Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.16.2 (PCP)
3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aromatic L-amino acid decarboxylase (AADC) is rate limiting in the production of 2-phenylethylamine (2PE). AADC activity and 2PE serum concentrations have been found to be increased in schizophrenic patients. Both antipsychotic and psychotogenic drugs, including amphetamine, affect the activity and encoding mRNA levels of AADC. Amphetamine is an analogue of 2PE and has a similar physiological effect. We have looked at the effects of chronic (32 day) treatment of rats with LSD (0.12 microg/kg/day) and phencyclidine (PCP; 10 mg/kg/day) on AADC mRNA levels. Both drugs up-regulated AADC mRNA levels in striatum, nucleus accumbens, hippocampus and cerebellum by between 50% and 150%. A splicing variant of AADC, present in human brain, which lacks the 3rd exon does not appear to be present in rat brain. These results are consistent with the hypothesis that over activity of AADC leading to increased production of 2PE is involved in endogenous psychosis such as schizophrenia.
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PMID:Does phenylethylamine have a role in schizophrenia?: LSD and PCP up-regulate aromatic L-amino acid decarboxylase mRNA levels. 938 86

Recent research into the pharmacological mechanism of hallucinogens (LSD, psilocybin) and dissociative anesthetics (PCP, ketamine) suggest that multiple neurotransmitter systems are involved in drug-induced and possibly also in naturally occurring psychoses. Specifically, animal models suggest that a dysbalance between serotonin, glutamate, and dopamine in the limbic cortico-striato-thalamic circuitry may be critical to psychotic symptom formation. To test this hypothesis, psychometric measures and metabolic PET investigations were performed (1) with FDG to elucidate the common neuronal substrates of different hallucinogens, (2) with specific receptor ligands before and after pretreatment with specific receptor antagonists to explore the putative interactions of hallucinogens with various neurotransmitter systems. Our data demonstrate that the neuronal substrate of normal and abnormal thought and behavior is associated with a distributed neuronal network and with multiple interactive neurotransmitter systems. The data also support the view that the hallucinogen challenge paradigm constitutes a powerful tool for elucidating the pathophysiology of neuropsychiatric disorders.
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PMID:Advances and pathophysiological models of hallucinogenic drug actions in humans: a preamble to schizophrenia research. 975 40

In an attempt to increase the selectivity of drug discrimination, rats were trained to discriminate LSD (0.08 mg/kg) from a group of "other" compounds consisting of cocaine (10 mg/kg), pentobarbital (5 mg/kg), and saline. Acquisition of this LSD-other discrimination was rapid (31 days) in chambers equipped with retractable levers and did not differ significantly from that of a group of animals trained to discriminate LSD from saline (26 days). In substitution (generalization) tests, hallucinogens such as LSD, DMT, and DOM mimicked LSD in a dose-dependent manner in both groups. The designer drug (+/-)MDMA substituted for LSD in the LSD-other group (ED50 = 1.38) but did not substitute for the training drug in the LSD-ND group; neither (+) MDMA nor PCP mimicked LSD in either group. Most importantly, lisuride, quipazine, and yohimbine, drugs that have been described as "false positives," substituted for LSD in animals trained to discriminate LSD from saline (ED50s = 0.012, 1.662, 2.344, respectively), but not in animals trained to discriminate LSD from other drugs. Thus, the LSD-other training procedure can be described as more selective than the standard drug-ND procedure.
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PMID:Increasing the selectivity of drug discrimination procedures. 1051 12

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.
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PMID:Antagonism of a PCP drug discrimination by hallucinogens and related drugs. 1078 61

To determine the prevalence of substance use in adolescents with eating disorders, compare the results with a data set of Ontario high school students, and explore why adolescents with eating disorders do, or do not, use various substances. From January 1999 to March 2000, 101 female adolescents who met the DSM-IV criteria for an eating disorder were followed up in a tertiary care pediatric treatment center. They were asked to participate in a cross-sectional study using a self-administered questionnaire assessing substance use and investigating reasons for use and nonuse; 95 agreed to participate and 77 completed the questionnaire (mean age, 15.2 years). The patients were divided into two groups: 63 with restrictive symptoms only, 17 with purging symptoms. The rates of drug use between subjects and their comparison groups were compared by z-scores, with the level of significance set at.05. During the preceding year, restrictors used significantly less tobacco, alcohol, and cannabis than grade- and sex-matched comparison populations, and purgers used these substances at rates similar to those of comparison subjects. Other drugs seen frequently in the purgers included hallucinogens, tranquilizers, stimulants, LSD, PCP, cocaine, and "ecstasy." Both groups used caffeine and laxatives, but few used diet pills. Restrictors said they did not use substances because they were bad for their health, tasted unpleasant, were contrary to their beliefs, and were too expensive. Purgers generally used substances to relax, relieve anger, avoid eating, and "get away" from problems. Female adolescents with eating disorders who have restrictive symptoms use substances less frequently than the general adolescent population but do not abstain from their use. Those with purging symptoms use substances with a similar frequency to that found in the general adolescent population. Because the sample size for the purging group was small, firm conclusions cannot be drawn from our analysis. Health care providers who treat adolescents with eating disorders are in a good position to identify those who use substances and may be at risk for substance abuse.
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PMID:Substance use in female adolescents with eating disorders. 1212 88

