Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interactions of the hallucinogenic drug PCP [1-(1-phenylcyclohexyl)piperidine] and some of its analogs with the nicotinic acetylcholine receptor-ionic channel complex were studied using electrophysiological techniques. The peak amplitude and the decay time constant of the nerve-evoked end-plate current (EPCs) recorded from the frog sartorius muscle were reduced by all the analogs in a concentration-dependent manner (IC50 between 5 and 90 microM). PCP, TCP [1-[1-(2-thienyl)cyclohexyl]-piperidine] and PCE (N-ethyl-1-phenylcyclohexylamine), among other analogs, caused a negative slope conductance in the current-voltage relationship at hyperpolarized potentials and a voltage- and time-dependent depression of the peak amplitude of the EPC. When the piperidine ring of the PCP molecule was substituted by a morpholino ring, as in 1-(1-phenylcyclohexyl)morpholine and 1-[1-(2-thienyl)-cyclohexyl]morpholine, the potency decreased and the negative conductance was eliminated. The removal of the piperidine ring of PCP in 1-phenylcyclohexylamine and the hydroxylation of the cyclohexane ring in 4-phenyl-4-piperidino-cyclohexanol reduced the potency and produced double exponential decays at potentials between +50 and -50 mV. At -100 mV, the potency for decreasing peak EPC amplitude was well correlated with the potency for reducing the decay time constant for all the analogs. The voltage- and time-dependent depression of the EPC amplitude was reduced by substitution of a morpholino ring and by the elimination of the piperidine ring of PCP. The behaviorally active analogs were the most potent EPC blockers, which suggests a synaptic role for the production of depressant behavioral effects observed with PCP.
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PMID:Effects of phencyclidine and its analogs on the end-plate current of the neuromuscular junction. 348 35

This retrospective study was conducted in response to a need to evaluate the overall utilization rates of the psychiatric consultation liaison service by nonpsychiatric units within Howard University Hospital, which deals almost exclusively with a black, inner-city population. The study covers a three-year period (July 1982 to July 1985). During this time only 815 patients (2 percent) were referred for psychiatric evaluation out of the total number of hospital admissions (40,000 patients).Patient characteristics and general attitudes appear to have had a major role in this low ratio of referrals, particularly a lack of awareness and bias against psychiatry. This latter finding is in disparity with other published reports. Diagnostically, depression, organic mental disorders (acute), and substance abuse (mainly PCP) constituted the greater bulk of the patients seen by the consultation liaison psychiatry service. The review of a random sample of psychiatric inpatients (n = 100) revealed that in 50 percent of the cases there was a coexisting physical illness or abnormality.The role of mental health education and the liaison function needs to be emphasized. It is suggested that efforts should be directed toward a wider acceptance and utilization of consultation liaison psychiatry by primary care physicians in general hospitals. The factors listed by physicians and patients that may account for the observed underutilization of consultation liaison services are discussed. The results of 20 interviews and the reasons given by referring physicians as to whether or not they will seek consultation from the consultation liaison services are also reviewed.
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PMID:Utilization of a consultation liaison psychiatry service in a general hospital. 358 47

The actions of the tertiary local anesthetic bupivacaine were studied on the nicotinic receptor-ionic channel complex (AChR) using electrophysiological and biochemical methods. Voltage clamp studies of the frog sartorius and cutaneous pectoris neuromuscular junction revealed a concentration-dependent depression of the decay time constant of the end-plate (tau EPC) and spontaneous miniature end-plate (tau MEPC) currents. The relationship of the reciprocal of either tau EPC or tau MEPC and bupivacaine concentration up to 100 microM was linear. Voltage dependence of EPC over the range +60 to -150 mV was reduced, whereas both EPC and MEPC decays were adequately described by a single exponential function at all concentrations tested. Peak MEPC and EPC amplitudes were also depressed in a concentration-dependent manner such that 100 microM bupivacaine reduced peak amplitude by about 50%. The current-voltage relationship remained linear under all conditions tested. Nerve-evoked responses were difficult to study at concentrations greater than 100 microM because of apparent blockade of nerve conduction. Extracellular recording of the MEPC afforded results similar to those obtained with EPCs. The tau MEPC could be reduced to less than 300 mu sec at a bupivacaine concentration of 400 microM. Fluctuation analysis showed that bupivacaine at concentrations of 10 and 25 microM did not change channel conductance but decreased single-channel lifetime to 76% and 39% of control values, respectively. Biochemical studies were performed on Torpedo californica membrane fragments using [3H]phencyclidine ([3H]PCP) and [3H]perhydrohistrionicotoxin ([3H]H12-HTX) as channel probes. Bupivacaine inhibited the binding of [3H]PCP and [3H]H12-HTX with inhibition constants (Ki) of 32 and 25 microM, respectively. The corresponding inhibition constants for bupivacaine methiodide were 1.8 and 3.2 microM. The preincubation of the membranes with carbamylcholine increased the affinity of bupivacaine for the ionic channel sites 5- to 8-fold and the affinity of bupivacaine methiodide 3- to 4-fold. Bupivacaine, however, had no affinity for the agonist recognition site as determined by [3H]ACh and [125I]alpha-bungarotoxin bindings. The electrophysiological and biochemical studies indicate that bupivacaine reacts primarily with the ionic channel of the nicotinic AChR. The results are consistent with a sequential model in which the drug interacts with the sites at the ionic channel of AChR in its open conformation, producing species with little or no conductance. From the present studies there is no evidence for an interaction of bupivacaine with the agonist binding site or closed states of AChR.
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PMID:Interactions of bupivacaine with ionic channels of the nicotinic receptor. Electrophysiological and biochemical studies. 609 Aug 84

