ABSTRACT
In this work, we studied the extraction systems for the separation f-elements based on the tetradentate N,O-donor ligand di(N-ethyl-4-ethylanilide) 2,2'-dipyridyl-6,6'-dicarboxylic acid (L). The organic phase of these systems was perspective fluorine-containing organic solvents-metanitrobenzotrifluoride (F-3), ionic liquid C4mimNTf2 (IL), and their mixture. The increase of Am(III) selectivity in the presence of Ln(III) in cases of the diluent mixture was shown. The mechanism of the f-element complexation leading to the improved properties of the extraction systems was studied by UV-visible, Raman-spectroscopy, XRD-study, and density functional theory calculations.
ABSTRACT
It is of particular interest for biopharmaceutical companies developing and distributing fragile biomolecules to warrant the stability and activity of their products during long-term storage and shipment. In accordance with quality by design principles, advanced kinetic modeling (AKM) has been successfully used to predict long-term product shelf-life and relies on data from short-term accelerated stability studies that are used to generate Arrhenius-based kinetic models that can, in turn, be exploited for stability forecasts. The AKM methodology was evaluated through a cross-company perspective on stability modeling for key stability indicating attributes of different types of biotherapeutics, vaccines and biomolecules combined in in vitro diagnostic kits. It is demonstrated that stability predictions up to 3 years for products maintained under recommended storage conditions (2-8 °C) or for products that have experienced temperature excursions outside the cold-chain show excellent agreement with experimental real-time data, thus confirming AKM as a universal and reliable tool for stability predictions for a wide range of product types.
Subject(s)
Vaccines , Drug Storage/methods , Drug Stability , Temperature , RefrigerationABSTRACT
BACKGROUND: Neuraxial administration of long-acting opioid is the "gold standard" for the management of postoperative pain following cesarean delivery. Respiratory depression, however, remains a concerning complication. METHODS: This retrospective single-center study of 4963 patients evaluated the frequency of respiratory depression after neuraxial morphine administration in a post-cesarean delivery population. The spinal dose of morphine varied from 100 to 450⯵g intrathecally, and from 3 to 5â¯mg epidurally. The primary outcome was the initiation of a Rapid Response Team (RRT) event for respiratory failure due to neuraxial opioid in the 24â¯h following morphine administration. Secondary outcomes studied included oxygen desaturation events (SpO2 <90%), initiation of oxygen therapy and naloxone administration. RESULTS: There were no respiratory RRT events within the study period (95% confidence interval [CI] 0 to 7 per 10â¯000). There were no desaturation events recorded and no patients received supplemental oxygen therapy or naloxone (95% CI 0 to 7 per 10â¯000). CONCLUSION: Clinically significant respiratory depression is rare among patients receiving neuraxial morphine for post-cesarean delivery analgesia.
Subject(s)
Analgesia, Epidural , Respiratory Insufficiency , Pregnancy , Female , Humans , Analgesics, Opioid/adverse effects , Retrospective Studies , Morphine/adverse effects , Pain, Postoperative/epidemiology , Respiratory Insufficiency/chemically induced , Respiratory Insufficiency/therapy , Analgesia, Epidural/adverse effects , Naloxone/therapeutic use , OxygenABSTRACT
Raman and optical absorption spectra of disordered hydrated iron fluoridotitanate (HITF) single crystal were studied. Temperature transformations of the Raman spectra indicate independent ordering processes of the [TiF6]2- and [Fe(H2O)6]2+ complexes below the structural phase transition. The absorption spectrum in the near-infrared and visible ranges includes transitions from the high spin ground state 5T2 of Fe2+ ion to the excited 5E state and a set of excited triplets. Analysis by Tanabe-Sugano method gives crystal field Dq = 490 cm-1 and Racah parameters B = 340 cm-1 and C = 1904 cm-1. Considerable decrease of B parameter as compared to the free ion value indicates a decrease of interelectron repulsion in the disordered neighborhood of Fe2+ ions.
