Animal models of serotonergic psychedelics

This review (2012) presents the behavioral effects induced by psychedelic drugs in animal models and evaluates how results from animal studies can be translate to humans. It also defines areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying the neuropsychological effects of classical psychedelics.

Abstract

“The serotonin 5-HT_2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.”

Authors: James B. Hanks & Javier Gonzalez-Maeso

Summary

Psychedelics are psychoactive drugs that induce unique neuropsychological effects. These effects are mediated by serotonin 5-HT2A receptors, whereas dissociatives and deliriants are mediated by NMDA and muscarinic receptors, respectively.

All hallucinogenic drugs profoundly alter perception, but different groups of hallucinogens induce overlapping, yet distinct sets of changes in sensory processing.

■ Modeling Psychosis in Animals

Modeling in rodents the neuropsychological effects induced by psychedelic drugs remains controversial. However, certain rodent behavioral models may be used to investigate the anatomy and molecular mechanisms of action underlying such behavioral outcomes.

Drug-induced head-twitch behavior is a mouse behavioral proxy of human psychedelic action, and is distinct from other behavioral responses in rodents such as head-weaving and wet-dog shakes.

The first study reporting that LSD produces abnormal behavior in mice was published in 1955. Subsequently, numerous psychedelic compounds were shown to induce head-twitch behavior, but it remains unknown whether 5-HTP is psychedelic in humans.

Before the first G protein-coupled receptors were cloned, pharmacological assays had shown that antiserotonergic drugs antagonized the head-twitch behavior induced by 5-HTP and LSD. The human 5-HT2A receptor was cloned and expressed heterologously in murine fibroblasts.

Blockade of the 5-HT2A receptor by ketanserin further supports the relevance of these findings, and the 5-HT2C receptor might be involved in the inverted U-shaped dose response of DOI on head-twitch behavior.

There are few examples of false positives obtained with head-twitch behavior as rodent model of psychedelic action, and it is suggested that CB1 receptor antagonists induce head-twitch behavior through a mechanism that requires serotonin release and activation of 5-HT2A receptors.

Psychedelic 5-HT2A agonists induce head-twitch behavior in mice, and this behavior is predictive of psychedelic potential in humans with a high degree of reliability.

Laboratory animals are trained to recognize the internal state (discriminative stimulus) induced by a specific dose of a particular drug. The animals are rewarded for pressing a lever on the drug-designated lever.

Using selective 5-HT2A receptor antagonists, it was shown that the discriminative stimulus properties of LSD are mediated by the 5-HT2A receptor in the anterior cingulate cortex.

When using two-lever drug discrimination assays, substitution for LSD does not occur with other psychoactive drugs such as PCP, salvinorin A, cocaine, or amphetamine. However, three-lever drug discrimination assays can distinguish between psychedelic and nonpsychedelic 5-HT2A receptor agonists.

Psychedelics increase the number of pauses on fixed-ratio schedules of reinforcement, and these pauses are interspersed with periods of responses that are similar to those of the control group. This effect is not observed in animals injected with other psychoactive drugs.

Mark Geyer and his laboratory found that psychedelics decrease locomotor activity and induce exploratory behavior in rats, but increase it in mice. The increase in locomotor activity was absent in 5-HT2A receptor knockout mice, and the reduction in locomotor activity was reversed by pretreatment with the 5-HT2C receptor antagonist.

Psychotomimetic drugs induce hyperlocomotion in rodents, which is attenuated by 5-HT2A receptor antagonists and inverse agonists.

PPI is a measure of sensorimotor gating that is affected by 5-HT2A and/or D2/D3-dependent signaling. PPI is disrupted by psilocybin at short, medium and long interstimulus intervals.

Anxiety-like behavior is induced in rats by DOI, a hallucinogen. This behavior includes punished-drinking behavior and punished-passages in conflict-based anxiety tests, as well as increased open-arm activity in the elevated plus-maze test.

Recent findings indicate that 5-HT2A receptor-dependent signaling plays a role in anxiety-like behavior, and that 5-HT2A receptors expressed in cortical and midbrain regions exert opposite effects on anxiety-like behavior.

The inability to withhold a behavioral response when such delay would produce a more favorable outcome is known as impulsivity. Psychedelics increase impulsivity in a 5-HT2A receptor-dependent manner.

Time perception has been demonstrated in a variety of species, such as bees, fish, and rodents. The peak interval timing task trains animals to indicate with their behavioral response when they perceive a particular duration of time to have passed.

Time discrimination is a retrospective timing task in which rodents must press a lever if the stimulus duration was less than 25 seconds or a lever if the stimulus duration was greater than 25 seconds.

Psychedelic 5-HT2A agonists DOI and amphetamine both cause rats to overestimate time intervals, but the effects are reversed by the 5-HT2A receptor antagonist MDL-100907, and the selective dopamine D1 receptor antagonist SKF-83566 blocks the effect of amphetamine, but not DOI, on the time discrimination task.

