clozapine and 3-methoxytyramine

Antipsychotic medications appear to exert their therapeutic effects by blocking D2 receptors. While D2 blockade occurs rapidly, reduction in psychotic symptoms is often delayed. This time discrepancy has been attributed to the relatively slow development of depolarization inactivation (DI) of dopaminergic neurons. The reduced firing rates associated with DI has been hypothesized to reduce dopamine release and thus psychotic symptoms. Studies assessing changes in dopamine release during chronic neuroleptic treatment, using microdialysis and voltammetry, have been inconsistent. This may be due to methodological differences between studies, the invasive nature of these procedures, or other confounds. To investigate the effects of DI on dopamine release, 3-MT accumulation, an index of dopamine release that does not involve disruption of brain tissue, was measured during acute and chronic neuroleptic treatment. These results are compared with those using other techniques. 3-MT levels remained elevated after chronic treatment, suggesting that DI does not markedly reduce release. Regulation of dopamine release during DI was examined using two techniques known to block dopamine neuronal impulse flow. 3-MT levels were markedly reduced by both, implying that DI does not alter the portion of dopamine release mediated by neuronal impulse flow. Overall, studies to date suggest that the delayed therapeutic effects of neuroleptics are not due to reductions in impulse dependent dopamine release. Recent studies using a neurodevelopmental animal model of schizophrenia have pointed to altered pre- and post-synaptic indices of dopamine neurotransmission. The results suggest that neuroleptics may exert their therapeutic effects, in part, by limiting the fluctuations in dopamine release, and raise new issues for future research.

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine; Haloperidol; Humans; Neurons; Reproducibility of Results; Time Factors

The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200 microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia. Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Dopamine; Haloperidol; Halothane; Homovanillic Acid; Kinetics; Male; Rats; Rats, Sprague-Dawley

3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3-MT formation was found to comprise > 60% of total DA turnover (sum of 3-MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3-MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3-MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O-methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3-MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3-MT, the ratio of 3-MT to DOPAC rates of formation can be a useful index of reuptake inhibition.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Dopamine; Frontal Lobe; Haloperidol; Kinetics; Male; Methylation; Models, Biological; Nucleus Accumbens; Rats; Rats, Sprague-Dawley

In a previous study, two coexisting mechanisms of dopamine release were identified in dopamine neuron terminals. One can be blocked with gamma-butyrolactone, suggesting it is impulse flow-dependent, while the other one cannot and is apparently impulse flow-independent. The goal of this study was to further characterize the gamma-butyrolactone-resistant mechanism and its relation to dopamine metabolism. Following acute and chronic haloperidol or clozapine treatment, gamma-butyrolactone was given to block dopamine neuronal impulse flow. In all groups, 3-methoxytyramine levels after monoamine oxidase inhibition with pargyline (an index of dopamine release) were measured in the frontal cortex, nucleus accumbens and striatum. Regional steady-state levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also measured in the rats treated acutely with neuroleptics. In all three regions, gamma-butyrolactone reduced the 3-methoxytyramine levels by over 50% after chronic neuroleptic treatment. This indicates that dopamine release from the terminals is primarily impulse flow-dependent during chronic neuroleptic treatment, both in the dopamine neurons which do undergo depolarization block, and in those that do not. No neuroleptic effect on the gamma-butyrolactone-resistant dopamine release was observed, while DOPAC and HVA were markedly elevated by the acute treatment, suggesting a predominant production of these metabolites from unreleased dopamine.

Topics: 3,4-Dihydroxyphenylacetic Acid; 4-Butyrolactone; Animals; Brain Chemistry; Cerebral Cortex; Clozapine; Dopamine; Dopamine Antagonists; Haloperidol; Homovanillic Acid; Male; Neurons; Rats; Rats, Sprague-Dawley; Receptors, Dopamine

1. The effects of the typical and typical neuroleptic agents clozapine (CLZ) (2.5-20 mg kg-1, i.p.) and haloperidol (Hal) (0.05-1.0 mg kg-1), were compared on dopamine release and metabolism in the rat prefrontal cortex (PFC), nucleus accumbens (ACC) and striatum (ST). Dopamine release was estimated by measuring the steady-state concentration of 3-methoxytyramine (3-MT) and the level of 3-MT 10 min after pargyline (3-MT accumulation); dopamine metabolism was evaluated from the steady-state concentrations of its acidic metabolites. 2. Both drugs increased 3-MT accumulation in the PFC in a dose-dependent manner. In contrast to Hal, CLZ failed to increase 3-MT accumulation in the ACC or ST. The ST was the region most sensitive to Hal in terms of 3-MT accumulation and, by inference, dopamine release. 3. Both CLZ and Hal dose-dependently elevated the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in all 3 brain regions studied. The ACC appears to be the region most sensitive to these drugs in terms of changes in the levels of HVA. 4. The result of the present investigations suggest measurements of 3-MT production in the 3 brain regions analysed might be a useful and simple pharmacological tool in the search for atypical neuroleptic drugs with a selectivity of action for the cortical systems.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Biogenic Monoamines; Brain Chemistry; Clozapine; Corpus Striatum; Dopamine; Frontal Lobe; Haloperidol; Homovanillic Acid; Male; Nucleus Accumbens; Pargyline; Rats; Rats, Inbred Strains