ABSTRACT
The data of intraoperative monitoring of brainstem acoustic evoked potentialities (BAEP) during parabrainstem tumors are analyzed. Of the 24 cases, 16 patients were found to have neurinoma of the acoustic nerve, 4 had petroclival meningioma, 2, tentorial meningioma, 1, cholesteatoma of the cerebellopontine angle, and 1, brainstem angioma. The authors proposed to identify the favorable and unfavorable patterns of BAEP as predictors of an early postoperative period, by comparing the patterns of BAEP, the data on the monitoring vital functions and outcomes of disease. The conformity of actual and predictable results was analyzed. By taking into account the high coincidence of actual and predictable outcomes (79.16%), it can be suggested that the data of intraoperative monitoring of BAEP are not only of value for obtaining information at the moment of surgery, but also informative as a predictor of an early postoperative period and outcomes of disease.
Subject(s)
Brain Stem Neoplasms/surgery , Evoked Potentials, Auditory, Brain Stem , Monitoring, Intraoperative/methods , Adult , Aged , Brain Stem Neoplasms/pathology , Female , Humans , Male , Middle Aged , Postoperative PeriodABSTRACT
In view to prepare Mars human exploration, it is necessary to promote and lead, at the international level, a highly interdisciplinary program, involving specialists of geochemistry, geophysics, atmospheric science, space weather, and biology. The goal of this program will be to elaborate concepts of individual instruments, then of integrated instrumental packages, able to collect exhaustive data sets of environmental parameters from future landers and rovers of Mars, and to favour the conditions of their implementation. Such a program is one of the most urgent need for preparing human exploration, in order to develop mitigation strategies aimed at ensuring the safety of human explorers, and minimizing risk for surface operations. A few main areas of investigation may be listed: particle and radiation environment, chemical composition of atmosphere, meteorology, chemical composition of dust, surface and subsurface material, water in the subsurface, physical properties of the soil, search for an hypothesized microbial activity, characterization of radio-electric properties of the Martian ionosphere. Scientists at the origin of the present paper, already involved at a high degree of responsibility in several Mars missions, and actively preparing in situ instrumentation for future landed platforms (Netlander--now cancelled, MSL-09), express their readiness to participate in both ESA/AURORA and NASA programs of Mars human exploration. They think that the formation of a Mars Environment working group at ESA, in the course of the AURORA definition phase, could act positively in favour of the program, by increasing its scientific cross-section and making it still more focused on human exploration.
Subject(s)
Atmosphere/chemistry , Cosmic Radiation , Mars , Soil/analysis , Space Flight , Atmosphere/analysis , Exobiology , Geological Phenomena , Geology , Meteoroids , Meteorological Concepts , Soil Microbiology , Telecommunications , WaterABSTRACT
Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain phamacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [11C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radio-tracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene.
Subject(s)
Brain/metabolism , Toluene/pharmacokinetics , Administration, Inhalation , Animals , Brain/diagnostic imaging , Carbon Radioisotopes , Female , Isotope Labeling , Mice , Papio , Tissue Distribution , Tomography, Emission-ComputedSubject(s)
Anticonvulsants/pharmacology , Biogenic Monoamines/metabolism , Fructose/analogs & derivatives , Fructose/pharmacology , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Animals , Brain Chemistry/drug effects , Dopamine/metabolism , Drug Interactions , Microdialysis , Norepinephrine/metabolism , Serotonin/metabolism , TopiramateABSTRACT
To explore the role of endogenous GABA in NMDA antagonist induced dopamine (DA) release, we used in vivo microdialysis to study the effects of pretreatment with gamma-vinyl GABA (GVG) on phencyclidine (PCP)-induced DA release in terminal regions of midbrain DA neurons. GVG, an irreversible inhibitor of the GABA catabolizing enzyme GABA-AT, significantly reduced the DA response to PCP (7.0 mg/kg) in freely moving animals. Preferential increases in PCP-induced DA release in the PFC (four-fold those of NAcc) were dose-dependently inhibited by acute pretreatment with GVG at doses of 150 (51% inhibition), 300 (68% inhibition), and 500 (82% inhibition) mg/kg, whereas NAcc PCP-induced DA activity was unresponsive to 150 mg/kg and only partially inhibited by 300 and 500 mg/kg. Subchronic treatment with GVG did not enhance the inhibitory capacity of the GABAergic system. While GVG evidently modulates PCP-induced increases in mesocorticolimbic DA transmission, the character of this modulation is regionally specific, with cortical NMDA-antagonist induced increases appearing more sensitive to inhibition by endogenous GABA than subcortical areas.
