clozapine and amfonelic-acid

In addition to its well-known behavioral effects in rats, amphetamine also produces patterned locomotion (referred to below as locomotor stereotypy) in an open field. Locomotor stereotypy may be mediated by different mechanisms than those mediating the better-known behavioral effects of amphetamine. To determine whether the ability to produce locomotor stereotypy is an exclusive property of amphetamine or is a property of many amphetamine-like stimulants, several doses of methylphenidate and amfonelic acid were tested. The ability of both atypical and typical neuroleptics to block amphetamine-induced locomotor stereotypy was also tested. Both amfonelic acid and methylphenidate produced some degree of locomotor stereotypy. In addition, amphetamine-induced locomotor stereotypy was reduced by haloperidol but not by clozapine or thioridazine. These data suggest that locomotor stereotypy is more closely related to focused stereotypy than to hyperlocomotion.

Topics: Animals; Antipsychotic Agents; Clozapine; Haloperidol; Male; Methylphenidate; Motor Activity; Nalidixic Acid; Naphthyridines; Rats; Rats, Wistar; Stereotyped Behavior; Thioridazine

This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats. DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes. Amfonelic acid (2.5 mg/kg s.c.) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens. Haloperidol (1 mg/kg s.c.) increased extracellular DOPAC in both regions. When amfonelic acid was injected 5 min before haloperidol, the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum. Clozapine (30 mg/kg i.p.) increased extracellular DOPAC in both regions, an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum. When ritanserin (5 mg/kg i.p.), a serotonergic antagonist (5-HT-2), was co-administered with haloperidol, the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum. The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo. The effects of amfonelic acid on the neuroleptic-induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens. These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms, supporting the view that the regulation of dopamine metabolism differs in the two regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Clozapine; Corpus Striatum; Drug Interactions; Haloperidol; Hydroxyindoleacetic Acid; Kinetics; Male; Membrane Potentials; Nalidixic Acid; Naphthyridines; Nucleus Accumbens; Rats; Rats, Inbred Strains; Ritanserin; Time Factors

The purpose of the present study was to establish the extent to which dopamine uptake inhibitors, for example, amfonelic acid (AFA) and GBR 12909, differentially affect the haloperidol- and clozapine-induced activation of dopamine neurons. In the striatum and nucleus accumbens, the haloperidol-induced increases in dopamine synthesis and metabolism, as well as striatal dopamine release, were either potentiated or unaffected by AFA or GBR 12909. In contrast, AFA or GBR 12909 markedly attenuated the clozapine-induced increases in dopamine synthesis, metabolism, and release. However, the clozapine-induced increase in dopamine synthesis within tuberoinfundibular dopamine neurons was not significantly altered by AFA treatment. AFA and GBR 12909, appear to differentially affect the haloperidol- and clozapine-induced activation of nigrostriatal and mesocorticolimbic dopamine neurons. However, the inhibitory effect of AFA on the clozapine-induced activation of dopamine neurons does not extent to the stimulatory effect of clozapine on tuberoinfundibular dopamine neurons.

Topics: Animals; Clozapine; Dopamine; Haloperidol; Male; Nalidixic Acid; Naphthyridines; Neurons; Neurotransmitter Uptake Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley

Previous ex vivo studies have shown that the non-amphetamine stimulant amfonelic acid potentiates the increase in DOPAC induced by classical but not by atypical neuroleptics. In the present study, we have demonstrated that this neurochemical model can be used to discriminate typical from atypical neuroleptics in vivo using differential pulse voltammetry with carbon fibre electrodes. The study also compared the effect of intracerebroventricular (i.c.v.) administration of neurotensin, on extracellular striatal DOPAC following amfonelic acid, with the effects of both classical and atypical neuroleptics. Saline or amfonelic acid (2.5 mg/kg s.c.) were administered; followed 5 min later by the classical neuroleptics haloperidol, perphenazine, or the atypical neuroleptics clozapine, thioridazine, or by neurotensin. After drug administration extracellular striatal DOPAC was recorded every 5 min for 90 min. Amfonelic acid did not alter basal striatal DOPAC but potentiated the increase in DOPAC induced by haloperidol (1.0 and 0.05 mg/kg s.c.) and perphenazine (10 mg/kg s.c.). Both clozapine (30 mg/kg i.p.) and thioridazine (20 mg/kg s.c.) increased extracellular DOPAC, but pretreatment with amfonelic acid prevented the increase in DOPAC produced by both drugs. Neurotensin (10 micrograms, i.c.v.), in a similar manner to the atypical neuroleptics, increased extracellular DOPAC in the striatum and the effect was prevented by amfonelic acid. The present study demonstrates that pretreatment with amfonelic acid is a valuable tool to discriminate between classical and atypical neuroleptics in vivo. The results also indicate that neurotensin in the presence of amfonelic acid has a profile similar to the atypical neuroleptics.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antipsychotic Agents; Cerebral Ventricles; Clozapine; Corpus Striatum; Electrochemistry; Haloperidol; Injections, Intraventricular; Male; Nalidixic Acid; Naphthyridines; Neurotensin; Perphenazine; Rats; Rats, Inbred Strains; Thioridazine

