Vulnerability to psychosis associated with hallucinogen use

Bowers, Malcolm B.; Swigar, Mary E.

doi:10.1016/0165-1781(83)90030-6

Cited by 31 publications

(19 citation statements)

References 19 publications

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“…Javitt and Zukin noted that the concentration of phencyclidine associated with psychosis was in the same range that would bind to the NMDA receptor, and proposed that schizophrenia might result from hypofunction of NMDA receptors (Javitt and Zukin 1991). However, there were concerns with this causal interpretation, an alternative explanation being that individuals who abused PCP or ketamine might be at high risk for a schizophrenic-type reaction (Bowers and Swigar 1983). …”

Section: Origins Of the Glutamate Hypothesis: Dissociative Anesthetmentioning

confidence: 99%

Glutamatergic Synaptic Dysregulation in Schizophrenia: Therapeutic Implications

Coyle

Basu

Benneyworth

et al. 2012

Handbook of Experimental Pharmacology

157

101

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Schizophrenia affects approximately 1% of the population and continues to be associated with poor outcome because of the limited efficacy of and noncompliance with existing antipsychotic medications. An alternative hypothesis invoking the excitatory neurotransmitter, glutamate, arose out of clinical observations that NMDA receptor antagonists, the dissociative anesthetics like ketamine, can replicate in normal individuals the full range of symptoms of schizophrenia including psychosis, negative symptoms, and cognitive impairments. Low dose ketamine can also re-create a number of physiologic abnormalities characteristic of schizophrenia. Postmortem studies have revealed abnormalities in endogenous modulators of NMDA receptors in schizophrenia as well as components of a postsynaptic density where NMDA receptors are localized. Gene association studies have revealed several genes that affect NMDA receptor function whose allelic variants are associated with increased risk for schizophrenia including genes encoding D-amino acid oxidase, its modulator G72, dysbindin, and neuregulin. The parvalbumin-positive, fast-firing GABAergic interneurons that provide recurrent inhibition to cortical-limbic pyramidal neurons seem to be most sensitive to NMDA receptor hypofunction. As a consequence, disinhibition of glutamatergic efferents disrupts cortical processing, causing cognitive impairments and negative symptoms, and drives subcortical dopamine release, resulting in psychosis. Drugs designed to correct the cortical-limbic dysregulated glutamatergic neurotransmission show promise for reducing negative and cognitive symptoms of schizophrenia as well as its positive symptoms.

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Section: Origins Of the Glutamate Hypothesis: Dissociative Anesthetmentioning

confidence: 99%

Glutamatergic Synaptic Dysregulation in Schizophrenia: Therapeutic Implications

Coyle

Basu

Benneyworth

et al. 2012

Handbook of Experimental Pharmacology

157

101

View full text Add to dashboard Cite

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“…More specifically, because use of hallucinogens, which exert their effects via activation of 5-HT 2A receptors, 16,17 can increase the risk of developing psychotic illnesses, 44 we assessed whether SNPs altered the affinity and relative efficacy of several 5-HT 2A receptor agonists. Our data demonstrated a 10-fold decrease in DOI potency and the 36% decrease in DOI relative efficacy due to the H452Y and I197V SNPs, respectively, along with the 30% decrease in 5-methoxy-DMT relative efficacy due to the I97V SNP.…”

Section: Differential Pharmacology Of 5-ht 2a Snpsmentioning

confidence: 99%

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

et al. 2005

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The 5-HT 2A -serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT 2A -serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT 2A -serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT 2A receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.

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“…These hypotheses do not explain the heavy use of alcohol and other drugs prior to the onset of psychiatric symptoms that characterizes many people with chronic illnesses (Barbee and others, 1989;Breakey, Goodell, Lorenz, and McHugh, 1974;Caton, Gralnick, Bender, and Simon, 1989). For them, drugs may precipitate or induce psychiatric disorder (Bowers and Swigar, 1983;Breakey, Goodell, Lorenz, and McHugh, 1974;McLellan, Woody, and OBrien, 1979). Painful internal states or interpersonal problems that exist prior to the onset of overt mental illness may be significant risk factors.…”

Section: Reasons For Usementioning

confidence: 99%