Dopaminergic mechanisms may be involved in the pathophysiology of posttraumatic stress disorder (PTSD), although the evidence for this is limited; serotonergic mechanisms are implicated largely by virtue of the modest efficacy of serotonergic drugs in the treatment of the disorder. Basal cerebrospinal fluid (CSF) dopamine and serotonin metabolite concentrations are normal in PTSD patients. However, in the present experiment, we postulated that perturbations in CSF dopamine and serotonin metabolites could be induced by acute psychological stress. Ten volunteers with war-related chronic PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6–9 weeks apart), using a randomized, within subject-controlled, crossover design. During one session a 1-h video with trauma-related footage (traumatic video) was shown and in the other session subjects viewed a 1-h neutral video. We quantified the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF at 10-min intervals, before, during, and after video provocation. Blood pressure, heart rate, and subjective anxiety and mood were monitored. Significant drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral movie. CSF HVA concentrations diminished significantly after the traumatic video (p < 0.05), in comparison with the neutral, while 5-HIAA tended to diminish (p < 0.10). We conclude that an acute decline in CNS HVA concentrations is associated with laboratory-induced symptoms in chronic PTSD patients. While further research is required to determine if the stress-induced dopaminergic changes are normative or pathological, the present data suggest that increasing dopaminergic neurotransmission be explored as a potential therapy, or adjunctive therapy, for PTSD.
Dopaminergic mechanisms may be involved in the pathophysiology of posttraumatic stress disorder (PTSD), but the evidence for this is limited. Investigations of dopaminergic candidate genes have yielded inconsistent, inadequately replicated, negative, or contradictory, results (for example, see Broekman et al., 2007 for a review and, more recently, Bailey et al., 2010; Valente et al., 2011). Clinically, dopamine D2 receptor antagonists may reduce certain symptoms in PTSD patients who manifest them, such as insomnia/hyperarousal (Stein et al., 2002; Rothbaum et al., 2008; Krystal et al., 2011) and/or psychotic symptoms (Hamner et al., 2003), but data on their general efficacy in PTSD are, to date, negative (Krystal et al., 2011). Conversely, although dopamine signal-promoting drugs have not been rigorously tested in PTSD, a few clinical cases of psychostimulant-induced improvements have been reported, one in a woman with car accident-related PTSD after phenethylamine diethylpropion for weight loss was added to a standing dose of fluoxetine (Daly, 2000) and three in combat veterans who were prescribed methylphenidate (in one case supplemented with dextroamphetamine) (Houlihan, 2011). However, it should be noted that diethylpropion, methylphenidate, and amphetamine all increase noradrenergic as well as dopaminergic signaling (Raiteri et al., 1975; Geranton et al., 2003; Kuczenski and Segal, 2005; Arnsten, 2006; Han and Gu, 2006; Santamaria and Arias, 2010).
A role for serotonin in the pathophysiology of PTSD is most strongly supported by the palliative effects of serotonergic drugs in the disorder. Serotonin-reuptake inhibitors, such as fluoxetine, sertraline, and paroxetine, ameliorate symptoms in many civilian patients with PTSD (van der Kolk et al., 1994; Brady et al., 2000; Davidson et al., 2001; Marshall et al., 2001) – although marginal benefit of serotonin-reuptake inhibitors in military combat-related PTSD is typically seen (van der Kolk et al., 1994; Hertzberg et al., 2000; Zohar et al., 2002).
In prior work we observed no differences in basal cerebrospinal fluid (CSF) and plasma concentrations of the major dopamine and serotonin metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, between combat veterans with PTSD and healthy comparison subjects (Geracioti et al., 1999; Strawn et al., 2002). However, examination of stress-induced effects on CSF 5-HIAA and HVA in PTSD (and in humans in general) has heretofore been lacking. This has been an important limitation. In the same way that suspected abnormalities in coronary artery blood flow or in glucose tolerance often require, respectively, a cardiac stress test or glucose tolerance test to elicit, CNS monoaminergic abnormalities in PTSD might be occult, manifesting only during stress.
To examine the effects of acute psychological stress on CNS dopamine and serotonin systems in patients with chronic combat-related PTSD, we combined continuous cerebrospinal fluid sampling, via an indwelling subarachnoid catheter, with exposure – in random order on two separate testing days – to either a 60-min stress-inducing video containing traumatic imagery or to a neutral videotape. By waiting for 2.5–3 h after placement of the thin, flexible subarachnoid catheter, and after removal of the needle used to place it, the neurohormonal response to the stress of the procedure resolves before CSF sampling starts (Hill et al., 1999).
As previously reported (Geracioti et al., 2008), during the 1-h traumatic videotape, subjective anxiety ratings were on average 23% higher than during the neutral videotape and increased more rapidly (two-sided p = 0.01 by Wilcoxon Signed Rank Test). Mood ratings changed dramatically for the worse during the Vietnam movie and were much lower than during the neutral videotape (F = 19.52, df = 1, p = 0.002). Even after the Vietnam videotape ended, subjective mood did not normalize for approximately 3 more hours. Hunger was significantly suppressed during the Vietnam film session (traumatic videotape) relative to the neutral session (F(1,7) = 15.16, p = 0.006), but rebounded such that by the end of the sampling procedure – 5 h after commencement of the 1-h videotape session – absolute hunger self-ratings were similar to corresponding ratings after the neutral videotape. Systolic blood pressure increased significantly during the stress videotape relative to the neutral videotape (F(1,6) = 15.42, p = 0.008). Also, maximum relative increases in diastolic blood pressure were significantly higher during the Vietnam film than during the neutral film (by Wilcoxon, z = 2.38, one-way p = 0.0085).
