The expression of cannabinoid receptor CB1 in distinct neuronal sub-populations of the central nervous system poses the question which neurons mediate the pharmacological effects of cannabinoids in the brain. To start answering this question, the well-known pharmacological actions of delta-9-tetrahydrocannabinol (THC, the primary psychoactive constituent of marijuana) were tested in conventional CB1 knockout mice and in a number of CB1 conditional knockout mouse lines, lacking the expression of the receptor in different neuronal subpopulations. Mutant and wild-type littermates controls were tested in the so-called behavioural “tetrad” battery of pharmacological effects of THC. Results showed that that GABAergic forebrain interneurons are not required for the manifestation of the typical pharmacological/behavioural symptoms produced by THC treatment: hypolocomotion, hypothermia, catalepsy and increase of nociceptive threshold. In order to control for the physiological functionality of CB1 expression in the ...

The ability of THC and endocannabinoids to stimulate food intake in rats has been demonstrated in recent studies using both peripheral and central administration and a variety of food types. Potential changes in motivational states have been hypothesized to account for some of the cannabinoid-related effects on ingestion. In addition, interactions between cannabinoid and opioid systems that impact ingestive states appear to exist, with synergistic suppression of intake following concurrent administration of antagonists for both CB1 and opioid receptors. The current set of studies first attempted to manipulate the motivational state of Lewis rats by varying the length of pre-drug exposure (prefeed) to food (chocolate cake batter). Duration of prefeed had a pronounced effect on orally-administered THC's ability to stimulate food intake, particularly in comparison to intake following vehicle. Following establishment of a prefeed paradigm in which THC produced reliable significant increases, the ability of, na...

The involvement of dynorphin on Δ-9-tetrahydrocannabinol (THC) and morphine responses has been investigated by using mice with a targeted inactivation of the prodynorphin ( Pdyn ) gene. Dynorphin-deficient mice show specific changes in the behavioral effects of THC, including a reduction of spinal THC analgesia and the absence of THC-induced conditioned place aversion. In contrast, acute and chronic opioid effects were normal. The lack of negative motivational effects of THC in the absence of dynorphin demonstrates that this endogenous opioid peptide mediates the dysphoric effects of marijuana.

MDMA (Ecstacy) is a drug that is widely used by young people in many countries. There is increasing evidence that heavy use of MDMA damages brain serotonin (5-HT) systems, leading to chronic emotional and cognitive problems. We have shown that male Wistar rats briefly exposed to MDMA (4 x 5 mg/kg i.p. over four hours on each of two days) show long term increases in anxiety-like behavior three months after MDMA exposure (Morley et al EJP (2001) 433, 91-99). Human MDMA users frequently consume cannabis while under the influence of MDMA and the present study examined whether this might modulate the long term behavioral and neurotoxic effects of MDMA in rats. The active constituent of cannabis Δ9-THC (4 x 2.5 mg/kg over 4 h) reversed the acute hyperthermic effects of MDMA (4 x 5 mg/kg) on each of two days of administration, with rats given the MDMA/THC combination showing a robust hypothermia. Six weeks later rats that had received the MDMA/THC combination were less anxious on the emergence test than rats that...

Chronic exposure to Δ9-tetrahydrocannabinol (THC) induces tolerance to cannabinoid-induced locomotor effects, which are mediated by cannabinoid receptors (CB1Rs) located in motor control regions, including the cerebellum. There is substantial evidence of cerebellar CB1R molecular adaptation and modifications in receptor signaling after prolonged cannabinoid exposure. However, very little is known about the effects of chronic cannabinoid administration on cerebellar synaptic plasticity, which may contribute to the development of cannabinoid behavioral tolerance. In the cerebellar cortex, activation of CB1R inhibits excitatory synaptic transmission at parallel fiber (PF)–Purkinje cell (PC) synapses by decreasing neurotransmitter release. Our study aimed to investigate the neurophysiological adaptive responses occurring at cerebellar PF-PC cell synapses after repeated THC exposure. In THC-tolerant mice, an increase of the basal release probability was found at PF-PC synapses, in parallel with a facilitation ...

Chronic adolescent exposure to Δ-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. l-Theanine is an amino acid analog of l-glutamate and l-glutamine derived from various plant sources, including green tea leaves. l-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exp...

Alterations of long-term synaptic plasticity have been proposed to participate in the development of addiction. To preserve synaptic functions, homeostatic processes must be engaged after exposure to abused drugs. At the mouse cortico-accumbens synapses, a single in vivo injection of Δ9-tetrahydrocannabinol (THC) suppresses endocannabinoid-mediated long-term depression. Using biochemical and electrophysiological approaches, we now report that 1 week of repeated in vivo THC treatment reduces the coupling efficiency of cannabinoid CB1 receptors (CB1Rs) to Gi/o transduction proteins, as well as CB1R-mediated inhibition of excitatory synaptic transmission at the excitatory synapses between the prefrontal cortex and the nucleus accumbens (NAc). Nonetheless, we found that cortico-accumbens synapses unexpectedly express normal long-term depression because of a reversible switch in its underlying mechanisms. The present data show that, in THC-treated mice, long-term depression is expressed because a presynaptic mG...

The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) in adult brain suggests its important role in a broad range of brain function, but the exact role remains largely unknown. Here we show evidence supporting a direct protein-protein coupling of PTEN with the 3L4F motif in the third intracellular loop of 5-HT2c receptor (5-HT2cR) in PC12 cells. We then design the membrane permeable peptide Tat-3L4F that is able to penetrate the blood brain barrier to disrupt the protein-protein coupling between PTEN and 5-HT2cR in the brain. Systemic Tat-3L4F or the 5-HT2cR agonist Ro600175 (3 mg/kg) suppresses the increased firing rate of VTA (ventral tegmental area) dopamine neurons induced by delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana. Using the conditioned place preference paradigm for behavioural testing, we further show that systemic Tat-3L4F or Ro600175 (3 mg/kg) block the rewarding effects of THC, which is abolished by...

Marijuana (Cannabis sativa) is widely used and can produce dependence as evidenced by withdrawal symptoms upon discontinuation of use. In order to examine tolerance and dependence to the main psychoactive component in marijuana (Δ9-tetrahydrocannabinol, Δ9-THC), the cannabinoid antagonist SR 141716A has been established as a discriminative stimulus in rhesus monkeys treated with 0.56 mg/kg/day of Δ9-THC. Other dependent measures, including directly observable (e.g. eye closing and head shaking) and physiological measures (e.g. body temperature), were assessed in this study to establish whether tolerance and dependence developed to Δ9-THC in the same monkeys (n = 4) that discriminate SR 141716A compared to another group of monkeys (n = 4) that had not received daily Δ9-THC. Acute Δ9-THC (0.56 mg/kg) increased eye closing and decreased body temperature in all monkeys (-1.0 ± 0.2 oC), and these effects were significantly greater in untreated monkeys compared to Δ9-THC-treated monkeys. SR 141716A (3.2 mg/kg) a...

Chronic adolescent exposure to Δ-9-Tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioural abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathological alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. L-theanine is an amino acid analogue of L-glutamate and L-glutamine derived from various plant sources, including green tea leaves. L-theanine has previously been shown to modulate levels of GABA, DA and glutamate in various neural regions and to possess neuroprotective properties. Using a pre-clinical model of adolescent TH...