Serotonergic/glutamatergic interactions: the effects of mGlu 2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli

Winter, J.C.; Eckler, J.R.; Rabin, Richard A.

doi:10.1007/s00213-003-1636-2

Cited by 78 publications

(62 citation statements)

References 55 publications

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“…Contrary to these predictions and previous work by Winter et al (2004), the (À)-DOB discriminative stimulus, a 5-HT 2A receptor-mediated behavior, is not modulated by compounds acting at mGlu2/3 receptors. A wide range of mGlu2/3 receptor agonist and antagonist doses tested at multiple times fail to alter the discriminative stimulus effect of (À)-DOB.…”

Section: Discussioncontrasting

confidence: 99%

“…A wide range of mGlu2/3 receptor agonist and antagonist doses tested at multiple times fail to alter the discriminative stimulus effect of (À)-DOB. Winter et al (2004) found that in rats the LSD discriminative stimulus was subtly potentiated by an mGlu2/3 antagonist and attenuated by an mGlu2/3 agonist. However, several experimental variables differ between that work and the present study.…”

Section: Discussionmentioning

confidence: 96%

“…This assay allows an objective quantification of the interoceptive cue in laboratory animals, and correlates with the subjective effects of hallucinogens reported by humans (Appel et al, 1982;Colpaert, 1999). Drug discrimination studies in rats have presented evidence that the discriminative stimulus effects of LSD and other hallucinogens occurs via activation of the 5-HT 2A receptor (Glennon et al, 1983;Glennon et al, 1984;Titeler et al, 1988;Fiorella et al, 1995;Winter et al, 2004). The recent development of genetically-modified mouse strains provides a unique opportunity to explore the molecular basis of the hallucinogenic drug action, however only a few studies have begun to characterize the hallucinogen-induced discriminative stimulus in mice (Smith et al, 2003;Benneyworth et al, 2005;Winter et al, 2005).…”

Section: Introductionmentioning

confidence: 88%

“…Activation of mGlu2/3 receptors dramatically attenuates 5-HT 2A receptor-induced EPSCs , supporting the use of hallucinogens as a model for studying the regulation of hyperactive glutamatergic signaling by mGlu2/3 receptors in vivo. Consistent with this model, mGlu2/3 receptor agonists attenuate the behavioral effects of hallucinogens (Gewirtz and Marek, 2000;Klodzinska et al, 2002;Winter et al, 2004). While a range of behavioral assays have been developed to test hallucinogenic drug action in rodents, of particular interest is the two-lever drug discrimination paradigm.…”

Section: Introductionmentioning

confidence: 98%

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Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

Benneyworth

Smith

Sanders‐Bush

2007

Neuropsychopharmacol

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Recent clinical studies in schizophrenic patients show that a selective agonist of group II metabotropic glutamate (mGlu) receptors has robust efficacy in treating positive and negative symptoms. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs, reducing the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogen-induced glutamatergic neurotransmission using genetic as well as pharmacological strategies. The current study sought to characterize the use of the two-lever drug discrimination paradigm in ICR (CD-1) mice, using the hallucinogenic 5-HT 2A/2C receptor agonist (À)-2,5-dimethoxy-4-bromoamphetamine [(À)-DOB)] as a stimulus-producing drug. The (À)-DOB discriminative stimulus was dose-dependent, generalized to the hallucinogen lysergic acid diethylamide, and was potently blocked by the 5-HT 2A receptor antagonist M100907. However, contrary to our prediction, the hallucinogen-induced discriminative stimulus was not regulated by mGlu2/3 receptors. In a series of follow-up studies using hallucinogen-induced head twitch response and phencyclidine-induced hyperlocomotion, it was additionally discovered that the repeated dosing regimen required for discrimination training attenuated the behavioral effects of the mGlu2/3 receptor agonist LY379268. Furthermore chronic studies, using a 14 day (À)-DOB treatment, confirmed that repeated hallucinogen treatment causes a loss of behavioral activity of mGlu2/3 receptors, likely resulting from persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 98%

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Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

Benneyworth

Smith

Sanders‐Bush

2007

Neuropsychopharmacol

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“…Discrimination training was then begun. The initial group of 12 subjects was trained to discriminate PCP (3.0 mg/kg, 30 min pretreatment time, IP; N = 12) from vehicle as described previously (Hirschhorn and Winter 1971;Fiorella et al 1995;Winter et al, 2004). Subsequently, a second group of 12 subjects was trained at a dose of 2.5 mg/kg using a pretreatment time of 15 min (West et al 2000).…”

Section: Training Proceduresmentioning

confidence: 99%

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

2008

Pharmacology Biochemistry and Behavior

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It has been observed that agents with agonist activity at 5-HT 2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors.

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Hallucinogenic Drugs

Bonson

2012

Encyclopedia of Life Sciences

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Hallucinogens constitute one of the oldest classes of drugs used by humanity, often in the context of spiritual practices. Classic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, N,N ‐dimethyltryptamine (DMT), mescaline and 2,5‐dimethoxy‐4‐methylamphetamine (DOM) produce complex psychological and physical effects, including perceptual changes, cognitive shifts in reality and emotional alterations. These drugs primarily act on serotonin systems through 5‐hydroxytryptamine 2A (5HT 2A ) receptors, with additional activity through dopamine and glutamate systems. Investigation of the neurochemical and behavioural effects of this class of drugs has provided important insights into pharmacology and psychiatric conditions. Given their popularity as recreational drugs, investigation of their actions and effects continues to be an important endeavour. After a long hiatus, clinical studies in humans have resumed with these drugs in laboratories around the world. Key Concepts: Hallucinogens have been used for thousands of years by various societies, often in conjunction with spiritual practices. In present day, hallucinogens remain highly popular as recreational drugs. The chemical structure of hallucinogens consists of tryptamines (LSD and psilocybin) and phenethylamines (mescaline and DOM). The potency of hallucinogens is directly correlated to their ability to act as agonists at the serotonin receptor subtype, 5‐HT 2A . Drugs that act at sites other than 5‐HT 2A receptors can also produce hallucinogen‐like effects (e.g. ketamine, MDMA, salvinorin A, nitrous oxide, GHB). The signature effects of hallucinogens include perceptual changes, alterations in affect and shifts in cognitive ability. Negative responses associated with hallucinogens include ‘bad trips’ (severe anxiety and a disconnection with reality) as well as rare instances of ‘flashbacks’ and psychotic breaks. Human research with hallucinogens has recently been revitalised, augmenting the scientific advances made previously with animal studies.

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Serotonergic/glutamatergic interactions: the effects of mGlu 2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli

Abstract: These data, obtained using a stimulus control model of the hallucinogenic effects of PCP and LSD, provide support for the hypothesis that glutamate release is a factor in hallucinogenesis by both 5-HT(2) agonists and non-competitive NMDA antagonists.

Cited by 78 publications

References 55 publications

Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

Hallucinogenic Drugs

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