Search PubMed⌕ Search

Biomedical subjects

G B Baker

Publications and source records attributed to G B Baker.

At least 91 records · Page 5Linked to original sources
PubMed1995

Effects of the MAO inhibitor phenelzine on glutamine and GABA concentrations in rat brain.

Phenelzine (PLZ), a frequently prescribed monoamine oxidase (MAO) inhibitor, is used as an antidepressant/antipanic drug and has been shown to cause marked increases in rat brain levels of the amino acids gamma-aminobutyric acid (GABA) and alanine. In an extension of previous studies related to GABA metabolism, we investigated the effects of PLZ on rat brain levels of glutamine (GLN). At 1, 3 or 6 h after injection of PLZ (15 mg kg-1 i.p.), rats were killed and the brains removed. Analyses (using HPLC with fluorescence detection of OPT derivatives) of whole brain or hypothalamus revealed a decrease in brain levels of GLN and an increase in GABA levels at 3 and 6 h after PLZ injection. The effects of PLZ on GLN and GABA were blocked by prior treatment of the rats with tranylcypromine, a MAO inhibitor that had been shown previously to have no direct effect itself on GABA levels in rat brain. Since PLZ is known to be a substrate (as well as an inhibitor) of MAO, the studies with tranylcypromine pretreatment suggest that the effects on GLN and GABA are caused, at least in part, by a metabolite of PLZ.

Animals↗
PubMed1995

Metabolism of agmatine (clonidine-displacing substance) by diamine oxidase and the possible implications for studies of imidazoline receptors.

Clonidine-displacing substance, thought to be the endogenous ligand for imidazoline receptors, has been identified recently as agmatine (1-amino-4-guanidinobutane). The similarity of this compound's structure to that of the diamine oxidase (DAO) inhibitor, aminoguanidine, led us to investigate the possibility that agmatine might be a substrate for this enzyme. The metabolism of agmatine by purified porcine kidney DAO was measured by a peroxidase-linked colorimetric assay. Agmatine was a substrate for this enzyme and, under the experimental conditions used here, was metabolised at a rate of 0.8 mumol agmatine h-1 (unit DAO activity)-1. In contrast, agmatine was a substrate neither for rat brain monoamine oxidase (MAO) -A or -B, nor for rat brown adipose tissue semicarbazide-sensitive amine oxidase (SSAO). The metabolism of agmatine by DAO was inhibited by aminoguanidine (IC50 14.9 nM) and by the antidepressant, phenelzine (IC50 1.95 microM). These results suggest that administration of DAO inhibitors may increase endogenous agmatine levels and thus alter imidazoline receptor densities. A review of the literature documenting ligand affinities for idazoxan-preferring (I2) imidazoline binding site subtypes and drug affinities for DAO enzymes indicates that some of the I2 sites described elsewhere may correspond to DAO and not to an imidazoline receptor.

Agmatine↗
PubMed1995

Obsessive-compulsive symptom clusters and urinary amine correlates in Tourette syndrome.

This study was conducted to identify clusters of obsessive-compulsive characteristics in Tourette syndrome subjects and to explore their neurochemical correlates. Patients completed a 40-item questionnaire assessing obsessive-compulsive symptoms. Each subject had a 24-hour urine specimen collected and analyzed for a variety of biogenic amines and their metabolites. Factor analysis identified eight symptom clusters, the majority of which appeared to reflect obsessive symptoms. Consistent relationships were observed between symptom clusters and levels of catecholamine and indolamine amines and metabolites. Overall, the primary metabolite of serotonin, 5-hydroxyindoleacetic acid, appeared to be the most highly correlated with the individual obsessive-compulsive symptoms.

Adolescent↗
PubMed1994

The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine.

The antidepressant fluoxetine (FLU) and its N-demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid beta-adrenergic receptor down-regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague-Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)-FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)-FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR-HCl (11.2 mg/kg) and then treated 1 h later with (R,S)-FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron-capture detection for free (R)-and (S)-FLU and (R)- and (S)-NFLU after extraction and reaction with (-)-(S)-N-(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)-FLU alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Tranylcypromine does not enhance the effects of amitriptyline on 5-HT2 receptors in rat cerebral cortex.

