Methylphenidate and desipramine combined treatment improves PTSD symptomatology in a rat model

S Aga-Mizrachi, A Cymerblit-Sabba, O Gurman, A Balan, G Shwam, R Deshe, L Miller, N Gorodetsky, N Heinrich, O Tzezana, S Zubedat, D Grinstein, A Avital, S Aga-Mizrachi, A Cymerblit-Sabba, O Gurman, A Balan, G Shwam, R Deshe, L Miller, N Gorodetsky, N Heinrich, O Tzezana, S Zubedat, D Grinstein, A Avital

Abstract

Antidepressant medication constitutes the first line pharmacological treatment for posttraumatic stress disorder (PTSD), however, because many patients display no beneficial drug effects it has been suggested that combinations of antidepressants with additional drugs may be necessary. The defining symptoms of PTSD include re-experiencing, avoidance and hyperarousal. In addition, PTSD patients were shown to become easily distracted and often suffer from poor concentration together with indications of comorbidity with attention-deficit hyperactivity disorder (ADHD). Methylphenidate (MPH) is the most common and effective drug treatment for ADHD, thus we aimed to investigate the effects of MPH treatment, by itself or in combination with the antidepressants fluoxetine (FLU) or desipramine (DES). We modified an animal model of PTSD by exposing rats to chronic stress and evaluating the subsequent development of behavioral PTSD-like symptoms, as well as the effects on proinflammatory cytokines, which were implicated in PTSD. We report that while FLU or DES had a beneficial effect on avoidance and hyperarousal symptoms, MPH improved all three symptoms. Moreover, the combination of MPH with DES produced the most dramatic beneficial effects. Serum levels of interleukin-1β (IL-1β) and IL-6 were elevated in the PTSD-like group compared with the control group, and were decreased by MPH, FLU, DES or the combination drug treatments, with the combination of DES+MPH producing the most complete rescue of the inflammatory response. Considering the versatile symptoms of PTSD, our results suggest a new combined treatment for PTSD comprising the antidepressant DES and the psychostimulant MPH.

Figures

Figure 1
Figure 1
(a) Procedures timeline. (b) A schematic description of PTSD-like rat definition. PTSD, posttraumatic stress disorder.
Figure 2
Figure 2
Pharmacological treatments' effect on re-experiencing and hyperarousal symptoms. (a) Re-experiencing in fear conditioning test (context condition). MPH or DES+MPH PTSD-treated rats showed lower immobility duration compared with the saline-injected PTSD group; *P<0.018, **P<0.013, ***P<0.001. (b) Hyperarousal in startle response. FLU, DES or DES+MPH treatments significantly decreased startle response compared with the PTSD group;*P<0.0001. (c) Hyperarousal in PPI test. MPH, DES or DES+MPH treatments significantly improved PPI impairment observed in the PTSD group; *P<0.012. Values represent mean±s.e.m. DES, desipramine; FLU, fluoxetine; MPH, methylphenidate; PPI, pre-pulse inhibition; PTSD, posttraumatic stress disorder.
Figure 3
Figure 3
Pharmacological treatments' effect on avoidance symptom. (a) Locomotor activity in the OF test was significantly recovered by MPH or DES+MPH treatments, compared with the saline-injected PTSD group; *P<0.011, **P<0.002, ***P<0.0001. (b) Freezing duration in the OF test was significantly improved by MPH treatment, compared with the PTSD group; *P<0.002, **P<0.001. (c) In the social interaction test, MPH, FLU+MPH, DES or DES+MPH treatments significantly improved social interaction compared with the PTSD; *P<0.0001. (d) In the SPT, treatment with DES or DES+MPH led to hedonic effect compared with PTSD group in 0.125, 0.5 and 1% concentrations; *P<0.0001, **P<0.029. However, in 0.25% significance was found only for DES+MPH treatment; #P<0.004. (e) Total consumption measures indicated a significant increase following DES and DES+MPH treatments compared with the PTSD group, along all concentrations; *P<0.028, **P<0.0001. (f) In the Porsolt test, shorter floating duration was observed following treatments with MPH, FLU, FLU+MPH or DES+MPH compared with PTSD group; *P<0.0001. Values represent mean±s.e.m. DES, desipramine; FLU, fluoxetine; MPH, methylphenidate; PPI, pre-pulse inhibition; PTSD, posttraumatic stress disorder; SPT, sucrose preference test.
Figure 4
Figure 4
Comparison of the accumulative effect of the various treatments. All measures were standardized relatively to the controls, demonstrating that the saline-injected PTSD group has the lowest Z-score that was partially improved by MPH, FLU, FLU+MPH or DES. However, the combined treatment of DES+MPH yielded the uppermost recovery score. DES, desipramine; FLU, fluoxetine; MPH, methylphenidate; PTSD, posttraumatic stress disorder.
Figure 5
Figure 5
Pharmacological treatments' effect on IL-1β and IL-6 serum concentration. (a) Saline-injected PTSD-like rats significantly increase IL-1β level compared with the controls. All treatments significantly decrease IL-1β level compared with the PTSD group; *P<0.008, **P<0.0001. (b) PTSD-like rats showed a significantly higher IL-6 serum level compared with the controls. All treatments except for DES significantly decrease IL-6 level compared with the PTSD group; *P<0.032, **P<0.0001. DES, desipramine; FLU, fluoxetine; IL, interleukin; MPH, methylphenidate; PTSD, posttraumatic stress disorder.

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