Cannabinoid Function in Learning, Memory and Plasticity 469may be very different in other brain areas, such as nucleus accumbens where CB 1
receptors are also present on excitatory terminals, and so modulation of synaptic
plasticity in these regions is more likely to be CB 1 receptor mediated. This makes
it all the more important that behavioural studies use selective administration of
drugs to specific brain areas, rather than global administration to whole animals.
In contrast to our original preconceptions, it is emerging that the role of the
endogenous cannabinoid system in the hippocampus may be to facilitate the in-
duction of LTP. Administration of exogenous-selective CB 1 agonists may therefore
disrupt hippocampus-dependent learning and memory by ’increasing the noise’,
rather than ’decreasing the signal’ at potentiated inputs.
An understanding of the role of the endogenous cannabinoid system in the
regulation of synaptic plasticity will depend on identification of the physiological
stimuli that trigger the synthesis and release of the endocannabinoid(s). There
may be a background level of endocannabinoid activity (controlled by, for exam-
ple, metabotropic, cholinergic and glutamatergic inputs) that sets the threshold for
induction of LTP throughout the hippocampus. Alternatively, the very firing pat-
terns that induce LTP may trigger synthesis and release of endocannabinoids and
the time scale over which this occurs will determine any impact on the induction
of LTP.
The situation is made more complicated by the diverse pharmacology of some
of the putative endocannabinoids. 2-AG appears to exert its effects via the CB 1
receptor, but anandamide may activate both CB 1 and TRPV1-like receptors. The
question of which endocannabinoid is released is therefore functionally important.
6
Where to Go from Here?
An obvious feature of this chapter is that, despite the increasing knowledge of the
physiology and pharmacology of cannabinoid function in the brain, little transfer
as to behavioural consequences has been achieved. While it is clear from the in
vitro approach that there are numerous stimulation patterns able to trigger release
of endocannabinoids, such conditions have yet to be identified in the behavioural
setting. This must involve not only the definition of the psychological circum-
stances that lead to endogenous cannabinoid release, but also the characterisation
of the cellular mechanisms that aid this release. It has also become clear from
the in vitro approach that cannabinoid receptors are present only in particular
neuronal cell types and that the types of neurone that express these receptors vary
between brain areas in a manner that is expected to affect the outcome of cannabi-
noid receptor activation in vivo. In order to understand this variation in terms
of behavioural outcome, it will be essential to apply cannabinoid agonists and
antagonists in behaving animals in a more restricted and site-directed manner. In
addition, local administration and behavioural testing should be combined with
physiological assessment of neural changes induced in response to drug-treatment.
This is achievable either by using ex vivo slice preparations of the area of interest
(for example cerebellum, hippocampus, visual cortex, etc.) or by chronic implan-