Alterations by ketamine (10-100 microM) and ditran (50-100 microM) of end-plate currents were studied using transected cutaneous pectoris muscles. Both drugs reduced peak current and shortened the time constant for end-plate current decay (tau). Ketamine was more effective at pH 5.3 than at 7.4 or 9.1. Recovery from blockade was asymmetrical in that tau recovered more quickly than did peak current when the drugs were removed from the bath. By contrast, 4-aminopyridine antagonized the depression of peak current by ketamine, but not the reduction of tau. Both ketamine and ditran disrupted the voltage dependence of tau. The binding to microsacs prepared from electric organs of [3H]phencyclidine ([3H]PCP) was blocked by ketamine and ditran. In microsacs treated with carbachol, the IC50 for ketamine block of [3H]PCP binding was 6.6 X 10(-6) M. For ditran, the IC50 for block of [3H]PCP binding in the presence of carbachol was 1.7 X 10(-6) M. The binding of [alpha-125I]bungarotoxin to the microsacs or to the cultured chick myotubes was reduced only slightly by ketamine. Because ketamine has no effect on transmitter release and little effect on [alpha-125I]bungarotoxin binding, it is concluded that, like PCP, ketamine and ditran block open channels in the end-plate. In addition, the asymmetrical recovery of end-plate current parameters suggests that ketamine may block closed channels. The recovery from block of closed channels (caused by either a direct action on closed channels or a very slow channel unblocking rate) proceeds more slowly than does the block of open channels.
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PMID:Ketamine and ditran block end-plate ion conductance and [3H]phencyclidine binding to electric organ membrane. 612 84

Phencyclidine (PCP) at high doses causes both excitation and depression in the rat. The visual evoked potential (VEP) was measured in rats following PCP administration in doses ranging from 1 mg/kg to 56 mg/kg. Consistent lengthening of VEP latencies suggests that PCP has an unusual inhibitory effect on visual function in the presence of the excitatory signs of bilaterally synchronous cortical spiking. The epileptogenic properties of PCP are quite evident in rats.
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PMID:Phencyclidine-induced alterations of rat electrophysiology. 626 54

The discriminant effects of several behaviorally active and inactive analogs of phencyclidine [PCP; 1-(phenylcyclohexyl) piperidine] and the actions of PCP and three Ca-channel antagonists were examined on electrical excitability in frog and crayfish skeletal muscles. In frog sartorius muscle, 1-[1-(2-thienylcyclohexyl)piperidine (TCP; 100 microM), a behaviorally active analog of PCP, increased action potential duration nearly 9-fold, blocked delayed rectification and at 0.5 to 1 microM also increased the quantal release of transmitter. A partial blockade of delayed rectification and slight prolongation of the action potential occurred with 1-(p-fluorophenylcyclohexyl)piperidine (p-F-PCP; 100 microM), which possesses about 25% of the behavioral activity of PCP. Of the remaining p-phenyl- substituted analogs which never exhibited more than 10% of the behavioral potency of PCP, only 1-(1-p-nitrophenylcyclohexyl)piperidine (p-NO2-PCP; 100 microM) produced a frequency-dependent prolongation of the action potential but, like the p-methoxy-, p-chloro- and p-methyl- analog, it did not block delayed rectification. The order of potencies of these analogs in blocking delayed rectification, prolonging the muscle action potential and in affecting alternation impairment and response rate depression is therefore: PCP much greater than TCP greater than p-F-PCP much greater than p-CH3-PCP = p-CH3O-PCP = p-Cl-PCP = p-NO2-PCP. Like PCP and its behaviorally active analogs, verapamil (50 microM) and bepridil (50 microM), two Ca-channel blockers, also blocked delayed rectification in frog sartorius muscles whereas nifedipine (50 microM), another Ca-channel blocker, did not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Discriminant effects of behaviorally active and inactive analogs of phencyclidine on membrane electrical excitability. 631 72

