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Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia

David Martin, Danuta Marona‐lewicka, D. E. Nichols, Charles D. Nichols

Neuropharmacology April 3, 2014 DOI: 10.1016/j.neuropharm.2014.03.013 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Observational animal study Peer reviewed
Population Rats
Intervention LSD
Duration 90-day treatment; gene expression assessed four weeks after cessation; behaviors followed for at least several months after cessation
Measures RNA-Sequencing, QPCR
Topics LSD
Key findings Chronic LSD administration in rats produced persistent schizophrenia-like behaviors and widespread changes in medial prefrontal cortex gene expression four weeks after cessation, with differentially expressed genes enriched in neurotransmission, synaptic plasticity, energy metabolism, and neuropeptide signaling pathways and overlapping with putative schizophrenia genes.

Abstract

Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those observed in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate molecular changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-Sequencing on the medial prefrontal cortex (mPFC), an area highly associated with both the actions of LSD and the pathophysiology of schizophrenia and other psychiatric illnesses. We observed widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes observed with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering analysis indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metabolism (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive analysis of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia.

Comparable studies

Other preclinical and animal studies on LSD, most cited first.

Study Year Design Participants
Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex Human embryonic kidney 293 cells stably expressing 5-HT2ARs; wild-type and 5-HT2AR... 2003 Experimental study
Evidence for a central 5‐hydroxytryptamine receptor stimulation by lysergic acid diethylamide Rats 1968 Experimental study
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission Male mice 2021 Multidisciplinary experimental study with in vivo electrophysiology, optogenetics, behavioral paradigms, molecular biology, and conditional knockout mice
A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons 2023 Preclinical study

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