Subject(s)
Anticonvulsants/pharmacology , Cerebral Cortex/drug effects , Dopamine/physiology , Excitatory Amino Acid Antagonists/pharmacology , Limbic System/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Synaptic Transmission/drug effects , Vigabatrin/pharmacology , Animals , Extracellular Space/drug effects , Extracellular Space/metabolism , Male , Nucleus Accumbens/metabolism , Phencyclidine/pharmacology , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Stereotaxic TechniquesABSTRACT
Environments previously associated with drug use can become one of the most common factors triggering relapse to drug-seeking behavior. To better understand the neurochemical mechanisms potentially mediating these cues, we measured nucleus accumbens dopamine levels in animals exposed to environmental cues previously paired with cocaine administration. In animals exposed to a cocaine-paired environment nucleus accumbens dopamine increased by 25%. When administered 2.5 h prior to presentation of the environmental trigger, racemic vigabatrin (an irreversible inhibitor of gamma-aminobutyric acid (GABA)-transaminase) abolished this cue-induced increase. Conversely, R-(-)-vigabatrin, the inactive enantiomer, had no effect. Combined with our earlier findings, these studies support the potential therapeutic benefit of this enzyme-based GABAergic strategy to modulate brain dopamine and the subsequent treatment of drug addiction.
Subject(s)
Cocaine , Cues , Dopamine Uptake Inhibitors , Dopamine/metabolism , Nucleus Accumbens/metabolism , 4-Aminobutyrate Transaminase/antagonists & inhibitors , 4-Aminobutyrate Transaminase/metabolism , Animals , Cocaine/pharmacology , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Dopamine Uptake Inhibitors/pharmacology , Enzyme Inhibitors/pharmacology , Male , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Stereoisomerism , Vigabatrin/pharmacology , gamma-Aminobutyric Acid/drug effects , gamma-Aminobutyric Acid/metabolismABSTRACT
Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.
Subject(s)
Brain/metabolism , Dopamine/metabolism , Extracellular Space/metabolism , Membrane Glycoproteins , Membrane Transport Proteins , Methylphenidate/administration & dosage , Nerve Tissue Proteins , Administration, Oral , Adult , Behavior/drug effects , Binding, Competitive/drug effects , Brain/diagnostic imaging , Carbon Radioisotopes , Carrier Proteins/antagonists & inhibitors , Cerebellum/diagnostic imaging , Cerebellum/metabolism , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Dopamine Antagonists/metabolism , Dopamine Antagonists/pharmacokinetics , Dopamine D2 Receptor Antagonists , Dopamine Plasma Membrane Transport Proteins , Genetic Variation , Heart Rate/drug effects , Humans , Male , Methylphenidate/blood , Raclopride/metabolism , Raclopride/pharmacokinetics , Receptors, Dopamine D2/metabolism , Tomography, Emission-ComputedABSTRACT
There is a greater prevalence of cigarette smoking among cocaine-dependent individuals and hyperactive children treated with stimulants (e.g., methylphenidate, MP). However, little is known about the neurochemical basis of the interaction between nicotine and cocaine or MP. It is thought that the reinforcing effects of cocaine and MP are due partly to increases in synaptic DA in the nucleus accumbens (NAc). These measurable increases are secondary to the blockade of the DA transporter. In contrast, nicotine stimulates acetylcholine receptors located presynaptically on dopaminergic projections from the ventral tegmental area (VTA) to the NAc and increases DA transmission. Here we investigate the effects of nicotine on NAc DA in animals simultaneously injected with cocaine or MP. Coadministration of nicotine (0.4 mg/kg s.c.) and cocaine (10 mg/kg i.p.) or MP (5 mg/kg i.p.) increased the extracellular NAc DA levels in an additive manner, while coadministration of nicotine (0. 4 mg/kg s.c.) and a higher dose of cocaine (20 mg/kg) or MP (10 mg/kg) clearly produced a synergistic elevation in NAc DA. These findings suggest that the degree of DA transporter (DAT) occupancy contributes to the synergistic interaction between nicotine and cocaine or MP.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Membrane Glycoproteins , Membrane Transport Proteins , Methylphenidate/pharmacology , Nerve Tissue Proteins , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Animals , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins , Dose-Response Relationship, Drug , Drug Synergism , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Nucleus Accumbens/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
