Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT2A receptors, with serotonergic receptors of the 5-HT1A and 5-HT2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT2A receptor density is decreased and, at a functional level, the head-twitch response following the...
Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of psilocybin was observed following...
A previous investigation in our laboratory found that the stimulus effects of the 5-HT2A agonist, LSD, are potentiated by 5-HT1A receptor agonists including the prototypic agonist, 8-OH-DPAT. Also suggestive of behaviorally relevant interactions between 5-HT1A and 5-HT2A receptors are behavioral analyses of locomotor activity, head-twitch response, forepaw treading and production of the...
Few studies have examined the effects of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in vivo. In these studies, 5-MeO-DIPT was tested in a drug-elicited head twitch assay in mice where it was compared to the structurally similar hallucinogen N,N-dimethyltryptamine (N,N-DMT) and challenged with the selective serotonin (5-HT)2A antagonist M100907, and in a lysergic acid diethylamide (LSD)...
It has been suggested that the 5-HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD). The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD. Twelve male Fischer 344 rats were trained in a two-lever,...
Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Although a variety of species has been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the...
Previous investigations in our laboratory have found that the stimulus effects of the hallucinogenic serotonergic agonists DOM and LSD are potentiated by phencyclidine [PCP], a non-competitive NMDA antagonist. Also suggestive of behaviorally significant serotonergic/glutamatergic interactions is our finding that stimulus control by both PCP and LSD is partially antagonized by the mGlu2/3...
Previous studies conducted in our laboratory have shown that acute administration of the selective serotonin re-uptake inhibitor (SSRI), citalopram, potentiates the stimulus effects of the phenethylamine hallucinogen [-]-2,5-dimethoxy-4-methylamphetamine (DOM) in the rat while neither substituting for the DOM stimulus when administered alone nor altering brain levels of DOM. The present...
The present investigation was undertaken to test the hypothesis that known metabolites of the phenylethylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) are pharmacologically active. This hypothesis was tested by evaluating the ability of racemic DOM metabolites 2-O-desmethyl DOM (2-DM-DOM) and 5-O-desmethyl DOM (5-DM-DOM) to substitute for the stimulus properties of...
Nefazodone is presently marketed as an antidepressant that inhibits both serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake while antagonizing pirenpirone (5-HT2) receptors. This 5-HT receptor type is believed to play a prominent role in the underlying mechanism of action of serotonergic hallucinogens. Antidepressant medications now represent the most commonly prescribed...
Previous reports from our laboratory have provided evidence that acute, i.e., concurrent, treatment with selective serotonin reuptake inhibitors (SSRIs) augments the stimulus effects of indoleamine and phenethylamine hallucinogens in the rat. In the present investigation, the acute effects of fluoxetine and citalopram on stimulus control induced by (-)-2,5-dimethoxy-4-methylamphetamine (DOM)...
The present investigation examined the interaction between 2,5-dimethoxy-4-methylamphetamine [DOM] and the selective serotonin reuptake inhibitor [SSRI] citalopram in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with citalopram at a dose of 1.0 mg/kg shifted the DOM dose response relationship to the left. Unlike previously tested SSRI's,...
The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to...
Indolamine and phenethylamine hallucinogens are drugs of abuse and, as well, mimic some aspects of idiopathic psychosis. To assist in investigating the mechanisms of action of (-)2,5-dimethoxy4-methylamphetamine ([-]-DOM), a member of the phenethylamine class of serotonergic hallucinogens, a sensitive and precise method for determining its levels in the brain tissue is required. We now describe...
The present investigation examined the interaction between 2,5-dimethoxy-4-methylamphetamine [DOM] and non-competitive NMDA antagonists in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with phencyclidine [PCP] at a dose of 3 mg/kg shifted the DOM dose-response relationship to the left. When a fixed dose of DOM [0.1 mg/kg] which by itself...
Stimulus control was established in rats trained to discriminate either 5-methoxy-N,N-dimethyltryptamine (3 mg/kg) or (-)-2,5-dimethoxy-4-methylamphetamine (0.56 mg/kg) from saline. Tests of antagonism of stimulus control were conducted using the 5-HT1A antagonists (+/-)-pindolol and WAY-100635, and the 5-HT2 receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and...
More than a quarter century has passed since the demonstration that indoleamine and phenethylamine hallucinogens can function as discriminative stimuli in the rat, and that serotonergic systems are critically involved. During that period our knowledge of the physiology, pharmacology, biochemistry, and molecular biology of serotonergic receptors has increased exponentially; with each advance it...
In a previous study it was observed that fluoxetine potentiates the stimulus effects of lysergic acid diethylamide (LSD). In the present investigation, stimulus control was established in groups of rats using as training drugs the hallucinogens lysergic acid diethylamide (LSD); 0.1 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine [(-)-DOM; 0.56 mg/kg], ibogaine (10 mg/kg), and...
1. 5-HT3, 5-HT2C, and 5-HT1A receptor ligands were assessed in rats trained to discriminate ibogaine from water. 2. Significant ibogaine-appropriate responding was observed following treatment with the 5-HT2C agonists MK-212 (79.6%) and mCPP (76.4%). This substitution was completely antagonized by metergoline, an agent with 5-HT2C antagonist properties. However, metergoline was ineffective...
The structural features and hallucinogenic properties shared by ibogaine and certain beta-carbolines prompted the evaluation of several representative beta-carbolines in rats trained with ibogaine as a discriminative stimulus. In a previous report from our laboratory harmaline completely substituted for ibogaine (83.5%). In the present study, only 6-methoxyharmalan completely substituted...
In the present investigation, the ability of two known hallucinogens, lysergic acid dimethylamide (LSD) and (-)-2,5-dimethoxy-4-methyl-amphetamine (DOM), to substitute for the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) was assessed in Fischer-344 rats. In these subjects, intermediate levels of generalization were observed to both agents (LSD, 63%; DOM, 66.4%)....
Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (sigma), and...
Stimulus control induced by (-)-2,5-dimethoxy-4-methylamphetamine (DOM) is believed to be mediated by agonism at 5-HT2A receptors. We hypothesized that blockade of (-) DOM-induced stimulus control may thus prove useful in the pre-clinical characterization of novel antipsychotic agents by providing an in vivo index of antagonism at that receptor. A previous study (Fiorella et al., 1995a)...
The effects of ibogaine were studied in 12 rats trained to perform in an 8-arm radial maze. In Phase I, the mean number of sessions to criterion and cumulative errors to criterion, as well as mean response rate, were determined for two groups of six animals in a task where only four arms were baited. Group 1 received a potentially neurotoxic dose of ibogaine (50 mg/kg IP administered twice,...
The present investigation assessed the chronic toxicity of ibogaine on cerebellar Purkinje cells in male Fischer 344 rats. A behaviorally active dose of ibogaine (10 mg/kg, i.p.) was administered to a group of six subjects every other day for 60 days while the control group received an equivalent volume of saline (1 ml/kg). Estimates of Purkinje cell number were determined using the optical...