Reducing Dopamine Overheating: Experiment with New Schizophrenia Drug

In Neuropsychopharmacology, it was shown that the experimental drug evenamide, a selective blocker of voltage-dependent sodium channels, calms the hippocampus, normalizes hyperactivity of dopamine neurons, and partially corrects behavioral failures in a neurodevelopmental model of schizophrenia in rats (MAM model). A single injection of 3 mg/kg was enough to reduce the “overheating” of pyramidal neurons in the ventral hippocampus (vHipp), return the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) to normal, and improve recognition of novel objects; in males, the social sniffing deficit also disappeared. Local injection of evenamide directly into the vHipp produced the same “anti-dopamine” effect, a hint at a mechanism via the hippocampus. The authors carefully suggest that such therapy may affect positive, negative, and cognitive symptoms because it hits the “upstream node” of the chain, and not just the D2 receptors.

Background of the study

• What is the problem? Schizophrenia is not only delusions and hallucinations ("positive" symptoms), but also negative (apathy, poor speech) and cognitive (memory, attention). Classic drugs block D2 receptors and usually suppress positive symptoms best. They have little effect on "negativity" and cognition, and do not work for all patients.
• A modern view of the top-down chain. There is growing evidence that in schizophrenia, the ventral hippocampus (vHipp) is operating at “high speed.” This hyperactivation via the basal ganglia “rocks” dopamine neurons in the VTA — and then results in symptoms. If you calm the hippocampus, you can normalize dopamine and behavior.
• Why sodium channels? The hyperexcitability of pyramidal neurons is supported, among other things, by currents through voltage-dependent sodium channels (VGSC). Drugs that selectively “calm” them reduce excessive discharge and pathological release of glutamate — without affecting D2 receptors.
• What is evenamide? A candidate drug that selectively modulates VGSC and reduces the "noise" in excitatory circuits. The idea is to turn down the volume in the hippocampus so that the dopamine system "downstream" is normalized. In the clinic, it is being studied as an adjunct to antipsychotics; here is a preclinical animal study.
• Why the MAM model was chosen. This is a neurodevelopmental model of schizophrenia in rats, where adult offspring consistently exhibit:
  1. hyperactive vHipp,
  2. hyperdopaminergia (more spontaneously active DA neurons in the VTA),
  3. deficits in memory and social behavior.
     That is, the model reproduces well the key links “hippocampus → dopamine → behavior”.
• The main question of the work. If we specifically reduce hippocampal hyperexcitability with dasenamid, will it be possible to:
  1. normalize dopamine activity in the VTA,
  2. improve memory/social behavior,
  3. show that the point of application is precisely vHipp (via local injections)?
• Why this is needed in practice. If the approach works in people, it could complement standard regimens and better cover negative and cognitive symptoms — where D2 blockade is traditionally a “weak spot.”

What did they do?

• A validated MAM model of schizophrenia was used: pregnant rats were injected with methylazoxymethanol (MAM) on day 17; adult offspring recapitulate key pathophysiological features: ventral hippocampal hyperactivity → VTA hyperdopaminergia, cognitive and social impairment.
• Electrophysiology was recorded in the VTA and vHipp in adult males and females, novel object recognition and social approach were tested, and systemic administration of dazenamide (3 mg/kg, ip) was compared with local injections into the vHipp (1 μM).

Key Results

• Dopamine returned to normal. MAM rats usually have “extra” spontaneously active DA neurons in the VTA; dazhenamid reduced this number to control values in both sexes. Local injection into the vHipp had the same effect, indicating that the “point of application” is indeed in the hippocampus.
• The hippocampus has cooled down. In MAM animals, vHipp "fires" more often; the drug reduced the firing rate of pyramidal neurons.
• Memory and sociality. Systemic daezinamide restored recognition memory in males and females; social deficits were pronounced in males and disappeared after treatment.

Why is this important?

• Schizophrenia is more than just “positive” symptoms. Classic antipsychotics mostly suppress delusions/hallucinations via D2 blockade; negative and cognitive symptoms often remain. The “top-down” idea of calming the hippocampus, which “rocks” the dopamine system, has been gaining traction for years. Dagenamide, as a sodium channel modulator and glutamate release reducer, fits this logic well.
• Precision of hit. The fact that local injection into vHipp normalizes dopamine in the VTA is a strong argument: the drug works at the circuit level, not “in general in the brain.” This is an important milestone for the development of drugs that target hippocampal hyperexcitability as the “upper switch” of psychosis.

What is this drug and where is it in the clinic?

• Dagenamide is a selective VGSC (sodium channel) blocker that reduces hyperexcitability and abnormal glutamate release; it spares D2 and other major CNS targets. In early trials as an add-on to antipsychotics, it showed signals of efficacy and was well tolerated in patients with inadequate response/resistance; a phase III trial (ENIGMA-TRS) is currently underway. Important: the current article is a preclinical study in rodents, not a proof of clinical benefit.

A Spoon of Realism

• This is a model, not a disease in humans: effects on memory/social behavior in rats are not a guarantee of clinical outcome. RCTs are needed where the primary endpoints are negative and cognitive symptoms, as well as long-term safety.
• In the model, gender differences were partially preserved (the social defect was in males) - in the clinic, differences by gender, stage, and type of course are also possible.

What's next?

The researchers propose testing daeghenamide in designs that target cognitive/negative symptoms and validating the hippocampus → dopamine hypothesis in humans using neuroimaging and neurophysiology (fMRI/MEG, EEG biomarkers of hyperexcitability). In parallel, selection biomarkers: who “lives” most on the vHipp→VTA axis and can benefit from such a mechanism.

Conclusion

In a rodent model of schizophrenia, dagenamide dampens the hippocampal “overheating” that keeps the dopamine system “noisy,” and improves behavior. This reinforces the idea that to extend the effects of therapy beyond positive symptoms, it’s worth hitting higher up the circuit, not just the D2 receptors. Now it’s time for clinical trials.