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Biomedical subjects

S Rotzinger

Publications and source records attributed to S Rotzinger.

12 recordsLinked to original sources
PubMed2000

Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI-cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myo-inositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myo-inositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI-cycle.

Animals↗
PubMed1999

Effects of lithium and amphetamine on inositol metabolism in the human brain as measured by 1H and 31P MRS.

BACKGROUND: The clinical effectiveness of lithium may be due to its decreasing the intracellular concentration of myo-inositol and increasing that of its inositol monophosphate precursors, which is known as the inositol depletion hypothesis. METHODS: Magnetic resonance spectroscopy (MRS) was used to measure the concentration of both myo-inositol (1H MRS) and phosphomonoesters (PME) [31P MRS], in healthy volunteers in a double-blind placebo-controlled study. MRS measurements were made at baseline, again on the 7th day of lithium (1200 mg, n = 10) or placebo (n = 6) administration, and again on day 8, 2 hours following oral administration of 20 mg dextroamphetamine to stimulate the phosphoinositol (PI) cycle. RESULTS: Subjects who received lithium showed a greater increase in PME ratios in response to amphetamine administration than did placebo-treated subjects. CONCLUSIONS: The present results support the hypothesis that lithium administration blocks the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent following PI cycle stimulation. The effects of lithium treatment on myo-inositol in healthy volunteers in vivo are uncertain, and may have to await improvements in the ability to measure myo-inositol in the brain.

Adolescent↗
PubMed1999

Metabolism of some "second"- and "fourth"-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine.

1. This review summarizes the major known aspects of the metabolism of second-generation (iprindole, viloxazine, bupropion, mianserin, maprotiline, and trazodone) and fourth-generation (nefazodone and venlafaxine) antidepressants. 2. Discussions about specific enzymes involved and about possible pharmacokinetic drug-drug interactions, particularly as they relate to cytochrome P450 enzymes, are provided.

Animals↗
PubMed1999

Lithium does not alter the choline/creatine ratio in the temporal lobe of human volunteers as measured by proton magnetic resonance spectroscopy.

OBJECTIVE: To study the effect of lithium administration on brain choline/creatine (Cho/Cr) ratios in healthy volunteers. DESIGN: Double-blind, placebo-controlled, prospective study. SETTING: The Nuclear Magnetic Resonance Research Unit at the University of Alberta. PARTICIPANTS: Sixteen healthy volunteers, recruited through advertisements. Subjects were excluded if they had a physical illness, or a personal or family history of psychiatric illness. The study period was from Feb. 6, 1996, to Mar. 21, 1996. INTERVENTIONS: Subjects received a baseline proton magnetic resonance spectroscopy (1H MRS) scan, and then were instructed to take either lithium (1,200 mg) or placebo at night for 7 days. On Day 8, the subjects returned for a second 1H MRS scan. Study participants were seen by a physician at the beginning and at the end of the experiment, and had access to the physician throughout the study period. OUTCOME MEASURES: Ratios of Cho/Cr measured in the temporal lobes by 1H MRS. RESULTS: There were no significant differences in the Cho/Cr ratios between the 2 groups on the test day (placebo 0.748 [standard deviation 0.29] versus lithium 0.811 [SD 0.25]; F = 0.147, p = 0.72), and there was no significant change from baseline in either group (0.003 above baseline for placebo; 0.056 above baseline for lithium; F = 1.21, p = 0.32). CONCLUSIONS: Lithium administration to healthy volunteers does not alter the Cho/Cr ratio in temporal lobe as measured by 1H MRS. The result concurs with reports that differences in Cho/Cr ratios observed in patients with bipolar disorder are likely specific to the illness, and are not the result of lithium therapy. Hence, alterations in choline function are not involved in the clinical effectiveness of lithium.

Adult↗
PubMed1998

Human CYP2D6 and metabolism of m-chlorophenylpiperazine.

