3. Umbruch 4.4..2005 - Online Pot

126 S.A. Varvel and A.H. Lichtman
expressed in the striatum [78, 84], and as discussed below the endocannabinoid
system has been shown to play a critical role in synaptic plasticity in this
structure.
Cellular effects/interactions with other transmitter systems
In addition to its activity at the CB 1 receptor, anandamide has been shown to
have activity at the peripheral cannabinoid (i.e. CB 2) receptor, potassium
channels [94], gap junctions [95], and the VR 1 vanilloid receptor [96, 97].
Nonetheless, endocannabinoid agonist activity at CB 1 receptors has been the
focus of work to understand their roles in learning processes. Activation of
CB 1 receptors leads to a cascade of events with consequences that affect the
electrophysiological properties of cells. Well-characterized effects of CB 1
receptors include activation of adenylate cyclase activity [98–100], promotion
of mitogen-activated protein kinases [101, 102], inhibition of N- and P/Q-type
voltage-gated calcium channels [81, 103–105], and the opening of A-type and
inwardly rectifying potassium channels through their coupling with G i/o proteins
[105–107]. These effects on ion currents have a hyperpolarizing influence
on cell membranes, inhibiting their excitability. As CB 1 receptors are
found almost exclusively presynaptically, the main effect of this location is to
inhibit transmitter release (see below).
Interactions with glutamatergic systems
Recent work has focused on the influence of CB 1 activity on glutamatergic
activity. In rat hippocampal cultures, cannabinoid agonists have been shown to
inhibit presynaptic glutamate release. This effect appears to be the result of
activation of CB 1 receptors located on presynaptic nerve terminals, which subsequently
inhibit N- and Q-type calcium channels via an inhibitory G protein
[108–110]. Given glutamate’s role as the primary excitatory input into the hippocampus
and its importance in LTP, it is highly likely that CB 1-mediated inhibition
of glutamate release is important to the mnemonic effects of cannabinoids.
However, elucidating the nature of the relationship between endocannabinoids
and glutamate in the whole animal represents a difficult challenge.
The ability of glutamate agonists to reverse cannabinoid-induced memory
impairments is limited by the behavioral toxicity associated with this class
of compounds. Additional difficulties arise when the mnemonic effects of
cannabinoids are compared with those of antagonists of glutamatergic receptors.
There are several reports suggesting that working-memory (i.e. short
time) systems are largely spared by doses of N-methyl-D-aspartate (NMDA)
antagonists such as phencyclidine and dizocilpine (MK801) that disrupt the
consolidation and retrieval of long-term reference memories [111–115], while
cannabinoids tend to produce the opposite spectrum of effects.