Heritable Differences in Catecholamine Signaling Modulate Susceptibility to Trauma and Response to Methylphenidate Treatment: Relevance for PTSD

Abstract

Alterations in cortical catecholamine signaling pathways can modulate acute and enduring responses to trauma. Heritable variation in catecholamine signaling is produced by a common functional polymorphism in the catechol-O-methyltransferase (COMT), with Val carriers exhibiting greater degradation of catecholamines than Met carriers. Furthermore, it has recently been suggested that drugs enhancing cortical catecholamine signaling may be a new therapeutic approach for posttraumatic stress disorder (PTSD) patients. We hypothesized that heritable differences in catecholamine signaling regulate the behavioral response to trauma, and that methylphenidate (MPD), a drug that preferentially blocks catecholamine reuptake in the prefrontal cortex (PFC), exerts COMT-dependent effects on trauma-induced behaviors. We first examined the contribution of the functional mutation COMTval158met to modulate enduring behavioral responses to predator stress in a unique “humanized” COMTval158met mouse line. Animals were exposed to a predator (cat) for 10 min and enduring avoidance behaviors were examined in the open field, light-dark box, and “trauma-reminder” tests 1–2 weeks later. Second, we examined the efficacy of chronic methylphenidate to reverse predator stress effects and if these effects were modulated by COMTval158met genotype. Mice were exposed to predator stress and began treatment with either saline or methylphenidate (3 mg/kg/day) 1 week after stress until the end of the testing [avoidance behaviors, working memory, and social preference (SP)]. In males, predator stress and COMTval158met had an additive effect on enduring anxiety-like behavior, with Val stressed mice showing the strongest avoidance behavior after stress compared to Met carriers. No effect of COMT genotype was observed in females. Therefore methylphenidate effects were investigated only in males. Chronic methylphenidate treatment reversed the stress-induced avoidance behavior and increased social investigation independently of genotype. Methylphenidate effects on working memory, however, were genotype-dependent, decreasing working memory in non-stressed Met carriers, and improving stress-induced working memory deficit in Val carriers. These results suggest that heritable variance in catecholamine signaling modulates the avoidance response to an acute trauma. This work supports recent human findings that methylphenidate might be a therapeutic alternative for PTSD patients and suggests that methylphenidate effects on anxiety (generalized avoidance, social withdrawal) vs. cognitive (working memory) symptoms may be modulated through COMT-independent and dependent mechanisms, respectively.

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

“…To study susceptibility empirically, research focuses on using preclinical rodent models to assess a PTSD-like phenotype (Milad et al, 2006;Yehuda and LeDoux, 2007;Goswami et al, 2012). Many animal models of PTSD with face and construct validity have been developed (Hartmann et al, 2012;Toth et al, 2016;Deslauriers et al, 2019). The purpose of this review is not to review these, but to identify those models that are suitable for investigating individual differences in susceptibility.…”

“…(3) Models with construct validity (e.g., knockout of FKBP5, COMT, or CRH overexpression in early life) do not produce a complex PTSD-like phenotype (Hartmann et al, 2012;Toth et al, 2016;Deslauriers et al, 2019). (4) Animal models can inform about some, but not all, aspects of the PTSD phenomenon.…”

“…While female sex remains a risk factor, the sexual dimorphism present in the acquisition (Inslicht et al, 2013), presentation (Olff et al, 2007;Hourani et al, 2015), and treatment efficacy (Blain et al, 2010) of PTSD suggests that there are underlying biological differences based on sex that need to be investigated separately in both sexes (Cahill, 2003a(Cahill, ,b, 2006Pineles et al, 2017). Similarly to humans, rodent models of PTSD-associated behaviors show sex differences in response to trauma (Faraday, 2002;Adamec et al, 2006;Graham et al, 2009;Cohen and Yehuda, 2011;Toth et al, 2016;Pineles et al, 2017;Deslauriers et al, 2019). The RISP model was developed in male rats and we hypothesize that female rats will require different behavioral parameters for classification and PTSD-phenotyping.…”

Prolonged Exposure Therapy: A Case of Comorbid PTSD, ADHD, and GAD

“…The benefit of using methylphenidate for the comorbid treatment of PTSD and ADHD has also been previously supported in rat models (Aga-Mizrachi et al, 2014). The reduction of PTSD symptoms in animal models has been replicated (Deslauriers et al, 2019). However, further exploration of simulant treatment for comorbid PTSD and ADHD in human subjects has not been explored, nor has stimulant medication in combination with PTSD interventions been investigated.…”

Differences in behavior between surface and cave Astyanax mexicanus may be mediated by changes in catecholamine signaling

“…Both foraging and predator avoidance behaviors are regulated by catecholamine systems in the brain (Björklund & Dunnett, 2007;Duboué et al, 2011;Rosen, 2017: Deslauriers et al, 2019. Catecholamines, such as dopamine (DA) and noradrenaline (NA), are primarily involved in the selection of behavioral responses to environmental stimuli (Chakravarthy et al, 2010;Wright & Panksepp, 2014).…”