In the present study we evaluated the interaction of amfonelic acid (AFA) with the typical neuroleptic haloperidol and the atypical antipsychotic clozapine on rat striatal dopamine metabolism in the absence or presence of the 5HT2 receptor antagonist ritanserin. In the absence of ritanserin, AFA significantly enhanced haloperidol stimulated 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) accumulation by 36% and 37% respectively above that produced by haloperidol alone. This effect is believed to be due to AFA's ability to facilitate dopamine release produced by the potent haloperidol-induced increase in nigrostriatal impulse flow. In contrast, AFA did not potentiate the ability of clozapine to stimulate DOPAC or HVA. This lack of potentiation could be explained by clozapine's known potent 5HT2 receptor blocking activity attenuating its stimulatory effects on impulse flow. To test this, we combined ritanserin with haloperidol and again studied the interaction with AFA on dopamine metabolism. In the presence of ritanserin, AFA failed to potentiate the effects of haloperidol on DOPAC or HVA accumulation; an effect similar to that seen with clozapine. This result extends the idea that 5HT2 receptor blockade modulates nigrostriatal dopaminergic neurotransmission.

Topics: Animals; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Corpus Striatum; Dopamine; Haloperidol; Male; Nalidixic Acid; Naphthyridines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Substantia Nigra; Synaptic Transmission

The purpose of this investigation was to determine if striatal or nucleus accumbens dopamine (DA) release, ACh release or DA receptor function were altered by acute and chronic haloperidol or clozapine treatment in a manner consistent with the reported pharmacological effects of each drug on A9 and A10 DA cell bodies and projection areas, when experiments were performed without a drug-free, or washout, period after drug treatment. The release of neurotransmitters reported here was evaluated using a slice-superfusion assay system. Transmitter release was induced either by an electrical field (for DA and ACh) or by application of either amphetamine or amfonelic acid (DA only). Dopaminergic receptor function was assessed by inhibiting electrically stimulated ACh release with in vitro TL-99 (a dopaminergic agonist) and by reversing that inhibition with in vitro neuroleptics or with ex vivo experimental paradigms (the in vitro analysis of transmitter release subsequent to in vivo drug administration). These data suggest that although there are differences between haloperidol and clozapine, there is no difference between the degree of postsynaptic DA receptor blockade produced that can be attributed to the duration of neuroleptic treatment. Chronic clozapine (20 mg/kg x 21 days) reversed TL-99-induced inhibition of ACh release in the nucleus accumbens only, whereas chronic haloperidol (0.5 mg/kg x 21 days) produced a similar reversal in both brain areas. One possible explanation for the lack of effect of chronic clozapine treatment in the striatum is that carrier-mediated (amphetamine-stimulated) DA release is enhanced in the striatum but not in the nucleus accumbens, suggesting that the potential DA receptor block in the striatum may be compromised by enhanced striatal DA levels. Acute haloperidol (0.5 mg/kg) was found to increase electrically stimulated ACh release in the striatum and DA release in the nucleus accumbens. Tolerance developed in the striatum, but not the nucleus accumbens, with repeated administration. However, acute clozapine had no effect on ACh release in either area, but it was found to enhance DA release in the striatum, an effect to which tolerance developed with chronic administration. Further, comparison of these data with data obtained using haloperidol and clozapine in vitro suggests that it is unlikely that these effects are due to residual drug still present in these tissues at the time of experimentation. These data are discussed w

Topics: Acetylcholine; Amphetamine; Animals; Clozapine; Corpus Striatum; Dibenzazepines; Dopamine; Electric Stimulation; Haloperidol; In Vitro Techniques; Male; Nalidixic Acid; Naphthyridines; Nucleus Accumbens; Rats; Rats, Inbred Strains; Septal Nuclei; Tetrahydronaphthalenes