BACKGROUND: Metabolic drug-drug interactions can occur between drugs that are substrates or inhibitors of the same cytochrome P450 (CYP) isoenzymes, but can be prevented by knowing which isoenzymes are primarily responsible for a drug's metabolism. m-Chlorophenylpiperazine (mCPP) is a psychopharmacologically active metabolite of four different psychiatric drugs. The present experiments were designed to identify the CYP isoenzymes involved in the metabolism of mCPP to its main metabolite p-hydroxy-mCPP (OH-mCPP). METHODS: The rate of production of OH-mCPP from mCPP was correlated with isoform activities in a panel of human liver microsomes, was assessed using a panel of individual complementary DNA-expressed human CYP isoenzymes, and was investigated in the presence of a specific inhibitor of CYP2D6. RESULTS: OH-mCPP production correlated significantly with CYP2D6 activity in human liver microsomes. Furthermore, incubations with microsomes from cells expressing CYP2D6 resulted in OH-mCPP formation, whereas no mCPP was formed from incubations with microsomes from cells expressing other individual isoforms. Finally, when the specific CYP2D6 inhibitor quinidine was preincubated with either human liver microsomes or cells expressing human CYP2D6, there was a concentration-dependent decrease in the production of OH-mCPP. CONCLUSIONS: These results confirm that CYP2D6 is the isoform responsible for the p-hydroxylation of mCPP, and indicate that caution should be exercised in coprescribing inhibitors or substrates of CYP2D6 with drugs that have mCPP as a metabolite.

Cytochrome P-450 CYP2D6↗
PubMed1998

Lithium does not attenuate the effects of D-amphetamine in healthy volunteers.

It has previously been suggested that an acute dose of 20 mg D-amphetamine can be a good model of mania. In the present study we attempted to validate this model by determining if subacute administration of lithium (for 7 days) would attenuate the effects of 20 mg D-amphetamine in human volunteers. Sixteen healthy volunteers were enrolled in this double-blind, placebo-controlled study. Subjects received either oral lithium at night for 7 nights (1200 mg) (n = 10) or matching placebo (n = 6). On day 8, subjects were assessed at baseline and then once each hour for 3 h following an oral dose of D-amphetamine (20 mg). Subjective states were measured with visual analog scales, and pulse, systolic and diastolic blood pressure were also repeatedly assessed. The results showed that D-amphetamine alone produced a number of subjective and cardiovascular changes, as expected. However, lithium did not attenuate any of these subjective or cardiovascular changes, as would be predicted if D-amphetamine were a valid model of mania. It is suggested that whilst D-amphetamine may produce effects similar to mania, its mechanism of action is different from that which occurs in mania, and therefore the usefulness of the amphetamine model of mania is called into question.

Adult↗
PubMed1998

Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources.

The metabolism of the antidepressant drug trazodone to its active metabolite, m-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomal preparations and cDNA-expressed human cytochrome P450 (P450) enzymes. The kinetics of mCPP formation from trazodone were determined, and three in vitro experiments were performed to identify the major P450 enzyme involved. Trazodone (100 microM) was incubated with 16 different human liver microsomal preparations characterized for activities of 7 different P450 isoforms. The production of mCPP correlated significantly with activity of cytochrome P4503A4 (CYP3A4) only. Trazodone (100 microM) was then incubated with microsomes from cells expressing human CYP1A1, CYP1A2, CYP2C8, CYP2C9arg, CYP2C9cys, CYP2C19, CYP2D6, or CYP3A4. Only incubations with CYP3A4 resulted in mCPP formation. In the third experiment, the CYP3A4 inhibitor ketoconazole was found to inhibit mCPP formation concentration dependently in both human liver microsomes and in microsomes from cells expressing human CYP3A4. The present results indicate that trazodone is a substrate for CYP3A4, that CYP3A4 is a major isoform involved in the production of mCPP from trazodone, and that there is the possibility of drug-drug interactions with trazodone and other substrates, inducers and/or inhibitors of CYP3A4.

Antidepressive Agents, Second-Generation↗
PubMed1995

The nitric oxide synthase inhibitor NW-nitro-L-arginine methylester attenuates brain catalase activity in vitro.

