Elsila, L. V. | Search bioRxiv

bioRxiv2024

Effects of serotonin agonists LSD and 25CN-NBOH on conditioned place preference and on synaptic plasticity of VTA dopamine neurons in mice

The current research on psychedelic compounds such as lysergic amide diethylamide (LSD) is leaning heavily on the notion that psychedelics are not addictive. While much of the literature supports this argument, some of the common use patterns and the descriptions of the subjective effects of these compounds in humans, together with rather lacking and mixed data from non-human animal studies leave room for questions of potentially rewarding or reinforcing stimulus effects. Initiated by a surprising finding in a control study, we investigated these potential rewarding effects of LSD and a selective 5-HT2A agonist 25CN-NBOH using both unbiased and biased designs of conditioned place preference as well as ex vivo patch-clamp electrophysiology measurements of glutamatergic synaptic plasticity on midbrain ventral tegmental area (VTA) dopamine neurons in C57Bl6/J mice. Our results showed no reliable formation of place preference with either compound, agreeing with previous claims of psychedelics having at most weak reinforcing effects. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons, implicating a role for the midbrain dopamine system in the effects of psychedelic drugs. Graphical abstractTreatment with mixed serotonin receptor agonist, psychedelics lysergic acid diethylamide (LSD) or selective serotonin 2A receptor agonist 25CN-NBOH did not cause reliable induction of conditioned place preference in C57Bl/6J mice. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons. These findings challenge some of the previous rodent data but are in general in line with the claims of psychedelics having at most weak reinforcing effects. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/628157v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@57a87org.highwire.dtl.DTLVardef@1af3827org.highwire.dtl.DTLVardef@8fb256org.highwire.dtl.DTLVardef@5504b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Somatostatin-expressing neurons in the ventral tegmental area innervate specific forebrain regions and are involved in the stress response

Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Recently, we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighbouring dopaminergic neurons (Nagaeva et al., 2020). Here, we report that VTA Sst neurons especially from the anterolateral part also project far outside the VTA and innervate several forebrain regions that are mainly involved in the regulation of emotional behaviour. Deletion of these VTA Sst neurons affected several behaviours and drug responses, such as home cage activity, sensitization of locomotor activity to morphine, fear conditioning responses, and reactions to inescapable stress of forced swimming, often in a sex-dependent manner. Together, these data demonstrate that VTA Sst neurons have selective projection targets, which are distinct from the main targets of VTA dopamine neurons and involved in the regulation of a variety of behaviours mostly associated with the stress response. This, makes Sst neurons a meaningful addition to the remote VTA circuit and stress-related neuronal network.

neuroscience↗