Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to
severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and
cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to
develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as
other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex
and hippocampus regulate and in turn are affected by stress, and have also been
implicated in the underlying neuropathology of PTSD. These areas are densely innervated
by cholinergic neurons originating from the basal forebrain. In this study, the time
dependent sensitization (TDS) model was used to induce symptoms of PTSD in animals.
The study was designed to determine the long-term effects of an intense, prolonged
aversive procedure on central muscarinic acetylcholine receptor (mAChR)
characteristics and the correlation if any of those findings to cognitive aspects and general
arousal as characteristics associated with PTSD.
In order to achieve this goal, male Sprague-Dawley rats were exposed to the TDS stress
paradigm with behavioral/neuro-receptor assessments performed on day 7 post re-stress
(duration of each experiment in whole is 14 days). Acoustic startle reflex (ASR) was
used to determine emotional state (hyperarousal), while the conditioned taste aversion
(CTA) paradigm was implemented in order to assess aversive memory. Muscarinic
receptor binding studies were performed in the frontal cortex and hippocampus. Moreover,
both the stress-exposed and control animals were pre-tested in the acoustic startle
chamber in order to attempt to separate stress sensitive from stress-resilient animals
based on predetermined ASR criteria.
The ASR niodel was previously validated in our laboratory, while the CTA model was
validated in this project before application. In the CTA model, an i.p. injection with lithium
chloride (LiCl) (associated with digestive malaise), was used as unconditioned stimulus
(US) and was paired with a saccharinlcyclamate drinking solution as conditioned stimulus
(CS) to induce aversion to the novel taste (CS) when presented in the absence of the US.
Population data of animals tested in the ASR experiment indicated no statistical significant
difference between stressed and control animals. However, when each animal was
assessed individually, 22.5 % of the exposed population displayed all increase above the
predetermined criteria of 35 % in startle response, indicating a state of heightened arousal.
In contrast, only 4.2 O h of control animals (no stress) displayed an increase in arousal
based on the above mentioned criteria. Muscarinic receptor densities (Bm,) in the total
population of animals exposed to stress showed a statistical significant increase in both the
hippocampus and frontal cortex when compared to controls, with no changes in & values
observed in either one of the areas.
In the CTA experiment, TDS stress was implemented as US paired with a
saccharinlcyclamate drinking solution as CS. An acute session of prolonged stress (as
used in the TDS model) effectively induced aversion to a novel taste and a subsequent
reminder of the stress (restress) paired with the CS sustained the acquire adversive
memory.
Furthermore, LiCl was reintroduced as US in order to assess the effect of prior exposure to
two types of stress (acute and TDS) on subsequently acquired CTA memory. Prior
exposure to acute stress had no significant effect on subsequently acquired aversive
memory when measured either 3- or 7 days post-conditioning (CS-US). Stress-restress
(TDS) exposure, however, indicated a significant decrease in aversive memory from 3- to 7
days post-conditioning (CS-US) as well as a significant decrease in aversive memory
between the control- and the TDS group 7 days post-conditioning. The mAChR density
(B,,) in the frontal cortex; but not in the hippocampus, was elevated at the same point in
time (7 days post CS-US pairing) that CTA memory was impaired following TDS stress (stress-restress).
Ultimately, these data support an association between altered cholinergic receptors and
hyperarousallanxiety in an animal model of PTSD. The data also support the phenomenon
of individual susceptibility to stress in animals that parallels that observed in humans
exposed to severe trauma. Impaired aversive memory (CTA) is a consequence of prior
exposure to TDS stress, but not acute stress, and is likewise mediated by an altered
central cholinergic transmission displayed as an increase in mAChRs in the frontal cortex.
The lack of studies regarding the influence of the cholinergic system in PTSD related
behavior earns ,this project value as inimitable PTSD research. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/1558 |
| Date | January 2006 |
| Creators | Groenewald, Ilse |
| Publisher | North-West University |
| Source Sets | North-West University |
| Detected Language | English |
| Type | Thesis |
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