Psychedelics and psychostimulants produce subjective and often positive affective effects in humans. In rats, positive affective states are often associated with frequency-modulated ultrasonic vocalizations (USVs). We examined whether the hallucinogenic 2,5-dimethoxy-4-iodoamphetamine (DOI; 1.25-2.5 mg/kg) and LSD (0.04-0.08 mg/kg), the non-hallucinogenic lisuride (0.03 or 0.3 mg/kg) and the...
Ketamine, known for its rapid-acting antidepressant effects, is often coadministered with other psychoactive drugs, including opioids and cannabinoids, in both clinical and recreational settings. We investigated whether ketamine (R-, S-, or racemic R, S-) isoforms alter the subjective effects of morphine or Δ9-tetrahydrocannabinol (THC) and whether the interoceptive effects of ketamine overlap...
Serotonergic psychedelics, which display a high affinity and specificity for 5-HT2A receptors like 2,5-dimethoxy-4-iodoamphetamine (DOI), reliably induce a head-twitch response in rodents characterized by paroxysmal, high-frequency head rotations. Traditionally, this behavior is manually counted by a trained observer. Although automation could simplify and facilitate data collection, current...
Background: In clinical studies, psychedelics including psilocybin and D-lysergic acid diethylamide (LSD) demonstrate rapid and persistent antidepressant effects. Since the effective treatment with psychedelics is usually provided with psychotherapy, it is debatable whether their prolonged efficacy can be observed in infrahuman species. Preclinical reports on psychedelics’ effects most often...
(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes...
Time underestimation produced by (S)-ketamine could be associated with its antidepressant effects; however, it was accompanied with severe behavioral disruption. We also hypothesize that behavioral disruption produced by psychedelics objectively reflects their psychotomimetic-like actions.
Substance abuse disorder continues to have devastating consequences for individuals and society and current therapies are not sufficient to provide the magnitude of medical impact required. Although some evidence suggests the use of ketamine in treating various substance use related- symptoms, its adverse event profile including dissociation, dysphoria, and abuse liability limit its potential...
Purpose: Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT 2A receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT 5A receptors, which mediate some of LSD-induced behavioural effects. Methods: Using male Sprague Dawley rats,...
The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety...
Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 μM. The affinities of all three compounds were then...
Rationale: Prefrontal cortical dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. Nevertheless, the effectiveness of second-generation antipsychotic drugs in treating specific prefrontal dysfunctions remains equivocal. Objectives: To model schizophrenia-like cognitive inflexibility in rats, we evaluated the effects of repeated...
Transitive inference, that is, the ability to infer relationships among stimuli that are only indirectly associated, is impaired in schizophrenic patients and in rats with lesions of the prefrontal cortex. Symptoms of schizophrenia can be pharmacologically modeled by administration of the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP). Here, a subchronic administration of PCP...
Depression is a chronic recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires > or =2-4 weeks of treatment and a first course of therapy provides symptom relief to...
We investigated the immediate and enduring effects of ketamine in behavioral and neurochemical assays predictive of antidepressant activity. One week after a single administration of ketamine (50-160 mg/kg), otherwise experimentally naive rats and mice were tested either in the forced swim test (FST) or the tail suspension test (TST). Other mice were also tested twice in the FST: immediately...
Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit...
Anecdotal observations in humans indicate that indole alkaloid ibogaine may have anti-addictive properties. It has been suggested that the therapeutic action of ibogaine may depend upon facilitated access to the past experiences, purportedly influencing the initiation of drug addiction. To determine if ibogaine may facilitate memory retrieval, rats were trained in the Morris maze spatial...
Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA...
Ibogaine is a putative anti-addictive drug with potential efficacy for the treatment of opiate, stimulant, and alcohol abuse. We now report ibogaine is a competitive inhibitor (Ki, 1.01 +/- 0.1 microM) of [3H]MK-801 binding to N-methyl-D-aspartate (NMDA) receptor coupled cation channels. Since MK-801 can attenuate the development of tolerance to morphine and alcohol as well as sensitization to...