Benzodiazepine (BZ) drugs, such as diazepam (Valium®) and
chlordiazepoxide (Librium®), are widely prescribed for their
sedative/anxiolytic properties but also impair mnemonic processes in both
humans and animals. In the Morris water maze, an aversively motivated
spatial learning task, BZs impair spatial learning but spare
retention/performance. This spatial learning deficit cannot be attributed to
sedation, gross sensorimotor impairments, hypothermia, state-dependent
learning, or reductions of escape motivation (anxiolysis). The following
series of experiments sought to further characterize the neurochemical,
neuroanatomical, and electrophysiological substrates of BZ-induced
impairments of spatial learning. In Experiment I, the role of endogenous BZs
in spatial learning was assessed. The BZ receptor antagonists flumazenil (Ro
15-1788) and CGS 8216, as well as the BZ receptor inverse-agonist β-carboline,
enhanced spatial learning in an inverted-U dose-dependent manner,
suggesting that endogenously released BZs impede optimal learning. In
Experiment II, the role of the BZ ω1 receptor subtype in spatial learning was
assessed. CL 218,872, a selective agonist for the BZ ω1 receptor subtype,
impaired spatial learning in a dose-dependent and flumazenil-reversible
manner, thereby implicating the ω1 receptor subtype in BZ-induced amnesia.
Together these results suggest that endogenous BZs activity, like BZ drugs, is
detrimental to spatial learning and that specific BZ receptors mediate this
impairment.
Several neurochemical systems are important for spatial learning
in the MWM and arc influenced by BZs. The contributions of two of these
neurochemical systems, the opioids and acetylcholine (ACh), to the spatial
learning deficit produced by BZs were assessed. In Experiment III, a better
understanding of the role of opioid systems in spatial learning was sought.
Morphine, a prototypical opioid, impaired spatial learning in a dose-dependent and naloxone-reversible manner. However, morphine also
impaired performance and escape to a visible platform and its effects on
spatial learning could be attenuated by increasing the escape incentive
(colder water). This impairment pattern suggests that morphine impairs
spatial learning by reducing escape motivation. Because both BZs and cold
water immersion increase endogenous opioid activity, it seemed possible
that the combination of drug- and water-induced opioid release might
mediate the spatial learning deficit produced by BZs. In Experiment IV,
naloxone, an opioid receptor antagonist, completely blocked the spatial
learning deficit produced by morphine but failed, even at a higher dose, to
block the spatial learning deficit produced by diazepam . Conversely,
flumazenil, a BZ receptor antagonist, completely blocked the spatial learning
deficit produced by diazepam but failed to affect the amnesic effects of
morphine. Together, these findings strongly suggest that the spatial learning
deficit produced by BZs is not due to enhanced opioid activity.
There is also biochemical evidence that BZs interact with ACh systems.
In Experiment V, flumazenil attenuated the spatial learning deficit produced
by scopolamine, an ACh (muscarinic) antagonist, but physostigmine, an
acetylcholinesterase inhibitor, failed to attenuate the spatial learning deficit
produced by chlordiazepoxide, even at doses that completely reversed the
spatial learning deficit produced by scopolamine. Together these results fail
to support the notion that BZs impair spatial learning by reducing ACh
activity but suggest that scopolamine impairs spatial learning by enhancing
endogenous BZ activity.
Several neuroanatomical regions possess a high density of BZ
receptors and are also integral for spatial learning in the MWM. In
Experiment VI, infusions of chlordiazepoxide into the medial septum, but
not frontal cortex, nucleus basalis magnocellularis, amygdala, hippocampus,
or cerebellum, impaired spatial learning but had little effect on anxiety.
Conversely, infusions of chlordiazepoxide into the amygdala reduced anxiety
but had little effect on spatial learning. These results suggest that the medial
septum mediates the amnesic effects of BZs and that the amygdala mediates
the anxiolytic effects. In Experiment VII, intraseptal infusions of
chlordiazepoxide were additionally found to impair spatial learning in a
dose-dependent and flumazenil-reversible manner. However, infusions of
flumazenil into the medial septum failed to block the amnesic effects of
systemically administered chlordiazepoxide, suggesting that the amnesic
to
effects of BZs are not mediated by the medial septum exclusively.
Tetrahydroaminoacridine, an acetylcholinesterase inhibitor, failed to
attenuate the spatial learning deficit produced by intraseptal infusions of
chlordiazepoxide, suggesting that the deficit was not due to a disruption of
the septohippocampal ACh projection. Together, these results suggest that
chlordiazepoxide impairs spatial learning by interacting with the
septohippocampal GABAergic projection.
The septohippocampal GABAergic projection regulates the
excitability of hippocampal afferents (e.g., perforant path). Experiment VIII
assessed the effects of systemically administered BZs on the induction of
long-term potentiation (LTP) in the perforant path. CL 218,872, but not
chlordiazepoxide or diazepam , significantly suppressed long-term
potentiation. However, all drugs impaired spatial learning. These findings
suggest that CL 218,872 impairs spatial learning by suppressing LTP but that
BZ-induced spatial learning deficits can occur in the absence of perforant
path LTP suppression.
Taken together, the above results suggest that endogenous BZ
systems, particularly those in the septohippocampal system, are important
modulators of mnemonic processes. These findings are discussed in the
context of understanding information storage processes and the
implications for clinical populations. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/9582 |
| Date | 04 July 2018 |
| Creators | McNamara, Robert Keith |
| Contributors | Skelton, Ronald William |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Available to the World Wide Web |
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