Effects of beta blockade, PTSD diagnosis, and explicit threat on the extinction and retention of an aversively conditioned response
Introduction
It is well known that memories for stressful and emotional events become more strongly established than memories for neutral events (McGaugh and Roozendaal, 2002). Intense emotional responses that accompany a traumatic event may help to explain why individuals with posttraumatic stress disorder (PTSD) develop strong memories for the experience. Memories for traumatic events can persist for many years, even decades (e.g., Orr et al., 1993). This “over-consolidation” may produce emotional memories that are highly resistant to extinction (Orr et al., 2000, Pitman et al., 2001). The ability to manipulate the stress hormones that are important to memory consolidation, perhaps immediately after a traumatic event, could reduce an individual's risk of developing anxiety disorders, such as PTSD.
The facilitation of emotional memory consolidation has been demonstrated to be influenced by adrenal hormones, i.e., catecholamines and glucocorticoids. These hormones are secreted after a stressful experience and appear to influence noradrenergic activity of the basolateral amygdala; the memory enhancing effects of glucocorticoids appear to primarily involve the hippocampus, but require input from the basolateral amygdala (see Roozendaal, 2002). Using an inhibitory avoidance procedure in animals, McGaugh and colleagues have shown that administration of propranolol, a b-adrenergic blocker, prior to, or immediately after, training inhibited the enhancement effects of norepinephrine on memory consolidation (Cahill and McGaugh, 1996, Miranda et al., 2003, Salinas et al., 1997). Similarly, injections of norepinephrine prior to training facilitated memory consolidation (Hatfield and McGaugh, 1999, Introini-Collison et al., 1992, Sullivan et al., 1991). Blockade of b-receptors with propranolol in animals also abolished memory facilitation in spatial learning tasks (Hatfield and McGaugh, 1999, Ji et al., 2003b), eye-blink conditioning (Gould, 1998, Ji et al., 2003a), as well as contextual fear conditioning in animals (Roozendaal et al., 2004).
Accumulating evidence from the human literature has begun to support the influence of norepinephrine on memory modulation. Cahill et al. (1994) showed that administration of propranolol blocked the memory enhancing effects of emotional arousal. Several other studies in humans have shown similar effects of propranolol on memory consolidation (e.g., Harmer et al., 2001). Propranolol has recently been found to influence conditioning to a fear context, but not to specific fear cues in healthy humans. In this study, Grillon et al. (2004) observed that individuals given propranolol prior to conditioning trials showed reduced SC levels when reexposed to the conditioning context. However, the magnitude of the SC conditioned response, during both acquisition and retention testing, was not influenced by propranolol.
A previous study by Orr et al. (2000) examined the acquisition and extinction of an aversively conditioned response in trauma-exposed individuals with and without PTSD. Results from this study demonstrated that individuals with, compared to without, PTSD produced larger SC responses to a stimulus paired with a mild shock (CS+) relative to a CS not paired with shock (CS−) during acquisition trials. The PTSD group's larger differential SC response to CS+ versus CS− trials persisted during extinction, even though participants had been told that they would no longer receive the electric shocks. Given that propranolol can reduce the memory enhancing effects of emotional arousal, it seems reasonable to expect that it might also reduce or eliminate the stronger conditioned responses (CRs) produced by some individuals. This prediction is based on the assumption that b-adrenergic activity plays a key role in the acquisition and extinction of conditioned emotional responses. However, the findings of Grillon et al. (2004) suggest that although b-adrenergic activity influences emotional memories, it may not influence the formation of conditioned emotional responses to specific fear cues.
The possibility that propranolol might retroactively interfere with the consolidation of a CR in PTSD is of particular interest. Might the administration of propranolol post-conditioning reduce the strength or durability of the CR? It is logical to hypothesize that if propranolol is present and exerting its actions from the start, as when it is administered prior to conditioning, it will be more effective. However, with regard to the clinical problem of PTSD, the potential advantages of an agent that could exert a beneficial effect when given following a traumatic event are obvious. Limited support for this possibility has been provided by findings from a study that examined the effect of administering propranolol shortly after a traumatic event on the subsequent development of PTSD (Pitman et al., 2002). Although propranolol did not prevent diagnosable PTSD from occurring, individuals who received propranolol showed significantly reduced physiological responses during mental imagery of the traumatic event, compared to those who did not receive it, when assessed several weeks after the event.
The study reported herein used a differential conditioning procedure to assess the acquisition and extinction of a skin conductance CR to emotionally neutral CSs (colored circles) paired with a mild electric shock UCS, as was done previously by Orr et al. (2000). The present study expands upon previous work in three ways. First, the study was designed to examine whether the administration of a single dose of propranolol before or after conditioning would influence the acquisition, extinction, and retention of an aversive CR, and whether it would diminish the heightened conditionability previously observed in PTSD. Second, durability of a CR established in the laboratory was examined by assessing the strength of the CR 1 week following conditioning. Third, the capacity of threat to modulate or even reinstate the experimental CR was tested by examining the CR under conditions where there clearly was or was not a possibility of receiving a shock UCS.
A potential problem with employing a b-adrenergic blocker to influence a central nervous system (CNS) process such as conditioning is that, because of its peripheral effects on the sympathetic nervous system (SNS), the presence of the drug could confound measurement of the peripheral-dependent variables that are being used to infer the central process the drug is putatively influencing. In this regard, measurement of skin conductance confers a distinct advantage. Although SC is unquestionably increased by central SNS activation, and in fact is probably one of the better dependent measures of this phenomenon, its peripheral action does not involve epinephrine or norepinephrine. Rather, both its preganglionic and postganglionic innervations are cholinergic. This fortunate consideration means that the conditioned SC response measured in the reported work may reasonably be expected to reflect propranolol's effect on central CR acquisition, extinction, and retention, free of peripheral contamination by the drug itself.
Section snippets
Participants
The sample consisted of 28 males with exposure to combat (n = 25) or firefighting (n = 3). Participants were recruited from the population of active and former VA outpatients, Vet Center clients, Professional Firefighters of New Hampshire, and posted notices at local fire stations. The research project was reviewed and approved by the Institutional Review Board of the Veterans Affairs Medical Center, Manchester, NH. Each research candidate underwent a diagnostic interview for the presence of Axis I
Demographic, psychometric, debriefing, UCS level and SC resting level, orienting response and unconditioned response
Means, S.D.s, and results of t-test comparisons between the PTSD and non-PTSD groups for the various demographic and psychometric measures, the UCS level set by the participant, SC resting level, orienting response and response to the UCS are presented in Table 2. As can be seen, the groups did not differ in age or education level. As expected, the PTSD group showed significantly more PTSD-specific and general psychopathology than the non-PTSD group. The PTSD and non-PTSD groups did not differ
Discussion
The present study found that: (1) administration of 40 mg of propranolol prior to cued conditioning had no effect on the acquisition of a differential conditioned SC response; (2) propranolol administered either prior to or following differential conditioning had no effect on the retention of extinction memory or reinstatement of conditioned fear. In addition, conditioned responses were found to be reinstated by threat-related cues (i.e., shock electrodes), thereby indicating that acquired
Acknowledgements
This project was supported by a grant from the Veterans Affairs Medical Research Service to Scott P. Orr. We wish to thank Michael L. Macklin and Heike B. Croteau for their technical assistance and the participants for their time and dedication.
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