3. Umbruch 4.4..2005 - Online Pot

122 S.A. Varvel and A.H. Lichtman
prevented this memory deficit; however, it failed to enhance performance
when given 30 min prior to acquisition. This pattern of findings suggests that
acute administration of CB 1 receptor antagonists may be effective in preventing
retrieval deficits associated with neurodegenerative states [60]. In contrast
SR-141716 does not appear to be effective in the scopolamine model of memory
impairment in which this nonselective muscarinic antagonist is known to
induce a variety of memory deficits. SR-141716 failed to enhance scopolamine-induced
deficits in a variety of animal models including the rat social
recognition task [13] a rat radial-arm maze task [61], and a monkey repeated-acquisition
task [30].
Endocannabinoid modulation of extinction
The studies outlined in Table 2, which found that blockade of CB 1 receptor
signaling enhanced in memory tasks, suggest that SR-141716 may potentially
serve as a memory-enhancing agent. However, disruption of CB 1 receptor signaling
has also been shown to impair another important component of cognition,
extinction. Extinction is defined as a process by which learned behaviors
that are no longer reinforced become actively suppressed. SR-141716-treated
mice and CB 1 –/– mice exhibited impaired extinction of conditioned freezing to
a tone that had been paired with foot shock [14]. Following the conditioning
procedure, presentation of the tone during extinction (i.e. in the absence of
shock) was found to increase endogenous levels of anandamide and 2-AG in
the amygdala, a brain area associated with fear. Moreover, nonreinforced presentation
of the tone following fear conditioning also led to differences in activation
of extracellular signal-regulated kinases (ERKs) between CB 1 +/+ and
CB 1 –/– mice [62]. Compared with wild-type mice, the CB1 –/– mice expressed
different levels of phosphorylated ERKs, its downstream effector Akt, and the
phosphatase calcineurin in different aspects of the amygdala and hippocampus.
These findings are consistent with the notion that release of endocannabinoids
plays a role in extinction learning. A subsequent study found that
SR-141716 also impaired conditioned freezing to the test chamber in which
the mice had received the shock [63]. Of consequence, conditioned freezing to
a context is believed to involve hippocampal processes, while the hippocampus
is not believed to play a role in conditioned freezing to a tone [64].
Interestingly, SR-141716 failed to disrupt the within-session (short-term)
extinction of conditioned freezing, but did disrupt extinction when the mice
were tested 24 h later, suggesting it was consolidation of the extinction learning
that was impaired.
Similarly, the endocannabinoid system also appears to play a role in
long-term extinction in the Morris water maze task [65]. In this model,
SR-141716-treated mice, CB 1 –/– mice, and appropriate C57Bl/6 control mice
were trained in a fixed-platform procedure, the platform was removed after
the mice learned the platform location, and then the mice were subjected to