In the present study, we have investigated the effects of two selective 5-HT6 receptor antagonists, Ro04-6790 and Ro65-7199, in three drug-induced models of PPI disruption and on latent inhibition (LI) utilizing a conditioned lick suppression (CLS) procedure. Clozapine was included in each experiment for comparison. Neither Ro04-6790 nor Ro65-7199 (both 30 mg/kg) affected the PPI disruption produced by PCP (1.5 mg/kg s.c.), apomorphine (0.1 mg/kg s.c.), or LSD (0.1 mg/kg s.c.). There was also no interaction between each drug and CS preexposure in the CLS test indicating a failure of each drug to facilitate LI. In contrast, clozapine (12 mg/kg) attenuated an apomorphine and PCP-induced PPI deficit, although the PPI disruption produced by LSD was not significantly affected. At a lower dose of 5 mg/kg, clozapine also facilitated LI. Since each of these tests bear some predictive validity for the detection of antipsychotic drugs, the present studies do not support a therapeutic potential of 5-HT6 receptor antagonists in this regard.
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PMID:Effect of the 5-HT6 receptor antagonists Ro04-6790 and Ro65-7199 on latent inhibition and prepulse inhibition in the rat: comparison to clozapine. 1287 17

Despite the fact that most researchers acknowledge the high prevalence of comorbid substance abuse among schizophrenic patients, there is no common agreement regarding the etiology of this serious public health problem. At the center of this debate though, Khantzian's self-medication hypothesis has captured most of the attention. In the present literature review, the authors evaluate this hypothesis in the light of our current knowledge. Formulated in a clinical context, in reaction to the psychoanalytic interpretation of addiction as a pleasure seeking pathology, Khantzian's hypothesis holds that schizophrenic patients use psychoactive substances to relieve their symptoms. Properly understood, this conjecture presupposes that, with the relief of certain target symptoms, substance use would no more be a necessity. But in reality, the use of psychoactive substances usually leads to a general deterioration of the patients' condition. Pharmacodependent schizophrenic patients relapse more often, they are more frequently hospitalized, they show more violent behaviors, and they are more frequently homeless. In particular, the positive symptoms of these patients are generally exacerbated by the psychoactive drugs--with the possible exception of opiates. This observation is in lign with the fact that psychostimulants (cocaine, amphetamines), anesthesic dissociatives (PCP, ketamine) as well as hallucinogens (cannabis, LSD) are all known to exert psychotomimetic effects. As for negative symptoms, the reality is more complex. Preliminary results certainly suggest that stimulants (minor or major) relieve these symptoms, but in the case of the other psychoactive substances, empirical evidence remains fragmentary. Still, the properties of psychoactive substances invite to pay close attention, among the negative symptoms, to the cognitive deficits, the social inaptitudes and the hedonic deficits of these patients. Unsatisfied with the self-medication hypothesis, an increasing number of researchers hypothesize that schizophrenic patients abuse drugs in hope to relieve the negative affects (stress, depression) that commonly accompany their symptomatology. Interestingly, increasing data link these negative manifestations and substance abuse among schizophrenic patients. But these same data do not elucidate whether these manifestations are primary or secondary to drug abuse. For the moment, these findings must be replicated. Furthermore, it remains to be clarified what negative affect is involved here. Is it stress, anxiety or, as commonly thought, depression? Other paths aim in the direction of personality traits and dissociation. The first path is suggested by recent studies demonstrating that pharmacodependent schizophrenic patients differ from non-abusing schizophrenics in that their personality is characterized by traits such as sensation seeking and impulsivity. As for the second path, it is suggested by a recurrent observation in addictive medicine practice, that is: alcohol, cannabis, ketamine, LSD, opiates, PCP, all these substances can induce dissociative states (depersonalization, derealization, etc.). Surprisingly, most of the hypotheses advanced so far have been formulated without reference to neuroscience. However, from a biological perspective, substance abuse among schizophrenic patients appears paradoxical: while the positive symptoms of schizophrenia might involve an hyperactivity of the reward system, the drugs of abuse all seem to increase dopamine release in that same system. That very paradox further casts some doubt on the self-medication hypothesis. And it opens an alternative: schizophrenic patients might be biologically vulnerable to the rewarding effects of drugs abuse. On the therapeutic level finally, the authors argue that polypharmacy medications such as clozapine and quetiapine, known to act on the reward system preferentially to the extrapyramidal system and known to dissociate fastly from the dopamine-D2 receptor, could simplify clinical intervention.
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PMID:[Schizophrenia and addiction: An evaluation of the self-medication hypothesis]. 1287 43

Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated.
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PMID:Diverse psychotomimetics act through a common signaling pathway. 1524 57

Surveillance data suggests that club drug use (Ecstasy, GHB, ketamine, LSD, methamphetamine, PCP and flunitrazepam) has been a predominantly White adolescent and young adult phenomenon in the United States. The authors investigated the use of club drugs among 323 street-recruited minority substance users in northern New York City (66.3% were Hispanic, 23.8% were Black, and 9.9% were White/other race; median age = 32 years old). While Whites were more likely than others to have used club drugs, club drug use among Hispanics and Blacks was not uncommon; 45.3% Hispanics and 56.4% of Blacks reported a lifetime history of club drug use. PCP was the most commonly reported club drug used among all racial/ethnic groups. Further investigation of club drug use in minority populations is warranted.
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PMID:Club drug use among minority substance users in New York City. 1555 86

The third in a series reviewing the HIV/AIDS antiretroviral drugs, this report summarizes the interactions between antiretrovirals and common drugs of abuse. In an overview format for primary care physicians and psychiatrists, the metabolism and drug interactions in the context of antiretroviral therapy are presented for the following drugs of abuse: alcohol, benzodiazepines, cocaine, GHB (liquid X), ketamine (special K), LSD (acid), MDMA (Ecstasy), opiates, PCP (angel dust), and THC (marijuana).
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PMID:Med-psych drug-drug interactions update. Antiretrovirals, part III: antiretrovirals and drugs of abuse. 1576 27


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