The accumulation of 3-methoxytyramine (3-MT), a reflection of dopamine release, was measured in the prefrontal cortex, nucleus accumbens, and striatum following administration of acute and chronic clozapine and haloperidol. Several doses of each drug were used. The effects of chronic drug treatment were measured 1 h (chronic 1 h groups), 24 h (chronic 24 h groups) and 48 h (chronic 48 h groups) after the final dose of each drug. In the prefrontal cortex, clozapine and haloperidol elevated 3-MT more in the acute groups than in the chronic 1 h groups, suggesting that partial tolerance developed. In the striatum and nucleus accumbens, acute and chronic (chronic 1 h) haloperidol produced equal increases in 3-MT above the appropriate baselines, suggesting that no tolerance developed. In the striatum, clozapine reduced 3-MT in the chronic 1 h group after high doses (25 mg/kg), and in the chronic 24 h group. These results suggest that neuroleptics may not produce the reduction in dopamine release that has been predicted with the development of depolarization inactivation. The reduction of striatal dopamine release during chronic clozapine treatment may be related to clozapine not being associated with the development of tardive dyskinesia.

Topics: Animals; Brain; Cerebral Cortex; Chromatography, Gas; Clozapine; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Haloperidol; Male; Nucleus Accumbens; Rats; Rats, Inbred Strains

The accumulation of 3-methoxytyramine (3-MT), the O-methylated metabolite of dopamine (DA), in rat striatum was used to assess the effects of drugs on dopaminergic activity. This was accomplished by pretreating rats with pargyline to completely inhibit 3-MT catabolism. Under the conditions used, 3-MT accumulation was linear over time for at least 90 minutes. Apomorphine and gamma-butyrolactone, drugs which depress the activity of DA-containing neurons, decreased striatal 3-MT accumulation; whereas typical neuroleptics (haloperidol, fluphenazine, chlorpromazine), which increase the activity of DA-containing neurons, increased striatal 3-MT accumulation. In addition, a number of other drugs which block DA receptors and exert various atypical actions on dopaminergic functioning were examined. These "atypical" compounds (clozapine, buspirone, molindone) also increased striatal 3-MT accumulation, but were generally less potent than the typical neuroleptics examined. Moreover, the potencies of the typical neuroleptics and "atypical" compounds that were tested appear to be somewhat related to their affinities for D-2 DA receptors, as measured by their abilities to displace 3H-spiperone from rat striatal membrane preparations. Interestingly, this relationship was less evident when NaCl was omitted from the 3H-spiperone binding assay buffer. The potential antipsychotic drugs, BW 234U and SCH 23390, were also investigated for their effects on 3-MT accumulation and 3H-spiperone binding, and they were relatively inactive in both of these measures of dopaminergic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Butyrolactone; Animals; Antipsychotic Agents; Apomorphine; Benzazepines; Buspirone; Carbazoles; Chlorpromazine; Clozapine; Corpus Striatum; Dopamine; Dopamine Antagonists; Fluphenazine; Haloperidol; Male; Molindone; Pargyline; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Regression Analysis

Studies were undertaken to evaluate the effect of certain dopamine (DA) agonists and antagonists on DA metabolite concentrations in rat striatum, with special regard to 3-methoxytyramine (3-MT). Quipazine, nomifensine and piribedil act as dopaminergic agonist drugs. However piribedil, which is a dopaminergic receptor agonist, reduced the concentrations of all 3 metabolites considered, while nomifensine produced an increase, and quipazine caused an early rise in 3-MT followed by a lowering of the concentration of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Haloperidol and clozapine are both DA antagonists. Haloperidol, which blocks DA receptors, caused an increase in the formation of all 3 metabolites while clozapine raised DOPA and HAV but not 3-MT. The importance of simultaneous determination of these 3 metabolites is discussed with relation to evaluation of the mechanism of action of these drugs and - more generally - of drugs acting on the dopaminergic system.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Clozapine; Corpus Striatum; Dopamine; Haloperidol; Homovanillic Acid; Male; Nomifensine; Phenylacetates; Piribedil; Quipazine; Rats