Animal models of serotonergic psychedelics

The extracted text presents a narrative review rather than a systematic meta-analysis; it summarises experimental findings from rodent studies and integrates pharmacological and genetic manipulations to interpret behavioural outcomes. The paper does not provide a description of search strategy, inclusion/exclusion criteria, databases searched, or other systematic-review methods in the extracted text. Instead of formal methods, the authors organise the material by behavioural paradigm and by the pharmacological or genetic manipulations that have been used to probe psychedelic action in rodents. Key assays discussed include the drug‑induced head‑twitch response, two‑ and three‑lever drug discrimination paradigms, pauses on fixed‑ratio schedules of reinforcement, locomotor and exploratory measures in open field paradigms, prepulse inhibition of startle, conflict-based anxiety tests and elevated plus‑maze, impulsivity and response inhibition tasks, peak‑interval and time‑discrimination tasks for time perception, and simple associative memory tasks such as trace conditioning. The review emphasises findings that link these behaviours to activity at 5-HT2A receptors and to modulation by other G protein‑coupled receptors.

Modeling psychedelic effects in rodents is challenging because subjective phenomena measured in humans (for example “oceanic boundlessness” or “ego dissolution”) cannot be reported by animals. Nonetheless, several rodent behaviours show predictive validity for psychedelic action and have been used to probe receptor mechanisms. Head‑twitch behaviour in mice is highlighted as a robust, predictive assay: all psychedelic 5-HT2A agonists tested induce head‑twitch, whereas nonpsychedelic 5‑HT2A agonists such as lisuride and ergotamine do not. Pharmacological blockade of 5‑HT2A receptors abolishes head‑twitch induced by systemic psychedelics, and 5‑HT2A receptor knockout mice do not show this response. The review also notes interactions with other receptors: activation or blockade of 5‑HT2C receptors modulates the dose–response of DOI on head‑twitch and locomotion, CB1 cannabinoid receptor manipulations can induce or attenuate head‑twitch (suggesting serotonergic release and 5‑HT2A involvement), and mGlu2 receptor knockout reduces DOI‑induced head‑twitch. A few false positives in the assay are reported, such as effects of CB1 antagonists and α2‑adrenergic antagonists, but overall head‑twitch is presented as a reliable predictor of psychedelic potential. Drug discrimination studies show that the interoceptive cues produced by classical psychedelics are mediated principally by 5‑HT2A receptor agonism. Two‑lever paradigms trained with a psychedelic training drug are typically substituted by other psychedelic 5‑HT2A agonists but not by non‑psychedelic drugs such as PCP, salvinorin A, cocaine or amphetamine. Lisuride can be a false positive in two‑lever assays but can be discriminated from LSD in three‑lever paradigms, indicating finer discrimination is possible. Intracerebral microinjections implicate the anterior cingulate cortex in LSD’s discriminative stimulus properties. Pauses on fixed‑ratio schedules (for example FR‑40) increase after psychedelic administration: animals emit longer periods of non‑responding interspersed with normal responding. This pause effect is not observed with many other psychoactive drugs. Notably, lisuride produces similar pause effects but the atypical antipsychotic and 5‑HT2A/D2 antagonist pipamperone reverses the effects of psychedelics on pauses while not affecting lisuride’s effect, suggesting mechanistic differences between psychedelic and nonpsychedelic 5‑HT2A agonists. Locomotor and exploratory effects are dose dependent and receptor selective. LSD and DOI commonly reduce horizontal activity, exploratory nose‑pokes and rearing in rats in a 5‑HT2A‑dependent manner. DOI shows an inverted U‑shaped dose–response on locomotion in mice, with lower doses increasing activity and higher doses suppressing it; the low‑dose increase is absent in 5‑HT2A knockout mice, whereas the high‑dose suppression can be reversed by a 5‑HT2C antagonist (SER‑082). Psychotomimetic noncompetitive NMDA antagonists and amphetamine produce hyperlocomotion, which can be attenuated by 5‑HT2A antagonists, indicating overlapping but distinct motor signatures across drug classes. Prepulse inhibition (PPI) findings are mixed. In humans, psilocybin disrupts PPI at short interstimulus intervals (ISIs), has no effect at medium ISIs and enhances PPI at long ISIs. Rodent studies are variable, with some reporting disruption of PPI by psychedelics across ISIs. Pharmacology differentiates lisuride and LSD: a 5‑HT2A antagonist (MDL11939) reverses LSD’s PPI disruption but not lisuride’s, whereas lisuride’s effects are prevented by the D2/D3 antagonist raclopride, implicating differing receptor contributions. Measures of anxiety‑like behaviour yield apparently contradictory results across paradigms. DOI produces anxiolytic‑like effects in some conflict‑based tests (for example increased punished drinking and elevated plus‑maze open‑arm activity) and reduces ultrasonic vocalizations in rat pups, yet induces freezing in open‑field exploration. Corticotropin‑releasing factor (CRF) in the frontal cortex can convert a low DOI dose into an anxiety‑like response via a 5‑HT2A‑dependent mechanism; 5‑HT2A knockout mice show reduced anxiety‑like behaviour and cortical rescue normalises it. The review notes that 5‑HT2A receptors in cortical versus midbrain regions may exert opposite effects on anxiety measures. On impulsivity and response inhibition, several studies report that psychedelics increase impulsivity in a 5‑HT2A‑dependent manner, typically at doses lower than those that induce head‑twitch. Time perception is altered by 5‑HT2A agonists: in peak‑interval timing tasks DOI and amphetamine produce an apparent overestimation of intervals (animals switch levers earlier), and MDL‑100907 (a selective 5‑HT2A antagonist) reverses the effects of both drugs. Dopamine D1 antagonism blocks amphetamine’s effect but not DOI’s, indicating different downstream pathways. MK‑801 produces opposite effects to psychedelics in timing tasks. Human studies with psilocybin show timing distortions consistent with the rodent peak‑interval findings, though task differences across species complicate direct comparisons. Memory effects are limited but notable: LSD and DOI enhance trace conditioning of simple associative responses and this enhancement is reversed by 5‑HT2A/2C antagonists. Post‑training administration of the selective 5‑HT2A agonist TCB‑2 enhances freezing in trace fear conditioning, implicating 5‑HT2A activation in modulation of certain forms of associative memory. Across paradigms, the review emphasises that the serotonin 5‑HT2A receptor is the principal molecular target for psychedelic behavioural effects in rodents, while other GPCRs (including 5‑HT2C, dopamine D1/D2, mGlu2, CB1, adenosine A1 and μ‑opioid receptors) modulate these effects in various ways.

The authors conclude that while no animal model can recapitulate all subjective effects of psychedelics, rodent assays reliably reproduce individual behavioural components that are relevant to human psychedelic action. Pharmacological and genetic evidence converges on the serotonin 5‑HT2A receptor as the primary mediator of psychedelic effects, but a range of other GPCRs influence 5‑HT2A‑dependent signalling and associated behaviours. The review identifies head‑twitch, drug‑discrimination and pauses on fixed‑ratio reinforcement as valuable predictive tools, and notes that other measures (for example PPI disruption, locomotor and exploratory changes, and time‑perception alterations) are affected by multiple classes of psychoactive drugs and therefore useful for dissecting similarities and differences between them. The authors call for further work to delineate the molecular mechanisms and neuronal circuits through which 5‑HT2A and interacting receptors modulate these behaviours, arguing that translational animal models are essential to understand how psychedelics affect cognition, perception and mood in humans and to reveal convergent or divergent neurochemical pathways underlying observable behavioural changes.