The therapeutic and stimulant properties of methylphenidate (MP), a drug commonly prescribed for the treatment of attention deficit hyperactivity disorder, have been attributed to increases in synaptic dopamine (DA) concentrations resulting from the blockade of DA transporters. In addition to obvious difficulties inherent in any interspecies comparison, interpretation of preclinical studies done with MP is further complicated by different routes of administration in animals (i.v. and i.p.) compared with humans (oral). In the present study we compared the effects of i.p. and intragastric (oral) MP both on rat nucleus accumbens DA assessed by in vivo microdialysis and on locomotor activity measured in a photocell apparatus. We also compared regional brain uptake and plasma levels of [(3)H]MP after administration of 5 mg/kg via both routes. Intraperitoneal MP (5 and 10 mg/kg) was approximately twice as potent as intragastric MP in terms of increasing extracellular DA levels and in stimulating locomotion. This was consistent with the higher brain uptake of [(3)H]MP when given i.p. rather than intragastrically. The dose of 2 mg/kg produced significant increases in both measurements when administered i.p., but not intragastrically. This study shows that relatively low doses of MP (2 mg i.p. and 5 mg intragastric) significantly increase extracellular DA and locomotor activity and indicates that the differences in the neurochemical and behavioral effects of MP between the intragastric and the i.p. routes are due to central drug bioavailability.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Dopamine/metabolism , Membrane Glycoproteins , Membrane Transport Proteins , Methylphenidate/administration & dosage , Motor Activity/drug effects , Nerve Tissue Proteins , Administration, Oral , Animals , Dopamine Plasma Membrane Transport Proteins , Injections, Intraperitoneal , Male , Methylphenidate/blood , Methylphenidate/pharmacology , Microdialysis , Rats , Rats, Sprague-DawleyABSTRACT
Dopaminergic activity in the mesocorticolimbic system is associated with reinforcing properties of psychostimulant drugs. We previously demonstrated that increased gamma-aminobutyric acid (GABA)-ergic activity produced by gamma-vinyl GABA [D,L-4-amino-hex-5-enoic acid (Vigabatrin(R))], an irreversible inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well as behaviors associated with these biochemical changes. In the present study, using in vivo microdialysis techniques, we compared three different strategies to increase GABAergic activity in order to modulate cocaine-induced increase in extracellular dopamine. Our data demonstrate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5, 6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GABA uptake inhibitor, dose and time dependently diminished increases in extracellular dopamine following acute cocaine challenge. Furthermore, we demonstrated that cyclized analogue of vigabatrin, a competitive reversible GABA-transaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversible inhibition of GABA transaminase, inhibition of GABA uptake represent another potentially effective, indirect strategy for the treatment of cocaine abuse.
Subject(s)
Cocaine/antagonists & inhibitors , Dopamine Uptake Inhibitors/pharmacology , Receptors, Dopamine/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Cocaine/administration & dosage , Cocaine/pharmacology , Dopamine Uptake Inhibitors/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , GABA Antagonists/pharmacology , Male , Microdialysis , Molecular Mimicry , Nipecotic Acids/pharmacology , Oximes/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine/drug effects , Sodium Chloride , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Elevation of endogenous GABA by the racemic mixture of gamma vinyl-GABA (GVG, Vigabatrin) decreases extracellular nucleus accumbens (NAc) dopamine (DA) levels and diminishes the response to many drugs of abuse known to elevate DA in the mesocorticolimbic system. We investigated the effects of the individual enantiomers (S(+)-GVG, R(-)-GVG) on cocaine-induced NAc DA in rodents as well as the effects of nicotine-induced increases in primates. In a series of microdialysis experiments in freely moving animals, S(+)-GVG (150 mg/kg), R(-)-GVG (150 mg/kg) or racemic (R, S) GVG (300 mg/kg) was administered 2.5 hours prior to cocaine (20 mg/kg) administration. When compared with cocaine alone, the R(-) enantiomer did not significantly inhibit cocaine induced NAc DA release. S(+)-GVG, at half the dose of the racemic mixture (150 mg/kg), inhibited cocaine-induced DA elevation by 40%, while the racemic mixture (300 mg/kg) inhibited cocaine-induced DA release by 31%. In addition, our PET studies in primates demonstrated that S(+)-GVG completely inhibits nicotine-induced increases in the corpus striatum, again at half the dose of the racemic mixture. The R(-) enantiomer was ineffective. Although the S(+) enantiomer has been well established as the active compound in the treatment of epilepsy, the efficacy of this enantiomer with regard to mesolimbic DA inhibition generates a complex series of clinical and neurochemical issues. Further investigations will determine the locus of action and physiologic properties of each enantiomer.