The combination of amitriptyline (a tricyclic antidepressant) and tranylcypromine (a monoamine oxidase inhibitor) has been reported to be effective for treatment of refractory depressed patients. In the study reported here, this drug combination was compared with amitriptyline administered alone on the number and affinity of 5-HT2 receptors in rat brain. Male Sprague-Dawley rats were given vehicle (distilled water), amitriptyline (3.5 mg/kg/day), or tranylcypromine and amitriptyline (0.5 and 3.5 mg/kg/day, respectively) in combination subcutaneously via osmotic minipumps for 4, 10, or 28 days. A membrane fraction prepared from whole cortex was employed for studying binding to 5-HT2 receptors ([3H]ketanserin as the radioligand). The combination of amitriptyline and tranylcypromine produced a small but significantly greater down-regulation (decrease in number) of 5-HT2 sites than did amitriptyline alone after 10 days of administration; at 4 and 28 days, both amitriptyline and the drug combination had produced down-regulation, but there was not a significant difference between the two treatments. These data suggest that the antidepressant efficacy observed with this combination is not likely due to an enhanced effect on 5-HT2 receptors.

Amitriptyline↗
PubMed1994

Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function.

The MAO inhibitor phenelzine (2-phenylethylhydrazine; PLZ) is used widely in psychiatry for the treatment of depression and panic disorder. Its N-acetyl metabolite, N2-acetylphenelzine (N2AcPLZ) is a reasonably potent nonselective inhibitor of monoamine oxidase (MAO) that causes elevation in brain levels of the biogenic amines. In the studies reported here, PLZ (0.05 mmol/kg/day), N2AcPLZ (0.10 mmol/kg/day) or vehicle were administered to male rats for 28 days s.c. with Alzet minipumps, and their effects on GABAergic function were examined. Whole brain concentrations of gamma-aminobutyric acid (GABA) were significantly elevated in the PLZ but not in the N2AcPLZ-treated group. PLZ was found to inhibit the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GABA-T). The results of these investigations suggest that the free hydrazine moiety in PLZ is crucial to producing the elevated levels of GABA, probably through inhibition of GABA-T. Despite the considerable increase in whole brain GABA levels in the PLZ-treated rats, there were no significant differences in GABAA or benzodiazepine receptor binding parameters (KD or Bmax) between the groups as measured using 3H-muscimol and 3H-flunitrazepam in radioligand binding assays.

4-Aminobutyrate Transaminase↗
PubMed1994

Comparisons of the actions of high and low doses of the MAO inhibitor tranylcypromine on 5-HT2 binding sites in rat cortex.

Tranylcypromine (TCP) is a commercially available antidepressant drug, and recent literature reports suggest that high doses of this drug may be particularly effective in treating refractory depression. Down-regulation of 5-HT2 receptors in rat cortex is an effect produced after chronic administration of several antidepressants, and we have conducted a chronic study comparing low- and high-dose TCP in this regard. Male Sprague-Dawley rats were administered TCP (0.5 or 2.5 mg/kg/day) or vehicle (distilled water) via Alzet minipumps implanted subcutaneously in the dorsal thoracic area. Groups of rats were killed 4, 10 or 28 days after pump implantation and whole cortex was dissected out and utilized for preparation of a membrane fraction. Binding studies were performed with this fraction using 3H-ketanserin as the radioligand. Down-regulation (decrease in Bmax) of the 5-HT2 binding site was observed in high-dose animals after 10 and 28 days but not after 4 days. Low-dose TCP had no effect on 5-HT2 densities at any time interval. The affinity of 3H-ketanserin for the 5-HT2 site was not affected by either dose at any time interval. These results suggest that down-regulation of the 5-HT2 site may contribute to the efficacy of high-dose TCP in the treatment of refractory depression.

Animals↗
PubMed1994

Monoamine oxidase inhibitors: effects on tryptophan concentrations in rat brain.

It has been suggested that inhibition of tryptophan (Trp) pyrrolase and a subsequent elevation of brain Trp may contribute to the actions of antidepressant drugs. In our laboratories, we have conducted a series of experiments measuring brain Trp levels in the rat after both acute and chronic administration of several monoamine oxidase (MAO) inhibitors. The drugs studied during the course of the long-term (28 day) experiments were phenelzine, N2-acetylphenelzine, tranylcypromine, 4-fluorotranylcypromine, 4-methoxytranylcypromine and (-)-deprenyl. High-pressure liquid chromatography with electrochemical detection was employed to measure Trp levels in brains of both MAO inhibitor- and vehicle-treated animals. No significant increases in brain Trp levels were observed as a consequence of MAO inhibitor treatment. Acute time-response (up to 24 h) and dose-response studies were conducted following the administration of phenelzine and tranylcypromine. Only after administration of high doses of these drugs was an elevation in brain Trp observed and the increase was relatively short-lived. These results suggest that elevation of brain Trp may be an important factor in the actions of MAO inhibitors only at high doses of these drugs.

Animals↗
PubMed1994

Effects of low- and high-dose tranylcypromine on [3H]tryptamine binding sites in the rat hippocampus and striatum.

