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

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-HT1A 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-HT1A 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.