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Control Lesion THC 2mg/kg
1-5 6-10 11-15 16-2O 21-25 26-
DELAY (sec)
478 Hampson and Deadwyler
FIG. 3. DNMS performance curves comparing lever position biases for lesioned animals vs animals exposed to 9-THC. DNMS
trial
performance was sorted according to the Delay interval of each trial, in 5-s increments as in Fig. 2. Data were additionally sorted
by Sample lever
position within each session. The trial type with higher performance was termed the Preferred lever type (filled circles), and the
trials with lower
performance were labeled as Nonpreferred lever type (open circles). Mean (and SEM) within each delay and trial type data are
plotted. Left:
Performance on trials with Preferred vs Nonpreferred Sample lever positions from 6 animals (15 sessions) that were fully trained
in the DNMS
task prior to lesions. Preferred trials averaged 13% more correct responses than Nonpreferred trials, across all delays. Center:
Preferred vs
Nonpreferred trial performance from 5 animals (10 sessions) that were fully trained in the DNMS task, but received 2.0 mg/kg
(ip) injections of
9-THC 10 min prior to the DNMS session. Preferred trials averaged 39% more correct responses than Nonpreferred trials
following THC
administration. Right: Performance on Preferred vs Nonpreferred trials from 3 animals (15 sessions) that received hippocampal
lesions prior to
training in the DNMS task. Preferred trials averaged 20% more correct responses than Nonpreferred trials.
to respond to a preferred lever on trials in which the
nonpreferred response is appropriate. As stated above,
this implies that without a hippocampus, animals do
not perform the DNMS task in the same manner as
animals with an intact hippocampus. In this respect,
activation of cannabinoid receptors in intact animals
influences more than just the retention of trial specific
events, it also affects the strategy by which the task is
performed.
BOTH HIPPOCAMPAL LESIONS
AND EXPOSURE TO CANNABINOIDS
ALTER SEQUENTIAL DEPENDENCY
IN THE DNMS TASK
The similarity in behavioral effects of both cannabi-
noids and hippocampal lesions shown in Fig. 2 sug-
gested that cannabinoid receptors in the hippocampus
may ‘‘disrupt’’information processing inthe hippocam-
pus by acting as a ‘‘reversible’’ hippocampal lesion
(64,65). The analysis of the types of errors per-
formed within the DNMS task following CB1 recep-
Copyright 1998 by Academic Press
All rights of reproduction in any form reserved.
40 - U 40 f 0 Preferred Lever
o NonPreferred Lever
1-5 6-10 11-15 16-20 21-25 26-30 1-5 6-10 11-15 16-20 21-25 26-30 1-5 6-10 11-15 16-20 21-25 26-
% Correct
100 100
THC, Pretrained Lesion, Not Pretrained
Non-Pref
1-5 6-10 11-15 16-20 21-25 26-30 1_5 6-10 11-15 16-20 21-25 26-30 Preœding Trial Preceding Trial Delay
480 Hampson and Deadwyler
Copyright 1998 by Academic Press
All rights of reproduction in any form reserved.
cannabinoid effects with those of ibotenate lesions
tion prevents stored information from being ‘‘overwrit-
revealed a more complex interaction. Recent results
ten’’ by extraneous stimuli. It seems likely in either
indicate that cannabinoid agonistsattenuate hippocam-
case that cannabinoids would not affect memory re-
pal neural activity during the Sample (storage) phase,
trieval, but could completely block retention of infor-
but not the Nonmatch (retrieval) phase of the DNMS
mation. The presence of endogenous cannabinoids
task (65). However, cannabinoid receptors are located
within thehippocampalcircuitcould thusvary continu-
on neurons that should be involved in both the
ously to regulate or ‘‘tune’’ the short-term memory
mnemonic storage and retrieval processes (Fig. 1).
storage process. Another prospective role for endog-
In-depth studies of hippocampal lesions in pretrained
enous cannabinoids may be to switch the hippocam-
and nonpretrained animals indicate that animals with-
pus in or out of the circuit for short-term memory
out an intact hippocampus learn a different strategy to
processing. The shift in behavioral performance strate-
perform the DNMS task than control animals (66). In
gies following THC administration may thus indicate
trained animals, successful DNMS behavior likely
that not only is processing interrupted within the
depends on the ‘‘learning’’ of a hippocampal neural
hippocampus, but also that the whole hippocampal/
circuit to store Sample phase information across the
retrohippocampal circuit for retention of DNMS trial
delay, and following the lesion, animals attempt to
relevant stimuli was inactive. This is confirmed by
continue this behavior, but are unsuccessful at delays
preliminary studies which indicate that a combination
10 s. Untrained lesioned animals, on the other hand,
of hippocampal lesions plus THC administration pro-
can learn the DNMS task better without a hippocam-
duces effects similar to those of hippocampal retro-
pus, primarily because the retrohippocampal areas
hippocampal lesions (64). Thus, the role of central
that are spared have not been modified by prior
nervous system cannabinoid receptors (and hence of
training (66). It seems likely that cannabinoid receptors
endogenous cannabinoids) in memory processing
in retrohippocampal areas are therefore also involved
in moderating the behavioral shift, since DNMS behav-
ior in animals with more extensive hippocampal and
retrohippocampal lesions do not show the same delay-
dependent deficits (66).
seems likely to involve ‘‘switching’’ of sections of the
hippocampal memory circuit both to regulate the
storage of information and to initiate other response-
based strategies to deal with delay-dependent contin-
gencies when the hippocampus is taken ‘‘off-line.’’
Recent studies of the effects of cannabinoid agonists
in vitro indicate that cannabinoid receptors may be
located presynaptically on interneurons in many brain
ACKNOWLEDGMENTS
regions such as substantia nigra (68,69), globus palli-
dus (70,71), and hippocampus (35). Application of
The authors thank Doug Byrd, Joanne Konstantopoulos, Janet
potent cannabinoid agonists such as WIN 55,212-2
produced a prolongation of GABA responses and
decreased GABA reuptake (69,70). This effect was
Brooks, Justin Rawley, and John Simeral for assistance. This work
was supported by NIH Grants DA08549 to R.E.H. and DA03502 and
DA00119 to S.A.D.
completely blocked by the antagonist, SR141716A (71).
Thus, cannabinoid receptors may subsequently modify
other neurotransmitter systems via their effects on
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