Chronic studies were initiated in rats to determine the effects of high- and low-dose tranylcypromine (TCP) on [3H]tryptamine (3H-T) binding sites. Male Sprague-Dawley rats were administered TCP (0.5 or 2.5 mg/kg/day) or vehicle (distilled water) for 4, 10 or 28 days via Alzet minipumps. After decapitation, the hippocampus and striatum were used to prepare membrane fragments for single point 3H-T binding. Hippocampal 3H-T binding was reduced after 10 and 28 days with the low dose and after 4, 10 and 28 days with the high dose. Striatal 3H-T binding was reduced by both doses at all time intervals. The high dose resulted in a significantly greater reduction in striatal 3H-T binding than did the low-dose after 4, 10, and 28 days. These results suggest that a more rapid reduction of 3H-T binding in the hippocampus and/or a greater reduction of 3H-T binding in the striatum by high-dose TCP than by low-dose TCP may be contributing factors in the reported efficacy of the former in refractory depression.

Animals↗
PubMed1994

Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food.

The effect of intraventricular infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), was examined in rats trained on a progressive ratio schedule for either IV cocaine or food reinforcement. Animals in the 5,7-DHT treatment group responded to significantly higher breaking points than vehicle-injected control animals, regardless of whether food or cocaine was used as the reinforcing stimulus. Analysis of the regional brain amines indicated that depletions of mesencephalic 5-HT correlated with postsurgical alterations in responding. These findings suggest that depletion of forebrain 5-HT produces a general effect on responding rather than a specific alteration in the reinforcing effects of psychomotor stimulant drugs.

5,7-Dihydroxytryptamine↗
PubMed1994

Involvement of CYP2D6, CYP3A4, and other cytochrome P-450 isozymes in N-dealkylation reactions.

Metabolic N-dealkylation is a commonly observed biotransformation with tertiary and secondary amine drugs and related N-alkylated amides, but surprisingly little is known about the cytochrome P-450 isozymes involved in these dealkylation reactions. In this review, evidence is provided that supports the involvement of various P-450 isozymes, but especially CYP3A4 and other isozymes of the CYP3A subfamily. Although CYP2D6 is generally not considered to be capable of catalyzing the N-dealkylation of basic drugs, some examples of the involvement of this important isozyme in N-dealkylation reactions are identified. Procedures used to identify individual P-450 isozymes involved in N-dealkylation reactions are discussed.

Amitriptyline↗
PubMed1994

Derivatization with acetic anhydride: applications to the analysis of biogenic amines and psychiatric drugs by gas chromatography and mass spectrometry.

Acetylation with acetic anhydride, under both aqueous and anhydrous conditions, has been utilized to derivatize various biogenic amines and psychotropic drugs for subsequent analysis by gas chromatography (GC) or gas chromatography-mass spectrometry (GC-MS). Under basic aqueous conditions, acetic anhydride derivatizes phenols and amines but not alcohols; under anhydrous conditions, all three functions are acetylated. Primary amines, once derivatized with acetic anhydride, can be further derivatized with other reagents; these diderivatives have proven useful for subsequent analysis by GC or GC-MS. Examples of applications of derivatization with acetic anhydride to analysis of biogenic amines, antidepressants, antipsychotics, and some of their metabolites are presented.

Acetic Anhydrides↗
PubMed1994

5-Hydroxytryptamine2 and beta-adrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination.

A chronic (14-day) study was initiated to investigate the effects of combined fluoxetine (FLU) and desipramine (DMI) treatment on the densities and affinities of beta-adrenergic and 5-hydroxytryptamine2 (5-HT2) receptors. Male Sprague-Dawley rats were administered the following doses using osmotic minipumps: FLU, 10 mg/kg/day; DMI, 5, 10, or 15 mg/kg/day; FLU, 10 mg/kg/day, plus DMI, 5 mg/kg/day; or vehicle (distilled water). After 14 days the cortex was dissected out and used for [3H]-ketanserin (5-HT2) binding, [3H]CGP-12177 (beta-adrenergic) binding, and drug level analysis. All animals receiving DMI showed significant down-regulation of 5-HT2 receptors except those receiving FLU in combination. DMI down-regulated beta-adrenergic receptors in a dose-dependent manner, with significantly greater down-regulation seen with the combination than with DMI (5 mg/kg/day) alone. This latter effect was apparently the result of greater levels of DMI in cortex with the combination than with DMI (5 mg/kg/day) alone. FLU had no effect on 5-HT2 or beta-adrenergic receptors on its own. Coadministration of FLU and DMI resulted in a doubling of levels of FLU and its demethylated metabolite, norfluoxetine (NFLU), and a tripling of DMI levels compared with values observed when FLU (10 mg/kg/day) or DMI (5 mg/kg/day) was administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

4-Ethoxyamphetamine: effects on intracranial self-stimulation and in vitro uptake and release of 3H-dopamine and 3H-serotonin in the brains of rats.