Evidence from a variety of experimental models has suggested the existence of mu 1, mu 2 and delta binding sites for morphine and the enkephalins in the central nervous system. Additional biochemical experiments now support this concept of a common high affinity site for opiates and opioid peptides. Mu sites have now been implicated in a number of pharmacological actions, including supraspinal analgesia, prolactin release, and catalepsy, but not in others (spinal analgesia, respiratory depression, and the guinea pig ileum). The hypothesis of mu 1 sites was supported by the unique opioid meptazinol, which selectively bound to mu 1 sites. As expected from its mu 1 binding selectivity, its analgesic actions in the mouse, localized supraspinally, were antagonized by the selective mu 1 antagonist naloxonazine and it had no respiratory depressant actions. Other binding studies suggested the presence of discrete SKF10,047-selective (KD approximately 5 nM) binding sites in rat brain which differed from both kappa sites and the previously reported PCP-binding sigma sites. Additional binding and autoradiographical studies have also implied the presence of beta-endorphin, or epsilon, sites in the CNS.
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PMID:Biochemical and pharmacological evidence for opioid receptor multiplicity in the central nervous system. 631 56

Effects of acute and chronic administration of phencyclidine (PCP) on heart rate (HR) and respiratory rate (RR) were studied in rhesus monkeys. Acute administration of PCP (2.0 and 4.0 mg/kg i.v.) produced decrements in both HR and RR within 15 to 30 min after drug administration. Simultaneously, with this cardiorespiratory slowing, EEG tracings evidenced High-Voltage Slow-Waves (HVSW) and delta-waves. As HR and RR began to recover, High-Voltage Fast-Waves (HVFW) along with theta-waves developed in EEG recordings and persisted for 2-6 h, while both HR and RR were gradually returning to their respective pre-drug control levels. The intensity and duration of these PCP-induced effects were directly related to dosage level. Following chronic administration of PCP (daily dose of 2.0 or 4.0 mg/kg i.v.), its ability to produce cardiorespiratory alterations was significantly diminished along with a decrease in PCP-induced depression of EEG and behavioral activities. These results suggest that chronic PCP administration produces a tolerance to its depressant effect on HR, RR, EEG and behavioral activities in rhesus monkeys.
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PMID:Effects of phencyclidine (PCP) on cardiorespiratory functions in the rhesus monkey. 647 27

A series of phencyclidine (PCP) related analogs, carbonitrile synthetic precursors and two monohydroxylated metabolites were compared pharmacologically in mice for their ability to produce ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. The slope of the PCP dose-ataxic response curve was steeper than those of diazepam, pentobarbital, morphine and ketocyclazocine but not the slope of the sigma agonist, N-allylnormetazocine curve. Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP. Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 X PCP and durations of action ranged from 18 to 65 min. N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine and 1-[1-(2-thienyl)-cyclohexyl]-pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl morpholines and 4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the piperidine or aromatic ring effected changes only in potency. Seizures and respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-piperidine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine, N-ethyl-1-phenylcyclohexylamine and ketamine and the smallest were for 1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the three precursors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phencyclidine analogs and precursors: rotarod and lethal dose studies in the mouse. 674 25

The effects of chronic dietary exposure to technical pentachlorophenol (PCP-T) on humoral immune responses in mice were examined. Primary and secondary splenic antibody responses to the T-dependent antigen, sheep red blood cells (SRBC), were examined in Swiss-Webster mice using our recently developed screening technique, the Hemolytic Antibody Isotope Release (HAIR) assay. To assess direct effects of PCP-T on B cells, the splenic plaque-forming cell response and serum antibody titers to the T-independent antigen, dinitrophenyl (DNP)-Ficoll, were examined. PCP-T exposure altered both the kinetics and the magnitude of the humoral antibody responses to SRBC and DNP-Ficoll. Peak splenic antibody production and serum antibody titers were delayed and the magnitude of the antibody responses were dose-dependently suppressed by PCP-T exposure. IgM responses appeared to be more sensitive to PCP-T-induced suppression than the IgG response. Significant depression of the IgM anti-SRBC splenic HAIR response was apparent as early as 2 weeks after initiation of PCP-T exposure and persisted for at least 8 weeks after termination of PCP-T feeding. Liver weight and serum lactate dehydrogenase (LD-L) and alanine aminotransferase (ALT) levels were significantly elevated during PCP-T exposure and returned to control levels after a 4-6 week recovery period. The immunotoxic effect of PCP on humoral immunity was observed only in animals exposed to technical grade PCP known to be contaminated with significant levels of other chlorinated phenols as well as non-phenolic impurities including chlorinated dioxins, furans, and diphenyl ethers. Animals exposed to analytical grade PCP did not exhibit depressed humoral immunity.
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PMID:Immunotoxicity of technical pentachlorophenol (PCP-T): depressed humoral immune responses to T-dependent and T-independent antigen stimulation in PCP-T exposed mice. 676 29


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