Summary The active compound in herbal cannabis, D 9 -tetrahydrocannabinol, exerts all of its known central effects through the CB1 cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB1 receptors and the generation of CB1 receptor knockout mice. Particularly important classes of neurons that express high levels of CB1 receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB1 receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB1 receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarizationinduced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, shortterm memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.

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Cannabis and the brain

Early-onset cannabis use and cognitive deficits: what is the nature of the association?

Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats.

Rationale and objective: The present study tested the hypothesis that chronic interference by cann- abis with endogenous cannabinoid systems during peri- pubertal development causes specific and persistent brain alterations in humans. As an index of cannabi- noid action, visual scanning, along with other atten- tional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. Methods: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physi- cal examination, analysis of routine laboratory para- meters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. Results : Of the potential pre- dictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclu- sively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not di⁄er from controls (n = 49). Conclusions: These data suggest that beginning cannabis use during early adolescence may lead to enduring e⁄ects on specific attentional func- tions in adulthood. Apparently, vulnerable periods dur- ing brain development exist that are subject to persistent alterations by interfering exogenous cannabi- noids.

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Specific attentional dysfunction in adults following early start of cannabis use.

During puberty, neuronal maturation of the brain, which began during perinatal development, is completed such that the behavioral potential of the adult organism can be fully achieved. These maturational events and processes of reorganization are needed for the occurrence of adult behavioral performance but simultaneously render the organism highly susceptible to perturbations, such as exposure to psychoactive drugs, during this critical developmental time span. Considering the variety of maturational processes occurring in the endocannabinoid system during this critical period, it is not surprising that the still-developing brain might by highly susceptible to cannabis exposure. Emerging evidence from human studies and animal research demonstrates that an early onset of cannabis consumption might have lasting consequences on cognition, might increase the risk for neuropsychiatric disorders, promote further illegal drug intake and increase the likelihood of cannabis dependence. These findings suggest that young people represent a highly vulnerable cannabis consumer group and that they run a higher risk than adult consumers of suffering from adverse consequences from cannabinoid exposure. The aim of the present review is to provide an overview over the possible deleterious residual cannabinoid effects during critical periods of postnatal maturation and to offer a more precise delineation of the vulnerable time window for cannabinoid exposure.

Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure.

Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.

Residual effects of chronic cannabis treatment on behavior in mature rats.

Chronic oral administration of cannabis extract to rats (daily Δ9tetrahydrocannabinol dose 20 mg/kg) was examined in three experiments for its residual effect on radialarm maze learning following a 1-month drug-free period. Learning a simple eight-arm maze was significantly impaired in rats treated for either 6 months (Experiment I) or 3 months (Experiment II) with the drug. In Experiment III, animals that received the extract for 3 months exhibited significant learning deficits on a much more difficult 12-arm radial maze. The results demonstrate that the deleterious effects of cannabis on radial-arm maze learning are probably due to a tendency toward increased vigilance and perseveration, possibly combined with an impaired utilization of spatial cues.

Learning impairment in the radial-arm maze following prolonged cannabis treatment in rats.

Rats treated chronically with Δ
9-tetrahydrocannabinol (THC, daily oral dose 20 mg/kg) were examined for residual effects on a variety of behaviors following a 1–4 month drug-free period. Learning a 12-arm radial maze and a differential reinforcement of low-rate responding (DRL-20) task was significantly retarded in THC-treated animals, although performance reached control levels by the end of testing. Learning two-way shuttle box avoidance was slightly facilitated in the drug-treated subjects. In open field tests THC-treated rats displayed an initial hypoactivity, followed by hyperactivity, but these changes were not significant. Most of the effects of THC resemble, but are weaker than those of chronic treatment with cannabis extract in a dose containing the same amount of THC. The findings are discussed in terms of the role of other constituents of cannabis that may add to, or potentiate the effects of THC itself.

Behavioral effects of prolonged administration of delta 9-tetrahydrocannabinol in the rat.

Chronic oral administration of cannabis extract to rats (daily Δ9 dose 20 mg/kg) was examined for its residual effect on open field activity and DRL (differential reinforcement of low-rate responding) performance, following a 2–3-month drug-free period. Locomotor activity during the latter part of an open field test was markedly increased in rats previously treated for either 6 months or 3 months with the drug. The same treatments also produced a significant impairment on a DRL-20 task relative to control subjects' performance. These and other findings (impaired maze learning and facilitated two-way shuttle box avoidance) might mean that cannabis produces long-lasting hippocampal, dysfunction in rats.

Residual effects of prolonged cannabis administration on exploration and DRL performance in rats

Chronic oral administration of cannabis extract to rats was examined for its residual effects on shuttle-box avoidance learning. In experiment 1 avoidance learning was assessed in rats that had been tested previosly on other behavioral tests. Chronic treatment (3 months) facilitated the learning of shuttle-box avoidance in cannabis-treated animals relative to vehicle controls. In experiment 2 very similar results were obtained in naive rats. These and other residual effects of chronic cannabis treatment are similar to the effects of hippocampal lesions.

Alexander Stiglick

Papers

Residual effects of chronic cannabis treatment on behavior in mature rats.

Learning impairment in the radial-arm maze following prolonged cannabis treatment in rats.

Behavioral effects of prolonged administration of delta 9-tetrahydrocannabinol in the rat.

Residual effects of prolonged cannabis administration on exploration and DRL performance in rats

Residual effects of prolonged cannabis treatment on shuttle-box avoidance in the rat.