Antipsychotic Drugs: Targeting the Wrong Neurons?

Introduction

A study that peered into live mouse brains suggests for nearly 70 years we’ve been targeting the wrong neurons in our design of antipsychotic drugs.

Untangling the Brain

Untangling the vast web of brain cells and determining how drugs work upon them is a tough task. Using a miniature microscope and fluorescent tags, a team of researchers led by Northwestern University neuroscientist Seongsik Yun discovered that effective antipsychotic drugs cling to a different type of brain cell than scientists originally thought.

Rethinking Schizophrenia Treatments

Just like research suggesting depression might not be a chemical imbalance in serotonin levels, our understanding of schizophrenia treatments may need a rethink if widely-used antipsychotics are targeting different neurons than expected.

Understanding Neural Circuits

“There is an urgent need to understand the neural circuits that drive psychosis and how they are affected by antipsychotic drugs,” Yun and colleagues write in their published paper.

The Mystery of Antipsychotic Drugs

As neuroscientist and study senior author Jones Parker told Wired’s Max G. Levy, most antipsychotic medications – including the first one approved in 1954, chlorpromazine – have been discovered serendipitously. “So we don’t know what they actually do to the brain.”

The Dopamine System

Upon discovering them, scientists noticed drugs that suppressed common symptoms of schizophrenia such as mania, hallucinations, and delusions, seemed to act on the brain’s dopamine system.

• Antipsychotic drugs stifle dopamine transmission between brain cells.
• The most potent ones were compatible with a particular type of dopamine receptor labelled D2.

Revealing the Truth

Linking the potency of antipsychotic drugs to D2 receptors gave rise to the idea that in schizophrenia, the striatum was awash with dopamine, a chemical imbalance that antipsychotics help correct.

• New drugs specifically designed to target D2 receptors did little to alleviate psychosis.
• No one had actually ever tested in animal models of psychosis whether decades-old antipsychotic drugs preferentially bound to D2 receptors, so their exact mechanism of action remained unclear.

The Study

To investigate, Yun, Parker and their team injected mice with one of four drugs used to treat psychotic illness, and watched how the animals behaved and how their brain cells responded.

• Haloperidol and olanzapine had some effect on D2 spiny neurons, but their interactions were mostly happening at D1 neurons.
• Clozapine steered clear of D2 neurons, and overwhelmingly suppressed D1 cells.
• MP-10 stayed glued to D2 neurons and made abnormal D1 activity worse.

A New Understanding

In other words, a drug’s clinical efficacy was closely related to its interaction with D1 neurons; those which normalized overactive D1 neurons relieved psychosis best – a finding which flips our understanding of these drugs on its head.

• D1 spiny neurons, not D2-expressing cells, may be a key driver of psychosis.
• Normalizing D1 activity may be a key indicator of antipsychotic effectiveness.

Implications and Future Research

While the findings come as a blow to decades of research, it helps explain why some antipsychotic drugs like clozapine work when others don’t. Though we should bear in mind dopamine isn’t the only neurotransmitter linked to psychosis.

The findings also offer a glimmer of hope that researchers can correct course and use these new insights to design much-improved treatments for schizophrenia. Treatments that can’t come soon enough.

Conclusion

The study has been published in Nature Neuroscience.