Drug Discrimination Studies in Rhesus Monkeys: Drug Dependence and Withdrawal

Li, Jun-Xu; Gerak, Lisa R.

doi:10.1002/9781118023150.ch13

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…Both ketanserin and pirenperone were soon found to very potently antagonize the stimulus effects of DOM, and DOM-stimulus generalization to, for example, mescaline (2), LSD (8), and 5-OMe DMT (9b), suggesting a common stimulus action via activation of 5-HT 2 receptors. 187 Later, the stimulus effect of DOM in monkeys, to which substitution occurred with DOI, R(−)DOM, and LSD, 188 was also blocked with 5-HT 2 antagonists including ketanserin. 189 AMI-193 or 8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro [4.5]-decanone is a combined 5-HT 2A /dopamine receptor antagonist with >2,000-fold selectivity over 5-HT 2C receptors; this compound potently blocked the stimulus actions of DOM in rats at an antagonist dose of 0.04 mg/kg suggesting that the DOM stimulus is quite likely a 5-HT 2Arather than 5-HT 2C -mediated event.…”

Section: -Ht 2a Serotonin Receptorsmentioning

confidence: 99%

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review

Glennon,

Dukat

2024

ACS Pharmacol. Transl. Sci.

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1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI, or DOX where X = −I) was first synthesized in 1973 in a structure–activity study to explore the effect of various aryl substituents on the then newly identified, and subsequently controlled, hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, or DOX where X = −CH3). Over time, DOI was found to be a serotonin (5-HT) receptor agonist using various peripheral 5-HT receptor tissue assays and later, following the identification of multiple families of central 5-HT receptors, an agonist at 5-HT2 serotonin receptors in rat and, then, human brain. Today, classical hallucinogens, currently referred to as serotonergic psychedelic agents, are receiving considerable attention for their potential therapeutic application in various neuropsychiatric disorders including treatment-resistant depression. Here, we review, for the first time, the historical and current developments that led to DOI becoming a unique, perhaps a landmark, agent in 5-HT2 receptor research.

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Section: -Ht 2a Serotonin Receptorsmentioning

confidence: 99%

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review

Glennon,

Dukat

2024

ACS Pharmacol. Transl. Sci.

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“…Drug discrimination studies with dopaminergics, serotonergics, cholinergics, opioids, and benzodiazepines have provided examples suggesting possible in vivo differentiation between high- and low-efficacy agonists. Thus, although a low-efficacy agonist may substitute fully for a high-efficacy agonist, raising the training dose of a high-efficacy, full agonist requires disproportionately raising the test doses of the low-efficacy, partial agonist to achieve substitution (Jutkiewicz et al 2011; Lelas et al 2000; Li et al 2011; Picker and Dykstra 1989; Wolff and Leander 1997; Woolverton and Schuster 1983). Other approaches to alter the pharmacological sensitivity are by reducing the receptor pool through receptor inactivation by an irreversible ligand or through tolerance induction (Bergman et al 2000; Walker and Young 2002).…”

Section: Introductionmentioning

confidence: 99%

Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats

et al. 2013

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Rationale The “subjective high” from marijuana ingestion is likely due to Δ9-tetrahydrocannabinol (THC) activating the central cannabinoid receptor type 1 (CB1R) of the endocannabinoid signaling system. THC is a weak partial agonist according to in vitro assays, yet THC mimics the behavioral effects induced by more efficacious cannabinergics. This distinction may be important for understanding similarities and differences in the dose–effect spectra produced by marijuana/THC and designer cannabimimetics (“synthetic marijuana”). Objective We evaluated if drug discrimination is able to functionally detect/differentiate between a full, high-efficacy CB1R agonist [(±)AM5983] and the low-efficacy agonist THC in vivo. Materials and methods Rats were trained to discriminate between four different doses of AM5983 (0.10 to 0.56 mg/kg), and vehicle and dose generalization curves were determined for both ligands at all four training doses of AM5983. The high-efficacy WIN55,212-2 and the lower-efficacy (R)-(+)-methanandamide were examined at some AM5983 training conditions. Antagonism tests involved rimonabant and WIN55,212-2 and AM5983. The separate (S)- and (R)-isomers of (±)AM5983 were tested at one AM5983 training dose (0.30 mg/kg). The in vitro cyclic adenosine monophosphate (cAMP) assay examined AM5983 and the known CB1R agonist CP55,940. Results Dose generalization ed50 values increased as a function of the training dose of AM5983, but more so for the partial agonists. The order of potency was (R)-isomer > (±)AM5983 > (S)-isomer and AM5983 > WIN55,212-2 ≥ THC > (R)-(+)-methanandamide. Surmountable antagonism of AM5983 and WIN55,212-2 occurred with rimonabant. The cAMP assay confirmed the cannabinergic nature of AM5983 and CP55,940. Conclusions Drug discrimination using different training doses of a high-efficacy, full CB1R agonist differentiated between low- and high-efficacy CB1R agonists.

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Drug Discrimination Studies in Rhesus Monkeys: Drug Dependence and Withdrawal

Cited by 2 publications

References 25 publications

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review

Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats

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