Marijuana and the Cannabinoids

Pharmacology of Cannabinoids 101
and acetylcholine in slices of hippocampus, cerebellum, and neocortex has been reported
either from direct observation or indirectly, through electrophysiological methods (25).
Other key proteins are regulated through signal transduction from cannabinoid receptors.
They include focal adhesion kinase, which is phosphorylated on tyrosine residues
and plays a role in synaptic plasticity (26), and PI3K activation by βγ-subunits of
G i , resulting in phosphorylation of Raf-1 and then phosphorylation of MAPK to activate
it. In turn, MAPK can activate phospholipase A 2 and trigger the arachidonic acid
cascade and production of prostaglandins (27), and can decrease growth factor receptor
synthesis in certain tissue, a basis for antiproliferative action of cannabinoids (28).
PI3K is also biochemically associated with mediation of insulin-like effects with
upregulation of glucose transporter 4 (insulin-dependent glucose uptake in skeletal
muscle and adipose tissue), stimulation of glycogen synthesis, and glycolysis (liver
cells). These latter effects would require the presence of receptors to anandamide on
the appropriate target cells.
Distribution of receptors and the role of the cells affected can give insight into
the pharmacology of agonists and antagonists of these receptors, and correlation
between observed effects and expected effects can be theorized. CB 1 has been mapped
mainly to the central nervous system (CNS) and peripherally to sensory neurons and
the autonomic nervous system. CB 2 receptors are strictly peripheral and are found
particularly on mature B cells and macrophages and on immune-related tissues such
as tonsils and spleen. In the CNS, CB 1 receptors have been mapped in various animal
species and in humans using autoradiography and immunohistochemical mapping techniques
(29–31). Whereas CB 1 receptors correlate poorly with anandamide distribution,
they are found in brain regions rich in the degradative enzyme FAAH. Interestingly,
FAAH is found postsynaptically and CB 1 receptors are found presynaptically, an anatomical
arrangement that correlates well with the role of endogenous cannabinoids as
retrograde synaptic messengers (32). The highest densities are found in the cerebral
cortex, particularly the association cortex, in the basal ganglia and cerebellum, and in
the limbic forebrain (particularly hypothalamus, hippocampus, and anterior cingulate
cortex). They are relatively absent from brainstem nuclei.
Cannabinoids affect cognitive and motor functions. Their subjective effects are
well documented by chronic users and include enhancement of senses, errors in time
and space judgment, emotional instability, irresistible impulses, illusions, and even
hallucinations. Objective effects have been measured and studied, and decreased psychomotor
performance, interference with attention span, and loss of efficiency in shortterm
memory are classically reported in the literature. Cannabinoids also have a number
of peripheral effects, notably vasodilatation, tachycardia, and immunosuppressant properties.
This chapter explains the neurophysiological and anatomical bases of these
disorders and correlate them with what is known of the cannabinoid receptors.
2. EFFECTS OF CANNABINOIDS ON MOTOR COORDINATION
2.1. Cortical Areas
Complex brain functions such as cognition, language, sexuality, sleep/wakefulness,
emotions, and memory require constant information processing. Of the human
cortex, 75% is association cortex (Fig. 4). The ability to attend, identify, and plan a