There is evidence from both rodents and humans that the serotonergic system regulates interval timing, a behavior that has been shown to be abnormal in patients with schizophrenia. This K01 Career Development application seeks support for a project that uses a mouse model to elucidate the neural and receptor mechanisms underlying the modulation of interval timing by both endogenous serotonin (5-HT) and hallucinogenic drugs. In light of the recent resumption of human studies with hallucinogens, and reports indicating that hallucinogens may possess clinical efficacy, a more complete understanding of the action of these drugs is urgently needed. The specific paradigm used is a discrete-trials interval timing task where rodents are trained to distinguish between short and long stimulus durations. The main training goals are for the applicant to: (1) develop expertise in the use of operant procedures in mice; (2) develop a cross-species operant task to assess interval timing in mice; and (3) gain expertise in the use of optogenetic techniques to control site-specific 5-HT release. The project has three specific aims.
Aim 1 is to characterize the effects of serotonin agonists and hallucinogens on interval timing in a discrete-trials task that te applicant has developed for use in mice. The task will be validated by testing whether 5-HT agonists (including the hallucinogens psilocin and 2,5-dimethoxy-4-iodoamphetamine, which act as 5-HT2A agonists) disrupt interval timing behavior in mice, as indicated by limited studies in rats.
Aim 2 will test the hypothesis that 5-HT acts specifically in the prefrontal cortex (PFC) to modulate interval timing. The PFC is a critical neural substrate for interval timing, and 5-HT receptor activation has profound effects on the activity of PFC neurons. Using optogenetic techniques based on a viral expression strategy to selectively activate serotonergic projections from the dorsal raphe nucleus to the PFC, studies in this aim will test the hypotheses that selectively increasing 5-HT release in PFC will disrupt interval timing in mice, and that the abiliy of 5-HT release in the PFC to disrupt interval timing is dependent on the 5-HT2A receptor.
Aim 3 will test the hypothesis that metabotropic glutamate receptors (mGluR2/3) modulate the effects of both exogenously administered 5-HT agonists and endogenously released 5-HT on interval timing. mGluR2/3 agonists functionally antagonize 5-HT2A receptor effects in the PFC, and may possess antipsychotic efficacy in schizophrenia. These studies address novel mechanisms of receptor interactions that have important implications for understanding the interplay between serotonergic and glutamatergic systems and may shed light on the pathophysiology of psychosis and thereby aid in identifying novel pharmacotherapeutic agents for the treatment of schizophrenia.
The perception of time, as reflected in behaviors used to time the durations of events, is disrupted in schizophrenia patients or by administration of serotonergic hallucinogens. This project will use measures of interval timing in mice to identify brain mechanisms responsible for serotonergic regulation of time perception. Understanding these mechanisms will contribute to our understanding of the linkage between serotonin and schizophrenia, provide insight into the mechanism of action of hallucinogenic drugs, and facilitate the development of interval timing as an animal model that could help discover new treatments for patients with schizophrenia.
|Halberstadt, Adam L; Geyer, Mark A (2018) Effect of Hallucinogens on Unconditioned Behavior. Curr Top Behav Neurosci 36:159-199|
|Brandt, Simon D; Kavanagh, Pierce V; Westphal, Folker et al. (2017) Return of the lysergamides. Part II: Analytical and behavioural characterization of N6 -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ). Drug Test Anal 9:38-50|
|Brandt, Simon D; Kavanagh, Pierce V; Dowling, Geraldine et al. (2017) Analytical characterization of N,N-diallyltryptamine (DALT) and 16 ring-substituted derivatives. Drug Test Anal 9:115-126|
|Halberstadt, Adam L (2017) Pharmacology and Toxicology of N-Benzylphenethylamine (""NBOMe"") Hallucinogens. Curr Top Behav Neurosci 32:283-311|
|Halberstadt, Adam L; Hyun, James; Ruderman, Michael A et al. (2016) Effects of the psychotomimetic benzomorphan N-allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice. Pharmacol Biochem Behav 148:69-75|
|Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten (2016) BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine. Int J Neuropsychopharmacol 19:|
|Halberstadt, Adam L (2016) Behavioral and pharmacokinetic interactions between monoamine oxidase inhibitors and the hallucinogen 5-methoxy-N,N-dimethyltryptamine. Pharmacol Biochem Behav 143:1-10|
|Wallach, Jason; Kang, Heather; Colestock, Tristan et al. (2016) Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues. PLoS One 11:e0157021|
|Brandt, Simon D; Kavanagh, Pierce V; Westphal, Folker et al. (2016) Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD). Drug Test Anal 8:891-902|
|Halberstadt, Adam L; Slepak, Natalia; Hyun, James et al. (2016) The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents. Psychopharmacology (Berl) 233:1215-25|
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