title: Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.
abstract: Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex.
authors.affiliation: Institute of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany. Electronic address: tobias.buchborn@med.ovgu.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Buchborn
authors.affiliation: Institute of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany. Electronic address: helmut.schroeder@med.ovgu.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Schröder
authors.affiliation: Institute of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany; Leibniz Institute for Neurobiology, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany. Electronic address: daniela.dieterich@med.ovgu.de.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Dieterich
authors.affiliation: Institute of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany. Electronic address: gisela.grecksch@med.ovgu.de.
authors.forename: Gisela
authors.initials: G
authors.lastname: Grecksch
authors.affiliation: Institute of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany. Electronic address: volker.hoellt@med.ovgu.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Höllt
mesh_terms: D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D004361:Drug Tolerance; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006213:Hallucinogens / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D017470:Receptors, Glutamate / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D017470:Receptors, Glutamate; D012702:Serotonin Antagonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C003943:2,5-dimethoxy-4-bromoamphetamine; D018698:Glutamic Acid; D008238:Lysergic Acid Diethylamide; D007650:Ketanserin
keywords: (mGlu(2/3)) glutamate receptor; 5-HT(2A) receptor; Frontal cortex; Lysergic acid diethylamide; Serotonergic hallucinogen; Tolerance; Wet dog shakes