Tolerance to LSD and DOB induced shaking behaviour: Differential adaptations of frontocortical 5-HT2A and glutamate receptor binding sites

Psychedelics

“…Ketanserin, a 5-HT 2A -selective antagonist, (0.5 or 1.0 mg/kg, i.p., 30 minutes before agonist), blocked the overall shaking behavior of both psychedelics. Both LSD and DOB shaking behavior significantly decreased over the time course of the experiment (Buchborn et al, 2015).…”

“…Substantial evidence suggests that shaking behavior primarily results from metabotropic glutamate mGlu2/3-sensitive glutamate release downstream of frontocortical 5-HT 2A activation (this review). Buchborn et al (2015) investigated whether behavioral tolerance to LSD and DOB resulted from adaptations of 5-HT 2A and mGlu2/3 signaling, or of 5-HT 2A and/or overall-glutamate binding sites in the frontal cortex. Male Sprague-Dawley rats were administered LSD tartrate (0.025 mg/kg, i.p.)…”

“…Repeated Buchborn et al (2015) concluded that the differential receptor adaptations observed for DOB and LSD, respectively, indicate that tolerance to serotonergic hallucinogens can arise at two levels. That is, if a psychedelic (e.g., LSD) for some reason fails to downregulate 5-HT 2A receptors, glutamate receptors might adapt instead and thus prevent cortical overstimulation.…”

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

“…Pretreatment with the 5-HT 2A receptor antagonist ketanserin completely prevented all perceptual and mind-altering effects of LSD in humans (Kraehenmann et al, 2017; Preller et al, 2017), indicating that the hallucinogenic effects of LSD are primarily mediated through 5-HT 2A receptors. Similar to humans, tolerance to the behavioral effects of LSD is also observed in rats (Buchborn et al, 2015). Consistent with a role for 5-HT 2A receptors in the development of tolerance, daily LSD administration for 3 days decreased 5-HT 2A receptor binding in the rat frontal cortex (Buckholtz et al, 1985, 1990; Gresch et al, 2005).…”

“…Consistent with a role for 5-HT 2A receptors in the development of tolerance, daily LSD administration for 3 days decreased 5-HT 2A receptor binding in the rat frontal cortex (Buckholtz et al, 1985, 1990; Gresch et al, 2005). However, another study reported only a non-significant trend toward a reduction of frontocortical 5-HT 2A receptor binding in rats during the development of tolerance to LSD (Buchborn et al, 2015). Additionally, no effects of acute LSD on 5-HT 2A receptor mRNA expression were found in the rat prefrontal cortex, hippocampus, or midbrain (Nichols and Sanders-Bush, 2002), although the effects of repeated LSD administration were not studied.…”