460 G. Riedel and S.N. Davies
5
Synaptic Plasticity
The anecdotal reports of effects of smoking cannabis on cognitive processes has
naturally prompted investigation into the effects of cannabinoids on synaptic
plasticity, and in particular long-term potentiation (LTP). To summarise 17 years
of effort, it has been easy to show that cannabinoids have effects on LTP, and most
commonly suppress it, but far more difficult to define the mechanisms by which
this occurs. Emerging themes are that the commonly reported inhibition of LTP
by synthetic cannabinoids may be mediated by non-CB 1 receptors, and that the
function of the endogenous cannabinoid system may be to facilitate induction of
LTP. The vast majority of studies have focussed on synaptic plasticity in the CA1
region of the rat hippocampal slice and we will start our review there.
5.1
LTP in the Hippocampus
The first reported investigation was that of Nowicky et al. (1987) who showed that
pre-incubation of adult rat hippocampal slices with∆^9 THC could either inhibit or
potentiate high-frequency stimulation-induced LTP, depending on the concentra-
tion used. High-frequency stimulation (200 Hz for 500 ms) induced a potentiation
of the CA1 population spike amplitude that had a decay half-time of 280 min. Pre-
incubation with 10 pM∆^9 THC increased this to 350 min, whereas pre-incubation
with 100 or 1,000 pM∆^9 THC reduced it to 91 and 31 min, respectively. These
changes in synaptic plasticity were associated with corresponding changes in the
baseline population spikes, so that 10 pM∆^9 THC increased the population spike
amplitude, and 100 or 1,000 pM∆^9 THC decreased it. Before delivering the high-
frequency train though, stimulus strength was adjusted to counter any effect on
baseline transmission. These experiments were performed before the dawn of the
age of the cannabinoid receptor and few pharmacological tools were available. It is
therefore possible that the effects could be a result of some non-specific mechanism
of membrane perturbation.
5.1.1
Effects of Synthetic Cannabinoids on LTP Are Stereoselective
One of the cardinal features of a receptor-mediated effect is stereoselectivity. It
was therefore significant that cannabinoids were shown to be stereoselective as
inhibitors of LTP. HU-210 and HU-211 were the first to be tested, since their
stereochemical purity is particularly high, and only HU-210 is psychoactive. The
experiments by Collins et al. (1994) showed that pre-incubation of adult rat hip-
pocampal slices with 100 nM HU-210, but not HU-211, blocked LTP of the CA1
field excitatory postsynaptic potential (fEPSP) induced by high-frequency stimu-
lation (100 Hz for 500 ms). Slices were pre-incubated with the drugs so there was