Working memory is an executive function that orchestrates the use of limited amounts of information, referred to as working memory capacity, in cognitive functions. Cannabis exposure impairs working memory in humans; however, it is unclear whether Cannabis facilitates or impairs rodent working memory and working memory capacity. The conflicting literature in rodent models may be at least partly because of the use of drug exposure paradigms that do not closely mirror patterns of human Cannabis use. Here, we used an incidental memory capacity paradigm where a novelty preference is assessed after a short delay in spontaneous recognition-based tests. Either object or odor-based stimuli were used in test variations with sets of identical [identical stimuli test (IST)] and different [different stimuli test (DST)] stimuli (three or six) for low-memory and high-memory loads, respectively. Additionally, we developed a human-machine hybrid behavioral quantification approach which supplements stopwatch-based scoring ...

Due to the legalization of Cannabis in many jurisdictions and trend of increasing THC content in Cannabis products, an urgent need exists to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we exposed female Sprague-Dawley rats to Cannabis smoke daily from gestational days 6 to 20 or room-air. Maternal reproductive parameters, offspring behavior, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis -exposed litters. In adulthood, male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. Ge...

Because of the legalization of Cannabis in many jurisdictions and the trend of increasing Δ9-tetrahydrocannabinol (THC) content in Cannabis products, an urgent need exists to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we exposed female Sprague Dawley rats to Cannabis smoke daily from gestational day 6 to 20 or room air. Maternal reproductive parameters, offspring behavior, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis -exposed litters. In adulthood, male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantl...

Evidence suggests that the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) differentially regulate salience attribution and psychiatric risk. The ventral hippocampus (vHipp) relays emotional salience via control of dopamine (DA) neuronal activity states, which are dysregulated in psychosis and schizophrenia. Using in vivo electrophysiology in male Sprague Dawley rats, we demonstrate that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma and ε oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1–2). Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD coadministration reverses these changes by downregulating pERK1–2 signaling, as pharmacological reactivation of pERK1–2 blocked the inhibitory properties of CBD. These results identify vHipp...

Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 \[2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e\]\[1,2,4\]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purin...

Marijuana and its principal psychoactive component, THC, produce characteristic behavioral and physiological effects in humans. However, THC's sites of action in the human brain and their relationships to the drug's actions are not yet well understood. We have previously demonstrated using BOLD fMRI imaging that THC produced dose-related alterations in brain function in several brain regions including nucleus accumbens, amygdala, anterior cingulate, and cerebellum. The purpose of the this study was to determine the relative contributions of neuronal and non-neuronal factors to the observed BOLD signal changes. With that in mind, we examined the effects of THC on cerebral blood flow using arterial spin labeling. Chronic marijuana users were injected iv with THC (0, 0.5, 1, and 3 mg over one-minute in an ethanol vehicle) while undergoing fMRI scanning. A single 8 mm slice containing motor cortex was imaged during rest and motor cortex activation (finger tapping). We found the average flow in the slice at res...

The abuse potential of marijuana in humans is well established but scientific evidence for reinforcing properties of its psychoactive constituent delta-9-tetrahydrocannabinol (THC) in animals is lacking. In the present experiments, high rates of self-administration behavior were consistently maintained in squirrel monkeys by intravenous injections of THC. Mean rates of responding ranged from 0.1 to 0.4 response/sec during daily 1-hr sessions, using a fixed-ratio 10, time-out 60 sec, schedule of i.v. THC injection with doses of 2 to 4 mcg/kg/injection. A second-order, fixed-interval schedule with fixed-ratio components was also studied, in which THC was repeatedly injected only at the end of each daily session in association with a brief visual stimulus (each completion of a fixed-ratio unit during a 30-min fixed interval produced only the brief visual stimulus). Mean rates of responding ranged from 0.06 to 0.2 responses/sec when 10 consecutive injections of 2 to 4 mcg/kg/injection THC spaced 2-sec apart en...

We have previously reported PET rCBF data from 5 volunteers following smoking of a marijuana cigarette (SNS 1998). The present study measured rCBF with PET using [O-15]water in 12 new volunteers (6M, 6F) who were occasional recreational users of marijuana. Subjects were imaged prior to and following smoking of a marijuana (20 mg THC) and placebo (marijuana with THC removed) cigarette as they repeatedly performed an auditory attention task. A double-blind design was used with order of THC and placebo counterbalnced across subjects. Subtraction of the post-placebo from the post-THC condition revealed dramatic rCBF increases in orbital frontal cortex, anterior cingulate, temporal pole, insula, and lateral cerebellum. Smoking marijuana decreased rCBF in L heschl’s gyrus, primary visual cortex, and a number of frontal regions (BA4, 6, 8, 10). Ventral brain regions showing increased rCBF may mediate the intoxicating and mood-related effects of smoking marijuana. The rCBF decreases in primary sensory cortices and...

Recent findings have provided the existence of a functional interaction between opioid, dopaminergic and cannabinoid systems on addictive related behaviours. We have analysed the consequences of nicotine administration on the behavioural responses induced by Δ9-tetrahydrocannabinol (THC). For this purpose, we have administrated THC (5 or 10 mg/kg) and nicotine (0.5 mg/kg) and evaluated acute responses, the development of tolerance and the somatic expression of THC withdrawal. Nicotine strongly potentiates hypothermia, antinociceptive responses and the decrease of locomotor activity induced by an acute injection of THC. The development of tolerance to THC responses was also modified by nicotine. Indeed, animals treated with THC alone developed a rapid tolerance to all the acute pharmacological responses. In contrast, the co-administration of nicotine decreased the degree of THC tolerance. Acute injection of the CB1 receptor antagonist SR 141716A (10 mg/kg) in THC-dependent mice precipitated somatic signs of...

E. Downer and V. Campbell. * Dept. of Physiology, Trinity College Dublin, Ireland. Δ9-Tetrahydrocannabinol (THC), the principle psychoactive component of marijuana, elicits diverse psychological effects in humans. At a cellular level THC has been shown to have both neurotoxic1 and neuroprotective effects2. The aim of this study was to examine the role of the stress activated protein kinase (SAPK) c-jun N-terminal kinase (JNK) in THC-induced neurotoxicity in cortical neurones. Treatment of cultured cortical neurones with THC (5µM) for 2h resulted in a 49% increase in genomic DNA strand breaks as assessed by TUNEL staining (p<0.01, paired t-test, n=10). Use of a fluorogenic assay has revealed that caspase-3 activity is increased from 13±6 pmol AFC produced/mg/min (mean±SEM) to 24±8 pmol AFC produced/mg/min following treatment of neurones with THC for 2h. Western Blot analysis showed that cell death was preceded by JNK activation (p<0.05, ANOVA, n=6). The specific role of JNK in this system was assessed by do...