Psilocybin effects on time perception have been studied in humans, and similar results to the peak interval task were found. However, further investigation is needed regarding the effects of psychoactive 5-HT2A receptor ligands on time perception.

Psychedelic 5-HT2A receptor agonists enhance trace conditioning of the nictitating membrane response in rabbits and rats, and this effect is reversed by 5-HT2A/2C receptor antagonists.

■ Conclusion

Rodent models of psychiatric disorders are lacking convincing animal models, but the serotonin 5-HT2A receptor is the primary target responsible for psychedelic effects. However, several GPCRs are involved in the modulation of 5-HT2A receptor-dependent cellular signaling pathways and behaviors.

Rodent behavioral assays are valuable tools to predict psychedelic potential in humans. These assays can be used to understand the similarities and differences between psychoactive drugs, such as psychedelics, dissociatives, and deliriants.

■ Acknowledgments

The authors would like to thank Terrell Holloway and Caitlin McOmish for critical review of the manuscript. They have also cited Hofmann, Shulgin, Griffiths, Richards, W. A., McCann, U., and Jesse, R. in their paper.

Salvinorin A is naturally growing in the United States and is a potent kappa opioid selective agonist.

Researchers have studied the effects of psilocybin on healthy volunteers and have developed a rating scale.

Several studies have been conducted to evaluate the altered states of consciousness rating scale, and the mechanisms of hallucinogen action on 5-HT receptors have been described. A number of papers have been written on the behavioral pharmacology of hallucinogens, including Appel, West, W. B., and Buggy (2004), Fantegrossi, W. E., Murnane, K. S., and Reissig, C. J. (2008), and Gonzalez-Maeso, J., and Sealfon, S. C. (2009).

Mouse somatosensory cortex, Martin, W. R., Wikler, A., Eades, C. G., and Pescor, F. T. (1963), Woolley, D. W. (1955), and Keller, D. L. (1956), and a method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine.

46% of rats with schizophrenia show a head-twitch response to 5-HT2A receptor agonists, and 47% of rats with bipolar disorder show a head-twitch response to serotonin agonists.

There are several studies that have been done on the role of serotonin 2C receptors in head-twitch behavior in mice induced by phenethylamine hallucinogens, including the studies done by Fantegrossi, Simoneau, J., Cohen, M. S., Zimmerman, S. M., Henson, C. M., Rice, K. C., and Woods.

The mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists.

Fribourg, Moreno, J. L., Holloway, T., Provasi, D., Baki, L., Mahajan, R., Park, G., Adney, S. K., Hatcher, C., Eltit, J. M., Ruta, J. D., Li, Z., Umali, A., Shim, J., Fabiato, A.

Serotonergic receptor subtypes and hallucinogen-induced stimulus control. In a study of C57BL/6J mice, ()-DOM and LSD were used to induce a state of dissociation from the environment.

LSD, DOM, and d-amphetamine have different effects on the brain, and 5-hydroxytryptamine (serotonin)2A receptors in the rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide.

Several studies have shown that 5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity in mice. In addition, a reduced level of serotonin 2A receptors underlies resistance of Egr3-deficient mice to locomotor suppression by clozapine.

Serotonin 2A receptors regulate sensorimotor gating of the startle reflex in rats. LSD, but not lisuride, disrupts prepulse inhibition.

CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling.

DOI and ketanserin, 5-HT(2A/C) receptor ligands, impair response control in rats. Koskinen, T., Ruotsalainen, S., Puumala, T., Lappalainen, R., Koivisto, E., Mannisto, P. T., and Sirvio, J. (2000).

Several studies have been conducted on the effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior, including a study on the effects of DOI on the ability of rats to discriminate the durations and intensities of light stimuli.

Psilocybin affects time perception and temporal control of behaviour in humans.

Serotonin 2A receptor agonists improve associative learning in rabbits and facilitate extinction of fear memory in mice. A study in mice showed that ketamine up-regulates muscarinic acetylcholine receptors in the forebrain and reduces behavioral sensitivity to scopolamine. The study also showed that alpha 1d Adrenoceptor Psychiatry 8 was effective in treating schizophrenia.

A number of studies have been conducted on the effects of kappa-opioid receptor ligands on prepulse inhibition and CRF-induced prepulse inhibition deficits in the rat.

5-HT2A and 5-HT2C receptors are located within the periaqueductal gray in the elevated plus-maze test-retest paradigm in mice, and salvinorin A, the main active ingredient of Salvia divinorum, may have anxiolytic- and antidepressant-like effects.

The 5-HT2 agonist (DOI) induces premature responding in a five-choice serial reaction time task, and the 5-HT2A receptor antagonist M100,907 attenuates motor and ‘impulsive-type’ behaviours produced by NMDA receptor antagonism.

Amphetamine, cocaine and MK801 induce impulsive action in rats but are reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade. Amphetamine effects on impulsive action and memory are opposite to those seen in people. Amphetamine affects both contextual and auditory-cue fear conditioning, and the effects are dependent on familiarity with the stimulus.