The effects of cannabinoids on the brain

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Abstract

Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is Δ9-tetrahydrocannabinol (Δ9-THC).

In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed Δ9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus.

The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densitities in the hippocampus, cerebellum and striatum.

The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase.

The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase.

The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana.

Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimibic dopamine system.

Introduction

The hemp plant, Cannabis sativa, has been used for over 4000 years as a recreational drug due to its mind-altering effects. Marijuana, the common name for cannabis, is by far the most commonly used street drug world wide today. However, since the 4th century BC, it also has been employed as a therapeutic drug. No other drug of abuse arouses greater controversy than cannabis. The public debate centers upon the possible legalization of the cannabis use, at least for therapeutic use. There are a number of well-proofed and potential therapeutic actions of cannabinoids, such as antiemetics, analgesia, anticonvulsant action and lowered intraoccular pressure (Hollister, 1986). More recently, its use as an appetite stimulant has been indicated in patients with cachexia or wasting disease such as AIDS (Timpone et al., 1997; Volicer et al., 1997). Unquestionably, existence of psychoactive effects, development of tolerance and the abuse potential of cannabinoids have discouraged their therapeutic use.

Due to the cloning and characterization of specific cannabinoid receptors, the discovery of endogenous cannabimimetic compounds and the availability of selective receptor antagonists, our knowledge of the mechanisms of action of cannabinoids has been greatly increased during the last few years. It is the aim of the present review to present the most important breakthroughs which leads to a better understanding of the actions and risks of cannabinoids. The principle psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC), as well as structurally related cannabinoids are highly lipophilic molecules which exert their central effects by binding at specific membrane receptors, the CB1 cannabinoid receptors. Beside their central effects, cannabinoids possess several peripheral effects, which are believed to be mediated by another type of cannabinoid receptor, the CB2 receptor. Recent advances in characterizing these cannabinoid receptors as well as their signal transduction mechanisms involved will be presented in the present review. A further concern will be the import discovery of the endogenous cannabimimetic system in the brain. The possible physiological role of the two endogenous cannabimimetic compounds, the eicosanoid anandamide (Devane et al., 1992), and the more recently identified 2-arachidonylglycerol (Mechoulam et al., 1995; Stella et al., 1997) will be discussed with regard to a potentially modulation of pain perception and memory.

Section snippets

Active ingredients

The flowering tops and leaves of the plant C. sativa secret a resin containing about 60 terpenophenolic compounds which are called cannabinoids. The highest amount of cannabinoids has been found in the flowering tops, followed by the leaves, whereas only small amounts are found in stem and roots. The seed does not contain any cannabinoids. Preparations, such as marijuana, which is made from dried leaves and tops of the plant, have a lower cannabinoid content than hashish, which is a preparation

Cannabinoid receptors

Since the major psychoactive constituent of marijuana, Δ9-THC, as well as other cannabinoids are highly lipophilic molecules, it was believed for a long time that the effects elicited by these compounds are due to a non-specific interaction with the membrane lipids and alteration of membrane fluidity. Speculation about the cellular actions of cannabinoids was finally resolved when functional inhibition of adenylate cyclase was observed following the addition of Δ9-THC to neuroblastoma cells (

Endogenous cannabinoids

The identification, pharmacological characterization, and localization of specific membrane receptors mediating the central and peripheral effects of the active principle of marijuana, Δ9-THC, and other cannabinoids raised the question about the existence of endogenous cannabinoid agonists to which the receptors must respond, similar to the existence of endogenous ligands for the opiate receptors. The only endogenous substances isolated and characterized so far that are capable of mimicking the

Modulation of neuronal activity in distinct brain region

This section focuses on the effects induced by cannabinoids via modulation of three main transmitters, glutamate, dopamine, and GABA, in such brain regions known to possess a high density of CB1 receptors and to be involved in some of the characteristic effects of marijuana.

Future directions

Cannabis does not appear to be a harmless recreational drug. Acute intoxication is characterized by euphoria, loss of short-term memory, stimulation of the senses, and impaired linear thinking. Depersonalization and panic attacks are adverse effects. Increased heart rate, reddened conjunctivae and immunosuppression are common peripheral effects. Chronically consumed high doses may cause impairment of cognitive abilities that are appear to be long-term, or even persistent.

The public debate

Unlinked references

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