EBioMedicine
September 1, 2016
David Martin, Charles D. Nichols
88 citations
Psychedelics directly activate a small subset of serotonin 5-HT2A receptor-expressing excitatory neurons in the cortex, which then recruit inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, producing distinct regional responses. This finding clarifies the cellular mechanisms underlying psychedelics' effects on perception and cognition, and their therapeutic potential for anxiety, depression, and addiction. The study also introduces a fluorescence-activated cell sorting (FACS) method for isolating specific brain cell subtypes based on cytoplasmic epitopes, enabling downstream nucleic acid analysis and expanding FACS applications in neuroscience.
Journal of integrative and complementary medicine
December 1, 2024
Markus Ploesser, David Martin
18 citations
A systematic review of 21 studies found that mindfulness meditation relieves pain through multiple mechanisms, including modulation of brain activity in regions such as the anterior cingulate cortex and anterior insula, and enhancement of structural and functional connectivity. The analgesic effects persist even when opioid receptors are blocked, indicating a nonopioidergic pathway. Pain acceptance and altered pain control beliefs serve as key mediators. Long-term practice increases pain threshold and reduces unpleasantness via heightened activity in salience and attentional control regions. Most studies involved healthy subjects with experimental pain, so findings require careful interpretation for chronic pain populations.
Neuropsychopharmacology
July 6, 2024
David Martin, Angel M. Delgado, Donna J. Calu
3 citations
A psychedelic 5-HT2A/2C agonist, DOI, increases dopamine signals in the nucleus accumbens core of rats during a learned reward task. The drug boosts dopamine responses to rewards and the cues that directly precede them, but not to earlier, distal cues. This effect occurs independently of changes in reward value, suggesting DOI amplifies prediction error signaling—a mechanism that may help disrupt entrenched associations or facilitate new learning. The findings point toward psychedelic strategies that engage error-driven learning for therapeutic benefit.
The FASEB Journal
April 1, 2016
David Martin, Connie Porretta, Charles D. Nichols
1 citation
The classic psychedelic (R)-DOI, a selective 5-HT2 receptor agonist, activates a diverse set of brain cells beyond just neurons. In the medial prefrontal and somatosensory cortex of mice, (R)-DOI induced immediate early genes like cfos in parvalbumin- and somatostatin-expressing interneurons, HTR2A-expressing neurons, and astrocytes. A new flow cytometry method that preserves intact cytoplasm and extracellular membranes allowed isolation of pure populations of somatostatin and parvalbumin interneurons from whole cortex. Further sorting by cFos activation revealed that different immediate early genes, such as egr2, are not uniformly induced across all activated cells. The technique is broadly applicable for studying cell-type-specific transcriptional and translational effects of any manipulation in the brain.
The FASEB Journal
April 1, 2015
David Martin, Connie Porretta, Charles D. Nichols
1 citation
Serotonin hallucinogens such as LSD and DOI primarily act through the 5-HT2A receptor, but their effects on brain function at the cellular and network levels remain incompletely understood. In adult rats treated with LSD, DOI, or saline, the somatosensory and medial prefrontal cortices were collected and dissociated into single cells. Using fluorescence-activated flow cytometry to separate neurons from glia and activated from non-activated neurons, qPCR analysis revealed an enrichment of immediate early genes (including c-fos, fosb, arc, krox-20/egr-2) in a small population of activated cortical neurons. Differences in gene abundance (htr2a, slc17a7, gad67) between activated and non-activated cells indicate which specific cell types are directly activated. Further research is needed to determine how this transcriptional program contributes to long-term psychological changes.
bioRxiv (Cold Spring Harbor Laboratory)
March 31, 2024
David Martin, Á.v. Delgado, Donna J. Calu
preprint
Psychedelics may help treat neuropsychiatric disorders by disrupting entrenched associations and promoting new learning. In rats performing a Pavlovian task where sequential cues predict rewards, the psychedelic DOI (a 5-HT2A/2C agonist) increased dopamine signaling in the nucleus accumbens core to rewards and to cues immediately preceding them, but not to more distal predictive cues. This elevated dopamine occurred independently of changes in reward value and supports increased prediction error signaling. The findings suggest psychedelics could engage error-driven learning mechanisms to disrupt or form new associations.
The FASEB Journal
April 1, 2012
David Martin, David E. Nichols, Charles D. Nichols
A novel rat model of schizophrenia was developed by treating rats with low doses of LSD for three months. This treatment caused persistent behavioral abnormalities including social deficits, hyperactivity, and anhedonia that continued after the drug was stopped. Protein analysis of the medial prefrontal cortex identified 12 differentially expressed proteins, 9 of which are also dysregulated in post-mortem brain tissue from people with schizophrenia. RNA sequencing showed that chronic LSD alters genes across all major neurotransmitter systems linked to schizophrenia, with many changes involving synaptic plasticity. The findings support chronic LSD treatment as a valid model for studying schizophrenia and may provide insights into the disease's underlying mechanisms.