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Role of the endocannabinoid system in learning and memory 115
Table 1. (Continued)
(c) Non-human primates
Model/species Drug Observations Reference
DNMS, concurrent discri- ∆ 9 -THC ∆ 9 -THC only disrupted [31]
mination/Rhesus monkeys DNMS task
Operant task battery: TRD Sensitivity of tasks (high–low):
DMTS, CPR, IRA, PR TRD>DMTS = IRA = CPR>PR [28]
Repeated acquisition/Squirrel ∆ 9 -THC disrupted task, blocked [30]
monkeys by SR-141716
Operant task battery (see Marijuana smoke Sensitivity of tasks (high–low): [27]
above)/Rhesus monkeys TRD = DMTS>IRA = CPR>PR
Repeated acquisition, ∆ 9 -THC, ∆ 9 -THC and WIN-55,212 produced [29]
conditional discrimination/ WIN-55,212-2 deficits in the repeated acquisition
Rhesus monkeys task, blocked by SR-141716
CPR, conditioned position responding; IRA, incremental repeated acquisition; PR, progressive ratio;
TRD, temporal response diffentiation; DNMS, delay non-match to sample
Operant tasks
For decades behavioral researchers have made use of operant (instrumental)
tasks to study the effects of drugs on mnemonic function. One implementation
of this paradigm that relies heavily on working memory processes is the
delayed-match (or non-match) to sample (DMTS or DNMS) instrumental task.
These experiments generally consist of a subject being presented with a sample
stimulus, an interval of time during which the stimulus is removed, and a
subsequent test phase when the sample stimulus is presented simultaneously
with a novel stimulus. The subject must indicate, usually by pressing a lever,
which was the sample (match) or which was the novel (non-match) stimulus.
∆ 9 -THC and WIN-55,212-2, a potent synthetic cannabinoid analog, have both
been shown to disrupt accuracy of such performance in a delay-dependent
manner, consistent with a selective disruption of working memory, and are
blocked by the CB 1 antagonist SR-141716 [18–20]. Importantly, these behavioral
deficits were associated with a selective reduction in hippocampal cell
ensemble firing during the sample phase, but not during the non-match phase
of these experiments [18, 20]. Further work has also shown that tolerance
develops to the disruptive effects of ∆ 9 -THC in this task [21], though it should
be noted that the occurrence of rate suppression in this study obfuscated the
assessment of choice accuracy.
Another series of experiments demonstrated that ∆ 9 -THC and anandamide
[in the presence of PMSF (phenylmethylsulphonyl fluoride), a nonspecific
amidase inhibitor], produced selective deficits in working memory performance
in a two-component operant task [22]. One component (conditional dis-