3. Umbruch 4.4..2005 - Online Pot

Role of the endocannabinoid system in learning and memory 125
this hypothesis comes from the observation that anandamide levels were
markedly decreased in the hippocampus of CB 1 –/– mice, but not in other brain
regions, suggesting that levels of anandamide in the hippocampus may be regulated
in part by tonic activation of CB 1 receptors [89].
Additional evidence suggesting the hippocampus as an important locus for
cannabinoid effects on learning and memory comes from experiments investigating
the memory-impairing effects of CB 1 agonists. Not only do the effects
of cannabinoid agonists resemble those of hippocampal lesions, but also the
∆ 9 -THC-induced deficits in the DMTS paradigm described above have been
associated with specific decreases in firing of individual hippocampal neurons
during the sample, but not the match, part of the experiment [18, 20] Site
microinjection studies also confirm the importance of the hippocampus. For
example, application of CP-55,940 directly into the dorsal hippocampus disrupted
working memory performance in an eight-arm radial maze without producing
other cannabinoid effects such as anti-nociception, hypomotility,
catalepsy, and hypothermia, believed to be mediated in other brain areas [33].
This dissociation between choice accuracy in the radial maze and other pharmacological
effects supports the notion that the hippocampus plays an integral
role in the cognitive alterations produced by cannabinoids. Similarly, microinjections
of ∆ 9 -THC into the dorsal and ventral hippocampus disrupted spatial
memory in the eight-arm radial maze, while injections into 11 other brain
regions, including different aspects of the cerebral cortex, amygdala, raphe,
caudate putamen, and mammillary body, were without effect [90].
Interestingly, ∆ 9 -THC administration into the dorsal medial thalamus disrupted
radial-arm maze performance, but it is likely that this was an indirect effect
on menemonic function as an array of abnormal behavior (e.g. increased repetitive
and pivoting [90]) was reported. Thus a strong case can be made for the
hippocampus as a primary neuroanatomical locus for the exocannabinoids and
endocannabinoid modulation of learning and memory.
Other brain regions linked to mnemonic and attentional tasks such as the
prefrontal (frontal) cortex have also been shown to be sensitive to CB 1 agonists.
For example, ∆ 9 -THC-induced working memory deficits have been associated
with increased dopaminergic activity in the prefrontal cortex [41], and
later studies have shown that ∆ 9 -THC produces increases of not only
dopamine, but also of glutamate, while decreasing γ-aminobutyric acid
(GABA) release [91]. Also, ∆ 9 -THC and WIN-55,212 have been shown to
increase acetylcholine release in rat frontal cortex in an SR-141716-reversible
manner when given systemically, but not locally [92]. CB 1 receptors are
expressed in the frontal cortex [78, 84]. It seems likely that these activating
effects of CB 1 agonists in the frontal cortex may be the result of a disinhibition
mediated via depressed GABAergic activity in other parts of the brain.
Another brain area which is just beginning to be fully appreciated for endocannabinoid
modulation of learning processes is the striatum, a brain region
whose role is in habit or procedural learning (e.g. [93]). As with the hippocampus,
high levels of CB 1 receptors as well as anandamide and 2-AG are