Nitric oxide has been implicated in mediating the neurotoxic effects of ischemia in the brain. However, studies of the effects of nitric oxide inhibition with nitric oxide synthase inhibitors have provided controversial results. One of the reasons for the controversy may be related to the specificity of the nitric oxide synthase inhibitors, such as Nw-nitro-L-arginine methylester (L-NAME), which has recently been questioned. The present work investigated the possible interaction of L-NAME with the enzyme catalase in vitro. Catalase is an iron containing enzyme which could potentially interact with the iron-binding groups of L-NAME. Since the normal function of catalase in the brain is to remove excess hydrogen peroxide, the inhibition of this process could have potentially toxic effects. L-NAME was found to attenuate the catalase inhibiting effects of the known catalase inhibitor cyanamide in vitro, suggesting a competition between cyanamide and L-NAME for catalase. In addition, L-NAME by itself attenuated catalase activity in vitro. These results indicate that in addition to inhibiting nitric oxide synthase, L-NAME may have effects on catalase activity.

Animals↗
PubMed1993

Anxiolytic effects of serotonergic interventions in the shock-probe burying test and the elevated plus-maze test.

Although serotonergic neural systems have been implicated in the control of anxiety for a number of years, evidence in favour of this role is controversial. The present experiments were designed to further characterize the putative role of serotonin (5-HT) in anxiety, using two pharmacologically validated animal models: the elevated plus-maze and the shock-probe burying tests. If the integrity of 5-HT neural systems is necessary for the expression of 'anxious' behaviors, then disruption of 5-HT systems should produce effects in the plus-maze and shock-probe tests that are similar to those of anxiolytic drugs. In the present experiments, serotonergic function was disrupted in rats, either by chemical depletion using the synthesis inhibitor p-CPA, by inhibitory autoreceptor activation using the selective 5-HT1A receptor ligand 8-OH-DPAT, or by electrolytic lesions of the serotonin-containing, dorsal raphe nucleus. p-CPA and dorsal raphe lesions produced robust anxiolytic effects in the elevated plus-maze and the shock-probe burying tests, whereas 8-OH-DPAT produced anxiolytic effects only in the shock-probe burying test, and 'anxiogenic' effects in the elevated plus-maze test. Although these results generally support the view that serotonin plays a role in the expression of 'anxious' behavior, the opposite effects of 8-OH-DPAT in the two behavioral paradigms suggest that the 5-HT1A receptor subtype exerts differential control over different types of experimental anxiety.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Dissociating the anti-fear effects of septal and amygdaloid lesions using two pharmacologically validated models of rat anxiety.

Effects of septal and amygdaloid lesions were compared in 2 models of rat "anxiety." Septal lesions decreased burying behavior in the "shock-probe burying test" and increased open-arm exploration in the "elevated plus-maze test," whereas amygdaloid lesions produced neither of these anxiolytic effects. However, amygdaloid lesions increased rats' contacts of the electrified probe, an anxiolytic effect not produced by septal lesions. Each of these distinct, anxiolytic effects of septal or amygdaloid lesions were displayed together in animals with lesions of both structures. Furthermore, the magnitude of these anxiolytic effects after combined lesions was comparable to their magnitude after individual lesions. Taken together, these results suggest the amygdala and the septum independently control the expression of different fear-related behaviors.

Amygdala↗
PubMed1993

Noninteractive effects of diazepam and amygdaloid lesions in two animal models of anxiety.

The role of the amygdala in mediating the anxiolytic effects of diazepam was examined in two models of rat anxiety. As in our previous experiments, amygdaloid lesions by themselves did not increase rats' exploration of the open arms of the elevated plus-maze or decrease rats' burying of an electrified probe in the shock-probe burying test. However, amygdaloid lesions did increase rats' shock-probe contacts. Diazepam (2 mg/kg) increased open-arm activity and decreased burying behavior to an equal extent in sham-lesioned and amygdala-lesioned rats and had no significant effect on the facilitation of probe contacts induced by amygdaloid lesions. These results suggest that many of the anxiolytic effects of benzodiazepines are not mediated by the amygdala.

Amygdala↗