Subject(s)
Cocaine/pharmacology , Dopamine/metabolism , Nicotine/pharmacology , Nucleus Accumbens/drug effects , Vigabatrin/pharmacology , Animals , Male , Microdialysis , Nucleus Accumbens/diagnostic imaging , Nucleus Accumbens/metabolism , Papio , Rats , Rats, Sprague-Dawley , Stereoisomerism , Tomography, Emission-ComputedABSTRACT
In the present study, we examined the effect of an acute administration of the selective suicide inhibitor of gamma-aminobutyric acid (GABA)-transaminase, gamma-vinyl GABA on increases in nucleus accumbens dopamine produced by a cocaine/heroin challenge in freely moving animals. Cocaine (20 mg/kg, i.p.) produced an elevation in extracellular nucleus accumbens dopamine of approximately 380% above baseline, while heroin produced only a moderate increase of 70%. Coadministration of these two drugs, however, produced a synergistic elevation in nucleus accumbens dopamine of 1000%. This response was reduced by 50% in animals pretreated with gamma-vinyl GABA (300 mg/kg, i.p.) 2.5 h prior to challenge. This same dose of gamma-vinyl GABA inhibited cocaine-induced increases in nucleus accumbens dopamine by 25% and completely abolished heroin-induced increase. These findings indicate that gamma-vinyl GABA can interfere with the synergistic effects produced by the combination of an indirect dopamine releaser (heroin) and a dopamine reuptake blocker (cocaine).
Subject(s)
Cocaine/pharmacology , Dopamine/metabolism , Enzyme Inhibitors/pharmacology , Heroin/pharmacology , Nucleus Accumbens/drug effects , Vigabatrin/pharmacology , 4-Aminobutyrate Transaminase/antagonists & inhibitors , Analysis of Variance , Animals , Drug Synergism , Male , Narcotics/pharmacology , Nucleus Accumbens/metabolism , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
The enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach was developed that had certain advantages over the synthesis originally reported for the isomers of 1. (+/-)-3-(N-Methylpyrrolidin-3-yl)-4-hydroxyindole, 5, was also prepared as a rigid analogue of psilocin and compared with its 5-methoxy counterpart 4. Radioligand competition assays were used to assess the affinity of compounds for the 5-HT(2A) receptor labeled with the agonist ligand [(125)I]DOI and the antagonist ligand [(3)H]MDL100907. Two-lever drug discrimination assays in rats trained to discriminate either LSD or DOI from saline were employed to assess the hallucinogen-like behavioral properties of these rigid tryptamine analogues. The receptor binding assay results clearly demonstrated a stereochemical preference for the R enantiomers that did not discriminate the position of the oxygen function. The receptor is 10-20-fold more selective for the R isomers. The affinities of the R enantiomers were virtually identical for both 1 and 3 at the agonist-labeled receptor, while racemic 4 and 5 had about one-tenth the affinity. The drug discrimination data in both LSD- and DOI-trained rats paralleled the binding data using [(125)I]DOI displacement. Both (R)-1 and (R)-3 are about equipotent, comparable to DOI in activity but about 10-fold less potent than LSD. Compound 4 produced only partial substitution, even at a dose nearly 5-fold higher than for (R)-1. Based on conformational energies, it seems doubtful that these compounds bind to the 5-HT(2A) receptor in an ergoline-like conformation. The results also suggest that both 1 and 3 would possess LSD-like psychopharmacology in humans.
