Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: a microdialysis study.

Masuzawa M, Nakao S, Miyamoto E, Yamada M, Murao K, Nishi K, Shingu K.

Department of Anesthesiology, Kansai Medical University, Osaka, Japan.

Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the actions of various psychotropic and addictive drugs. Ketamine and barbiturates have psychotropic effects and addictive properties, but barbiturates prevent ketamine's psychotomimetic effects. We investigated the effects of ketamine and pentobarbital on dopamine release in the NAC. A microdialysis probe was implanted in the NAC in 35 rats, which were randomly assigned to seven groups: a normal saline intraperitoneal injection (ip) group, 50 and 100 mg/kg of ketamine ip groups, 25 and 50 mg/kg of pentobarbital ip groups, and a normal saline or 25 mg/kg of pentobarbital ip followed by 50 mg/kg of ketamine ip groups. Perfusate samples were collected every 20 min, and dopamine concentration was measured by high-performance liquid chromatography. Ketamine at doses of 50 mg/kg and 100 mg/kg significantly increased dopamine release in the NAC. Conversely, pentobarbital significantly decreased dopamine release in the NAC and inhibited the ketamine-induced dopamine release. These data suggest that the dopamine release in the NAC may be involved in ketamine-induced, but not barbiturate-induced, psychotropic effects and addiction. Inhibition of ketamine-induced dopamine release by barbiturates may be a mechanism by which they prevent ketamine emergence reactions. IMPLICATIONS: Ketamine increased dopamine release in the nucleus accumbens, which was inhibited by pentobarbital. The mesolimbic dopamine system may be involved in the psychotomimetic effects of ketamine, and the suppression of ketamine emergence reactions by barbiturates may be because of the inhibition of ketamine-induced dopamine release in the nucleus accumbens.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12505941&dopt=Abstract barbiturate Butalbital Fioricet





Correlates of benzodiazepine use among a sample of arrestees surveyed through the Arrestee Drug Abuse Monitoring (ADAM) Program.

Yacoubian GS Jr.

CESAR, College Park, Maryland, USA. gyacoubian mcfarlandassociate.com

While marijuana and cocaine are the two most prevalent drugs used among arrestee populations, benzodiazepine use has surpassed that of opiates in several jurisdictions across the United States. Despite this proliferation, few scholarly works have focused on benzodiazepine use among individuals under criminal justice supervision. In the present study, chi-square statistics and logistic regression are utilized to identify significant associations between recent benzodiazepine use (as measured by urinalysis), demographic characteristics, and alcohol and other drug (AOD) use among a sample of 862 adult Philadelphia arrestees interviewed in 1997 through the Arrestee Drug Abuse Monitoring (ADAM) Program. Compared to nonusers, benzodiazepine-positive respondents were more likely to be White, to have used alcohol and barbiturates in the three days preceding the interview, and to have tested positive by urinalysis for marijuana, cocaine, opiates, and phencyclidine (PCP). Moreover, logistic regression identified that if an arrestee reported three-day barbiturate use, the odds ratio (OR) of recent benzodiazepine use was more than nine times higher than an arrestee who reported no three-day barbiturate use. Implications for drug surveillance are assessed in light of the current findings.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12602810&dopt=Abstract barbiturate Butalbital Fioricet





Thermodynamics and kinetics of t-butylbicyclophosphorothionate binding differentiate convulsant and depressant barbiturate stereoisomers acting via GABAA ionophores.

Maksay G, Molnar P, Simonyi M.

Department of Molecular Pharmacology, Central Research Institute for Chemistry, Hungarian Academy of Sciences, Budapest, Hungary.

The temperature dependence of [35S]-t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites of the GABAA receptor complex was studied in membrane preparations of rat forebrain. Although specific [35S]TBPS binding was maximal around 20 degrees C, the rate constants of dissociation decreased monotonously between 37 degrees C and 2 degrees C. The displacing potencies of the convulsant S(+) enantiomer of 1-methyl-5-phenyl-5-propyl-barbituric acid (MPPB) (IC50 = 1250 +/- 30 microM) and the depressant R(-) MPPB (IC50 = 310 +/- 5 microM) did not show significant changes between 19 degrees C and 37 degrees C. Therefore barbiturate binding seems to be driven by entropic, rather than enthalpic changes. An excess of MPPB enantiomers elicited accelerated and polyphasic dissociations of [35S]TBPS as compared to the monophasic dissociation by TBPS. Arrhenius analysis was applied to the measurable initial rate constants of dissociation. Arrhenius plots were linear between 2 degrees C and 37 degrees C. Activation parameters were similar when [35S] TBPS dissociation was triggered by the convulsants TBPS and S(+) MPPB. It can be attributed to similar conformations of the closed ionophore complex. In contrast, the depressant R(-) MPPB strongly decreased the activation energy of TBPS dissociation from the open ionophore ternary complex. In whole-cell patch-clamp experiments R(-) MPPB, but not S(+) MPPB, elicited chloride currents in rat primary cortical cultures with an EC50 value of 560 +/- 30 microM and a Hill coefficient of 2.9 +/- 0.2. These currents were similar to those elicited by GABA and blocked by TBPS. A kinetic scheme is proposed for the dissociation of TBPS and to explain the different effects of MPPB enantiomers. Submillimolar R(-) MPPB is supposed to bind to (about three) barbiturate sites on GABAA-ionophores and to open them in a cooperative manner to result in a decreased activation energy for accelerated displacement of convulsant binding.

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Anesthetic technique influences brain temperature, independently of core temperature, during craniotomy in cats.

Erickson KM, Lanier WL.

Department of Anesthesiology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota 55901, USA.

Because anesthetic technique has the potential to dramatically affect cerebral blood flow and metabolism (two determinants of brain thermoregulation), we tested the hypothesis that, after craniotomy, anesthetic technique would influence brain temperature independent of core temperature. Twenty-one cats (2.7 +/- 0.4 kg; mean +/- SD) undergoing a uniform right parasagittal craniotomy received 1) halothane 1.5% end-expired and normocapnia (HN), 2) halothane 1.5% and hypocapnia (HH), or 3) large-dose pentobarbital and normocapnia (PN) (n = 7 per group). Heating devices initially maintained core and right subdural normothermia (38.0 degrees C). Thereafter, cranial heating was discontinued. Brain-to-core temperature gradients during the 3 h study were greatest in the right subdural area, averaging -2.5 degrees C +/- 0.9 degrees C in HN, -2.5 degrees C +/- 0.8 degrees C in HH, and -4.1 degrees C +/- 1.1 degrees C in PN. Gradients within the unexposed left subdural area and in the right cortex 0.5 and 1.0 cm below the brain surface were -0.8 degrees C +/- 0.5 degrees C to -1.1 degrees C +/- 0.6 degrees C for both HN and HH but were twice this amount in PN (-1.9 degrees C +/- 0.5 degrees C to -2.1 degrees C +/- 0.7 degrees C) (P < 0.05 for PN versus HN and HH). Deep barbiturate anesthesia can reduce brain temperature independently of core temperature, presumably by reducing the metabolic rate and associated brain heat production. The magnitude is sufficient to augment any direct cerebroprotective properties of the barbiturates. IMPLICATIONS: Deep barbiturate anesthesia reduced brain temperature independently of body temperature in cats and significantly more than the reduction seen with halothane anesthesia. The magnitude of temperature reduction was sufficient to account for cerebral protection by barbiturates independently of any other properties of the drug.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12707150&dopt=Abstract barbiturate Butalbital Fioricet