Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline

Abstract

Lysergic acid diethylamide (LSD) is a serotonergic psychedelic compound receiving increasing interest due to putative anxiolytic and antidepressant properties. However, the potential neurobiological mechanisms mediating these effects remain elusive. Employing in vivo electrophysiology, microionthophoresis, behavioral paradigms and morphology assays, we assessed the impact of acute and chronic LSD administration on anxiety-like behavior, on the cortical dendritic spines and on the activity of serotonin (5-HT) neurons originating in the dorsal raphe nucleus (DRN) in male mice exposed to chronic restraint stress. We found that while the acute intraperitoneal (i.p.) administration of LSD (5, 15 and 30 and 60 μg/kg) did not produce any anxiolytic or antidepressant effects in non-stressed mice, the dose of 30 µg/kg (daily for 7 days) prevented the stress-induced anxiety-like behavior and the stress-induced decrease of cortical spine densitiy. Interestingly, while LSD acutely decreased the firing activity of 5-HT neurons, repeated LSD increased their basal firing rate and restored the low 5-HT firing induced by stress. This effect was accompanied by a decreased inhibitory response of 5-HT neurons to microiontophoretic applications of the 5-HT 1A agonist 8-OH-DPAT (8-hydroxy-N, N-dipropyl-2-aminotetralin). In conclusion, repeated LSD prevents the exacerbation of anxiety-like behavior following chronic stress exposure, but has no behavioral effects in non-stressed mice. These effects are paralleled by increased cortical spinogenesis and an enhancement of 5-HT neurotransmission which might be due to 5-HT 1A receptors desensitization. Increased cortical spine density and enhancement of serotonergic neurotransmission may thus represent a candidate mechanism which mediate the therapeutic effects of serotonergic psychedelics on stress-induced anxiety.

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice

“…Lasting adaptations in synaptic homeostasis have been linked to the therapeutic potential of psychedelics, which ultimately suggests that different postacute effects could share a common mechanistic substrate and impact one another. Since recent observations indicate that repeated LSD reverses stress-induced anxiety-like behavior and cortical synaptic plasticity deficits in mice, it will be interesting to expand this concept in future studies to characterize the function of these genes in processes related to synaptic plasticity, as well as the role of psychedelic-induced down-regulation of frontal cortex 5-HT 2A R density in these long-lasting therapeutic effects.…”

Towards an understanding of psychedelic-induced neuroplasticity

“…Additionally, DMT has been seen to enhance both neurogenesis and memory performance [44]. Other studies have reported improvements in fear extinction learning and reductions in anxious behaviors and learned helplessness following exposure to psychedelics, while also observing increased dendritic spine density in separate cohorts of animals [27,37,103]. Finally, the enhanced spinogenesis induced by ketamine, which is also a psychoplastogen, has been associated with reductions in depression-related behaviors [117,118].…”

“…Psychedelics have been shown to enhance dendritic growth, including spinogenesis, in cortical neurons [36,40]. In the frontal lobe specifically, animal studies show that psychedelics upregulate plasticity-related genes and promote the growth of synapses and dendritic spines [25,27,36,37,103]. In the prefrontal cortex (PFC), several psychedelics have been shown to rapidly upregulate genes related to neuroplasticity [25,26,104].…”

“…While large doses of psychedelics are not taken chronically due to their intense subjective effects, microdoses can be taken regularly and have been hypothesized to enhance neuroplasticity [48,112]. Chronic dosing with LSD has been associated with enhanced eyeblink conditioning, as well as improved avoidance learning and reversal of stress-induced deficits in synaptogenesis in rodent models of depression [103,113,114]. However, chronic dosing with DMT may cause retraction of dendritic spines [115].…”

Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

“…Previous studies have investigated the effects of serotoninergic psychedelics on stress coping in rodents [ 12 , 89 , 103 , 104 , 105 , 106 , 107 ]. One previous study found that a single administration of DOI did not have an acute effect on immobility behavior in the forced swim test in rats [ 42 ].…”