Experiments were conducted to compare the effects of 4-ethoxyamphetamine, a novel "designer" amphetamine, with (+)-amphetamine and an earlier "designer" amphetamine, 4-methoxyamphetamine, on rats. (+)-Amphetamine significantly decreased frequency threshold measures in an intracranial self-stimulation (ICSS) procedure using medial forebrain bundle electrodes, while 4-methoxyamphetamine and 4-ethoxyamphetamine increased these ICSS frequency thresholds. 4-Methoxyamphetamine and 4-ethoxyamphetamine had more potent effects on inhibition of uptake and stimulation of spontaneous release of 5-hydroxytryptamine (serotonin) than of dopamine. It is concluded that the neuropsychopharmacological profile of 4-ethoxyamphetamine is unlike that of (+)-amphetamine, but similar to that of 4-methoxyamphetamine, a potent hallucinogen in humans.

Amphetamines↗
PubMed1993

Chronic antidepressant drug treatment attenuates motor-suppressant effects of apomorphine without changing [3H]GBR 12935 binding.

The effects of chronic administration (28 days s.c. via osmotic minipumps) of the antidepressants phenelzine sulphate, desipramine hydrochloride and clomipramine hydrochloride (each at 10 mg/kg per day) on dopamine function have been measured in rats. Both phenelzine and desipramine attenuated the suppression of locomotor activity induced by apomorphine hydrochloride (0.05 mg/kg s.c. 15 min). Clomipramine did not affect the behavioural response to apomorphine. Analyses of brain tissue from these animals using the radioligand [3H]GBR 12935 revealed that there were no changes in dopamine uptake site density or affinity following the administration of phenelzine, desipramine or clomipramine. Analyses of brain monoamine oxidase activity and tricyclic levels were used to confirm the efficacy of the drug administration protocol. These data indicate that changes in dopamine uptake site density do not mediate antidepressant-induced changes in behavioural responses to apomorphine.

Animals↗
PubMed1993

Metabolism of imipramine in vitro by isozyme CYP2D6 expressed in a human cell line, and observations on metabolite stability.

A metabolism study of imipramine (IMI) has been conducted in vitro with commercially available human CYP2D6 isozyme expressed in a human AHH-1 TK +/- cell line. This enzyme system catalyzed the anticipated ring-oxidative biotransformation of IMI to 2-hydroxyimipramine (2-OH-IMI). In addition, however, the human CYP2D6 isozyme preparation was found to be unequivocally involved in the N-dealkylation of IMI to desmethylimipramine (DMI). 2-Hydroxydesipramine was also identified as a trace metabolite of IMI, but no 10-hydroxyimipramine was detected. The 2-OH-IMI metabolite was unstable and disappeared from metabolic solutions on standing. A procedure involving the O-acetylation of 2-OH-IMI was developed to minimize this decomposition. When an authentic sample of 10-OH-IMI was subjected to the same acetylation procedure, it was partially dehydrated to 10,11-dehydroimipramine, but also underwent unexpected degradations to two other products in which the dimethylaminopropyl side-chain was deaminated. Plausible structures for these two decomposition products are suggested from their gas chromatographic-mass spectrometric behaviour.

Acetylation↗
PubMed1993

Induction of functional down-regulation of beta-adrenoceptors in rats by 2-phenylethylamine.

The effects of chronic administration of antidepressant drugs and 2-phenylethylamine on beta-adrenoceptor function were assessed. Monoamine oxidase inhibitors [phenelzine sulfate, 5 or 10 mg kg-1 per day, and (-)-deprenyl HCl, 1 mg kg-1 per day] and 2-phenylethylamine HCl (10 mg kg-1 per day) were administered to male Sprague-Dawley rats via Alzet osmotic minipumps. On days 21 and 22, the motor-suppressant actions of the beta-adrenoceptor agonist salbutamol hemisulfate (3 mg kg-1 intraperitoneally after 15 min) were assessed as a measure of beta-adrenoceptor sensitivity. On day 28, the animals were killed, and their brains were used for the measurement of monoamine oxidase activity and concentrations of 2-phenylethylamine, an endogenous amine and a metabolite of phenelzine. Phenelzine sulfate at 10 mg kg-1 per day (but not 5 mg kg-1 per day) and the combination of (-)-deprenyl and 2-phenylethylamine resulted in a decrease in the response to salbutamol. These treatments also resulted in substantial increases in brain 2-phenylethylamine concentrations. The phenelzine treatments each resulted in an equivalent inhibition of brain monoamine oxidase activity. These results support the proposal that 2-phenylethylamine may, at least in part, mediate the effects of phenelzine on beta-adrenoceptor function.

Albuterol↗