Subject(s)
Indoles/chemical synthesis , Lysergic Acid Diethylamide/pharmacology , Pyrrolidines/chemical synthesis , Tryptamines/chemical synthesis , Animals , Binding, Competitive , Discrimination Learning/drug effects , Frontal Lobe/metabolism , In Vitro Techniques , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Male , Pyrrolidines/chemistry , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/metabolism , Stereoisomerism , Structure-Activity Relationship , Tryptamines/chemistry , Tryptamines/metabolism , Tryptamines/pharmacologyABSTRACT
We examined the acute effect of the irreversible GABA-transaminase inhibitor, gamma-vinyl GABA (GVG, Sabril((R)), Vigabatrin((R))) on increases in nucleus accumbens (NAc) dopamine (DA) following acute administration of methamphetamine, heroin, or ethanol. Methamphetamine (2.5 mg/kg) produced a dose-dependent increase (2, 700%) in NAc DA. GVG preadministration (300 or 600 mg/kg), however, inhibited this response by approximately 39 and 61%, respectively. The lower dose of methamphetamine (1.25 mg/kg), increased DA by 1, 700%. This response was inhibited to a similar extent (44%) regardless of the GVG dose preadministered (300 or 600 mg/kg). In addition, heroin-induced increases in NAc DA (0.5 mg/kg, 170%) were inhibited or completely abolished by GVG (150 or 300 mg/kg, 65 and 100%, respectively). Finally, at half the dose necessary for heroin, GVG (150 mg/kg) also completely abolished ethanol-induced increases in NAc DA following a 0.25 g/kg challenge dose (140%). Taken with our previous findings using nicotine or cocaine as the challenge drug, these results indicate that GVG attenuates increases in NAc DA by a mechanism common to many drugs of abuse. However, it appears unlikely that an acute dose of GVG can completely inhibit increases in NAc DA following challenges with a drug whose mechanism of action is mediated primarily through the DA reuptake site.
Subject(s)
Analgesics, Opioid/antagonists & inhibitors , Anticonvulsants/pharmacology , Central Nervous System Depressants/antagonists & inhibitors , Dopamine Uptake Inhibitors/antagonists & inhibitors , Dopamine/metabolism , Ethanol/antagonists & inhibitors , Heroin/antagonists & inhibitors , Methamphetamine/antagonists & inhibitors , Nucleus Accumbens/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , Analgesics, Opioid/pharmacology , Animals , Central Nervous System Depressants/pharmacology , Dopamine/cerebrospinal fluid , Dopamine Uptake Inhibitors/pharmacology , Ethanol/pharmacology , Extracellular Space/metabolism , Heroin/pharmacology , Male , Methamphetamine/pharmacology , Microdialysis , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Time Factors , Vigabatrin , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Previously, we demonstrated that gamma vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-induced increases in dopamine (DA) concentrations in both the rodent and primate brain. Furthermore, it abolishes cocaine self-administration and conditioned place preference, while having no effect on locomotor activity or drug delivery to the brain. In an effort to better understand the mechanisms underlying this inhibition, we examined the effect of the selective GABA(B) receptor antagonist SCH 50911 on the GVG-induced decrease in cocaine's elevation of extracellular DA concentrations in the nucleus accumbens (NACC). Cocaine administration alone (20 mg/kg i.p.) produced a 480% increase in extracellular NACC DA levels. GVG (300 mg/kg i.p.) significantly reduced this increase by 25% (P<0.01). In sharp contrast, extracellular DA levels increased to 550% after the sequential administration of SCH 50911 (3 mg/kg i.p.), GVG, and cocaine. This increase is significantly different than GVG and cocaine (P<0.05) but similar to cocaine alone. These results demonstrate that the GABA(B) antagonist SCH 50911 was able to completely abolish GVG's inhibition of cocaine-induced increases in DA in the NACC and implicates the GABA(B) receptor in the mechanism underlying this inhibition.