岡田 剛史

PURPOSE: Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options. SUBJECTS AND METHODS: Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration. RESULTS: Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response. CONCLUSION: Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.

Tramadol (TRA) overdose can induce severe hyperthermia associated with monoaminergic dysregulation, particularly serotonin toxicity, and may lead to fatal outcomes. Although supportive treatments such as hydration and external cooling are commonly used, effective pharmacological interventions are yet to be established. Here, we aimed to evaluate the effects of risperidone (RIS) and ambient temperature on TRA-induced hyperthermia and changes in central monoamines in a rat model. Male Wistar rats received intraperitoneal TRA (100 mg/kg) under ambient temperatures of 18 °C, 23 °C, or 28 °C. RIS (0.25 or 0.5 mg/kg) and various monoamine receptor antagonists were administered to assess pharmacological responses. Core body temperature and locomotor activity were continuously monitored via implantable sensors, and in vivo microdialysis was conducted in the anterior hypothalamus to quantify extracellular levels of serotonin (5-HT), norepinephrine (NA), and dopamine (DA). TRA significantly elevated 5-HT, NA, and DA levels in a temperature-dependent manner, with DA and NA being strongly affected by ambient temperature. RIS at 0.25 mg/kg effectively suppressed hyperthermia and reduced DA elevation, whereas the 0.5 mg/kg dose did not. 5-HT2A and D1 receptor antagonists replicated the hyperthermia-suppressive effect, whereas 5-HT1A, 5-HT2B/2C, and D2 antagonists did not. These findings suggest that RIS attenuates TRA-induced hyperthermia primarily via DA suppression through 5-HT2A and D1 receptor antagonism and that elevated environmental temperatures exacerbate monoaminergic dysfunction and hyperthermic outcomes. RIS may represent a potential therapeutic option for managing tramadol toxicity.