Transcriptional changes in response to ketamine ester-analogs SN 35210 and SN 35563 in the rat brain

• Published in: BMC genomics Vol. 20; no. 1; p. 281
• Main Authors: Jacobson, Gregory M, Voss, Logan J, Klockars, Anica, Bird, Steve, Dimitrov, Ivo, Denny, William A, Olszewski, Pawel K, Sleigh, James W, Harvey, Martyn G
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.04.2019; BioMed Central; BMC
• Subjects: Acids; Amygdala; Analgesia; Analgesics; Analogs; Analysis; Animal models; Biochemistry; Brain; Cytoskeleton; Gene expression; Genes; Genomes; Genomics; Glutamate; Glutamatergic transmission; Hypnosis; Ketamine; Nociception; Nucleus accumbens; Pain; Pain perception; Paraventricular nucleus; Pharmacodynamics; Pharmacology; Potassium channels; Proteins; Receptors; Scaffolding; Structure-function relationships; Synapses; Thalamus; Transcription; Transcription (Genetics); Transcriptome; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; Nociception; Analgesia; Ketamine; Potassium channels; Glutamate; Transcriptome
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-019-5649-6

Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared across four relevant target regions of the rat brain. SN 35563 produced large-scale alteration of gene expression in the Basolateral Amygdala (BLA) and Paraventricular Nucleus of the Thalamus (PVT), in excess of 10x that induced by ketamine and SN 35210. A smaller and quantitatively similar number of gene changes were observed in the Insula (INS) and Nucleus Accumbens (ACB) for all three agents. In the BLA and PVT, SN 35563 caused enrichment for gene pathways related to the function and structure of glutamatergic synapses in respect to: release of neurotransmitter, configuration of postsynaptic AMPA receptors, and the underlying cytoskeletal scaffolding and alignment. The analgesic ketamine ester analog SN 35563 induces profound large-scale changes in gene expression in key pain-related brain regions reflecting its unique prolonged pharmacodynamic profile.