Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT₂ signalling

Abstract

A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.

Psychedelics

“…This finding was similar to an earlier article in which Grecksch et al, (1997) found reversal of these deficits by imipramine; Buchborn et al (2014) conclude that LSD has an antidepressant-like effect in this model.…”

“…Using olfactory bulbectomy in rats as an animal model of depression, Buchborn et al (2014) demonstrated that repeated LSD treatment reversed the marked deficits in active avoidance learning in this animal model. This finding was similar to an earlier article in which Grecksch et al, (1997) found reversal of these deficits by imipramine; Buchborn et al (2014) conclude that LSD has an antidepressant-like effect in this model.…”

d-Lysergic acid diethylamide has major potential as a cognitive enhancer

“…In the former, a single dose immediately after learning enhanced memory consolidation in adult mice, while treatment immediately before learning facilitated the extinction of fear memory (21). In the latter, chronic treatment of adult rats with d-LSD for 11 days improved learning in animals deprived of olfaction by bulbectomy, but no effects were observed in sham controls (22). The lesion increases hippocampal 5-HT2A levels, and d-LSD down-regulated these to normal levels, with no effects in sham animals.…”

“…These substances have also been shown to induce neural plasticity and synaptogenesis both in vitro and in vivo (18)(19)(20), and are therefore likely to enhance learning capacity. Indeed, psychedelics have been shown to enhance memory consolidation when administered after fear learning or novel object exploration (21,22). In the former, a single dose immediately after learning enhanced memory consolidation in adult mice, while treatment immediately before learning facilitated the extinction of fear memory (21).…”

Restructuring consciousness –the psychedelic state in light of integrated information theory

“…By expanding the reality cone and promoting conceptual overlap, the high entropy state facilitates creativity, novel thinking, and imagination, which are obviously of great importance in human cognition. Furthermore, psychedelics are beginning to show great promise as psychotherapeutic agents in the treatment of depression, anxiety, and obsessive compulsive disorder (Moreno and Delgado, 1997; Berman et al, 2000; aan het Rot et al, 2010; Buchborn et al, 2014), perhaps by allowing sufferers to break out of the inflexible and circular modes of thinking that characterize these conditions (Carhart-Harris et al, 2014). …”