By Dean Haycock
Special To BioWorld Today
To politicians and law-enforcement officers, it a threat and a scourge to be eliminated. To many biomedical researchers, it is a promising source of new drugs if its psychoactive effects can be dissociated from its therapeutic effects. Marijuana and its active ingredients, cannabinoids, are still trapped in a mire of politics and misunderstanding, despite strong indications that they may be a source of appetite-enhancing, anti-emetic, analgesic and anti-inflammatory compounds.
Last year, neuropharmacologist Daniele Piomelli, a leading figure in cannabinoid research, expressed a sentiment shared by many in his field.
¿The problem for me,¿ he told BioWorld Today, ¿is that, as a pharmacologist, I find it hard to believe that in 1997, people would want to take a whole plant and smoke it as a means of providing medicinal entities. In 1997, it seems we ought to be able to do something better than that. One reason we haven¿t is because we don¿t understand the cannabinoid system very well in the first place.¿ (See BioWorld Today, Aug. 21, 1997, p. 1.)
Since then, Piomelli, an associate professor of pharmacology with the University of California, in Irvine, and his collaborators have continued their efforts to provide a better understanding of the cannabinoid system in the brain. Their latest results, described in the April Nature Neuroscience article titled ¿Dopamine activation of endogenous cannabinoid signaling in dorsal striatum,¿ provides convincing evidence that the brain¿s natural cannabinoid, anandamide, is an important neuromodulator of dopamine activity.
The finding strengthens anadamide¿s position as an influential player in the central nervous system¿s complex, interacting network of neurotransmitters. It also suggests additional potential therapeutic applications of cannabinoid drugs for treating disorders that involve dopamine dysfunction, such as Parkinson¿s disease and schizophrenia.
¿These studies are quite preliminary and preclinical in terms of treatment. There is some possibility that, due to the interaction with the dopamine system, other diseases involving the dopamine system could be targeted with these drugs,¿ said David Self, assistant professor of psychiatry at the Yale University School of Medicine, in New Haven, Conn.
The authors of the report studied the release of the endogenous cannabinoid in the brains of awake, freely moving rats using a technique called microdialysis. This method allows collection of chemical samples from the brain, without inhibiting the movement of the animals. The samples were then analyzed using gas chromatography/mass spectrometry.
Dopamine Connection To Cannabinoid Unexpected
Stimulating dopamine release in the striatum, either electrically or pharmacologically, stimulates movement in rats. The researchers found that electrical stimulation of a part of the brain involved in motor control, the dorsal striatum, resulted in the release of the naturally occurring cannabinoid anandamide, which binds to the same receptor that binds the active ingredient in marijuana, delta9-THC.
¿This is the first demonstration,¿ Self observed, ¿of release of an endocannabinoid in vivo. One of the major criteria for showing that a compound is a neurotransmitter is the demonstration that it is released by physiological activity. That is basically what they demonstrate here. The release mechanism is not very well understood.
¿It is not the classical neurotransmitter release mechanism of synaptic vesicles fusing with the pre-synaptic membrane and releasing their transmitter into the [synaptic] cleft,¿ Self said. ¿It seems to be more of a cleavage of the membrane-bound lipid-like molecules that then diffuse out of the cells all around the terminal. In that sense, I think endocannabinoid will never be viewed as classic neurotransmitters, but more as a neuromodulators.¿
Piomelli said it was ¿completely unexpected to us that dopamine should engage at all the cannabinoid system.¿
A drug that stimulates dopamine D2 receptors, quinpirole, significantly increased anandamide release, while a drug that blocks D2 receptors, raclopride, prevented this effect. These and other pharmacological data indicate that anandamide may be closely tied to dopamine signaling in the brain. But how? Does it add to or subtract from dopamine¿s effects, which were represented in these experiments by increased movement of the rats? Because a drug that blocks cannabinoid receptors, SR141716A, produced increased motor behavior following D2 receptor stimulation, it appears that the answer, under these conditions, is that anandamide inhibits, or tones down, dopamine¿s positive effect on the animal¿s movements.
In the words of the authors, ¿The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity.¿ Anandamide may thereby help modulate dopamine¿s effects, acting to keep dopamine¿s effects within normal limits, and serving as a type of ever-present braking mechanism.
Blocking Andamide May Help Inactivation
¿The main area that I think this will affect in the long run, but hopefully not that long, are the pathologies that are characterized by a hyperactivity of the dopamine system,¿ Piomelli said. ¿This is a spectrum of conditions that includes schizophrenia, autism, attention deficit hyperactivity disorder, to a certain extent obsessive-compulsive disorders, Tourette syndrome [and] all these very different psychopathologies that have in common what can best be explained as a hyperactivity of the dopamine system.¿
One way to counter dopamine hyperactivity might be to increase anandamide activity, to ¿just prevent hyperactivity on the dopaminergic side by enhancing its natural functional antagonist,¿ Piomelli explained. Last year, Piomelli and his co-workers developed a series of compounds that blocked anadamide¿s inactivation. These, he suggests, offer a very realistic approach to enhancing the activity of the endocannabinoid.
¿If there is no release of anandamide, nothing happens,¿ Piomelli said. ¿But, if there is a release of anandamide, as when dopamine D2 receptors become active, anandamide will be released but not inactivated because of the presence of the drug. It will stay longer in the synaptic cleft or wherever it acts and produce greater effects. I think the message behind this paper is that we may be able to alleviate the symptoms of many different disorders that are characterized by dopamine hyperactivity by acting on the natural system that counteracts dopamine activity instead of on the dopamine receptor itself.
¿We could do so,¿ Piomelli concluded, ¿presumably by blocking the inactivation of the endogenous cannabinoid system, anandamide in particular, which seems to be involved in this response.¿