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Mefloquine in the nucleus accumbens promotes social avoidance and anxiety-like behavior in mice
Mitra Heshmati1, Sam A Golden1, Madeline L Pfau1
1Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
Mefloquine continues to be a key drug used for malaria chemoprophylaxis and treatment, despite reports of adverse events like depression and anxiety. It is unknown how mefloquine acts within the central nervous system to cause depression and anxiety or why some individuals are more vulnerable. We show that intraperitoneal injection of mefloquine in mice, when coupled to subthreshold social defeat stress, is sufficient to produce depression-like social avoidance behavior. Direct infusion of mefloquine into the nucleus accumbens (NAc), a key brain reward region, increased stress-induced social avoidance and anxiety behavior. In contrast, infusion into the ventral hippocampus had no effect. Whole cell recordings from NAc medium spiny neurons indicated that mefloquine application increases the frequency of spontaneous excitatory postsynaptic currents, a synaptic adaptation that we have previously shown to be associated with increased susceptibility to social defeat stress. Together, these data demonstrate a role for the NAc in mefloquine-induced depression and anxiety-like behaviors.
Insights
Mefloquine use for malaria can cause depression. This study found mefloquine directly impacts the nucleus accumbens (NAc) in mice, triggering anxiety and social avoidance behaviors.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Mefloquine is a crucial antimalarial drug.
- Adverse effects include depression and anxiety, with unknown mechanisms.
- Individual vulnerability to these side effects is not understood.
Purpose of the Study:
- To investigate the central nervous system mechanisms underlying mefloquine-induced depression and anxiety.
- To identify specific brain regions involved in mefloquine's adverse behavioral effects.
Main Methods:
- Mefloquine was administered to mice, combined with subthreshold social defeat stress.
- Direct infusions of mefloquine were performed into the nucleus accumbens (NAc) and ventral hippocampus.
- Whole-cell recordings were used to analyze synaptic activity in NAc medium spiny neurons.
Main Results:
- Mefloquine combined with stress induced depression-like social avoidance behavior in mice.
- Direct mefloquine infusion into the NAc exacerbated stress-induced social avoidance and anxiety.
- Infusion into the ventral hippocampus did not produce these effects.
- Mefloquine increased excitatory postsynaptic current frequency in NAc neurons, a change linked to stress susceptibility.
Conclusions:
- The nucleus accumbens (NAc) plays a critical role in mefloquine-induced depression and anxiety-like behaviors.
- Synaptic changes in the NAc may mediate mefloquine's adverse effects on mood and social behavior.
