcium but does not involve known voltage-operated calcium channels, glutamate receptors, or protein kinases A and C. These results may indicate the presence of a novel cannabinoid receptor/ion channel in the pain pathway.

Delta 9-tetrahydrocannabinol (Δ9-THC) is the active chemical in cannabis. To better understand the central effects of Δ9-THC, we sought to identify brain areas and neuronal populations responsive to acute and chronic administration of different doses of Δ9-THC. We used c-Fos positive immunoreactivity as a marker for Δ9-THC-responsive neurons. Acute Δ9-THC treatment. Rats were habituated to vehicle injections for 2 weeks, and killed two hours after receiving an IP injection on the 15th day of either vehicle or Δ9-THC (5 or 10 mg/kg). Brains were processed for immuno-detection of c-Fos. Δ9-THC induced c-Fos expression in the central nucleus of the amygdala (CNA). All rats treated with 10 mg/kg showed high levels of c-Fos expression, the lower dose (5 mg/kg) induced variability of c-Fos expression in the CAN. These results may indicate variability in the rat population in response to low doses of acute Δ9-THC. Chronic Δ9-THC treatment. Rats were injected for 2 weeks with daily single injections of 5 or 10 mg/...

Chronic Δ9-tetrahydrocannabinol (Δ9-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study uses in vitro autoradiography of agonist-stimulated [35S]GTPγS binding to localize cannabinoid receptor-activated G-proteins after chronic Δ9-THC treatment. Cannabinoid (WIN 55212-2)-stimulated [35S]GTPγS binding was performed in brain sections from rats treated chronically with 10 mg/kg Δ9-THC for 21 d. Control animals received saline or an acute injection of Δ9-THC. Acute Δ9-THC treatment had no effect on basal or WIN 55212-2-stimulated [35S]GTPγS binding. After chronic Δ9-THC treatment, net WIN 55212-2-stimulated [35S]GTPγS binding was reduced significantly (up to 70%) in most brain regions, including the hippocampus, caudate-putamen, perirhinal and entorhinal cortex, globus pallidus, substantia nigra, and cerebellum. In contrast, chronic Δ9-THC treatment had no effect on GABAB-stimulated [35S]GTPγS bindi...