Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.
Tobias Buchborn, Helmut Schröder, Daniela C. Dieterich, Gisela Grecksch, Volker Höllt
Behavioural Brain Research March 15, 2015 DOI: 10.1016/j.bbr.2014.12.014 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rodents |
| Interventions | LSD DOB ketanserin |
| Dose | LSD and DOB 0.025 and 0.25 mg/kg, i.p.; ketanserin 0.5 mg/kg, i.p. |
| Duration | 7 administrations in 4 days |
| Measures | shaking behaviour (head twitches, wet dog shakes), [3H]spiroperidol binding, [35S]GTP-gamma-S binding, [3H]glutamate binding |
| Topics | LSD Serotonin |
| Keywords | Mglu2/3 glutamate receptor Frontal cortex Serotonergic hallucinogen Tolerance Wet dog shakes |
| Key findings | Tolerance to DOB correlated with reduced frontocortical 5-HT2A binding sites (r=.80) and unchanged glutamate binding sites (r=.84), whereas tolerance to LSD correlated only with decreased glutamate binding sites (r=.86). The authors infer that tolerance can develop via either 5-HT2A or glutamate receptor adaptations, potentially preventing cortical overstimulation when 5-HT2A downregulation fails. |
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
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- Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex Brain Research August 27, 2004
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