Effects of intrastriatal infusion of D2 and D3 dopamine receptor preferring antagonists on dopamine release in rat dorsal striatum (in vivo microdialysis study).

Dopamine D2-like receptor antagonists haloperidol, spiperone, clozapine, cis -( +)- (1S,2R)-5-methoxy-1-methyl-2-(n -propylamino)tetralin, ( +)-AJ76, cis -( +)- (1S,2R)-5-methoxy-1-methyl-2-(n -di-propylamino)tetralin, ( +)-UH232, and putative D3 dopamine receptor agonist ( +/-)- 7-hydroxy-N,N-di- n -propyl-2-aminotetralin, 7-OH-DPAT, were infused via a transcerebral microdialysis probe into the dorsal striatum of freely moving rats. Local infusion of all the dopamine antagonists studied resulted in concentration-dependent increase of striatal dopamine release in vivo. Subsequent i.p. administration of the drugs did not produce a further rise of dopamine release as compared to the maximal increase elicited by local administration of the same substances. The difference between effects of D2 and D3 dopamine receptor preferring antagonists applied locally was observed only in the degree of dopamine release elevation [the maximal responses were about 160% for haloperidol and spiperone, 190% for clozapine and ( +)-UH232 and 400% for ( +)-AJ76, of basal]. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were elevated only slightly following local infusion of haloperidol, spiperone and clozapine, while systemic administration of the drugs resulted in a marked increase of metabolite extracellular levels. Both ( +)-UH232 and ( +)-AJ76 were found to increase significantly DOPAC and HVA levels during infusion, but the effect was less pronounced in comparison to that produced by systemic drug administration. Infusion of 7-OH-DPAT in the concentration range 5 x 10(-9)to 10(-6) M significantly decreased dopamine release but not metabolite levels down to the values observed following systemic drug administration. The present results give further evidence for the hypothesized leading role of nerve terminal dopamine autoreceptors, presumably of D3 type, in neuroleptic-induced augmentation of dopamine release in rat dorsal striatum.

Effects of a psychostimulant drug sydnocarb on rat brain dopaminergic transmission in vivo.

Transcerebral microdialysis was used to evaluate the effect of a psychostimulant drug, sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine), on the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal striatum and nucleus accumbens of freely moving rats. Sydnocarb dose dependently (4.4, 8.75 and 17.5 mg/kg, i.p.) induced a relatively modest (up to 350% of control) and long-lasting (up to 6 h) increase in dopamine extracellular level in the rat dorsal striatum. The drug at 8.75 mg/kg, i.p., produced an approximately similar increase in dopamine efflux in the dorsal striatum and in the nucleus accumbens of freely moving rats. Sydnocarb had no effect on DOPAC or HVA extracellular levels in the rat basal ganglia in vivo at any dose studied. It is important that the drug increased the efflux of dopamine in a tetrodotoxin-sensitive and Ca2+-dependent manner. Measurements of behavioral parameters in non-operated rats revealed that sydnocarb markedly increased locomotor activity and induced stereotyped behavior. These data suggest that the stimulant action of sydnocarb is accompanied by a facilitation of central dopaminergic transmission involving an increase in Ca2+-dependent vesicular dopamine efflux.

In vivo evidence for preferential role of dopamine D3 receptor in the presynaptic regulation of dopamine release but not synthesis.

Brain microdialysis was used to investigate the effects of the putative dopamine D3 receptor agonist (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on dopamine release, metabolism and synthesis in the dorsal striatum and nucleus accumbens of awake rats. The drug administered i.p. dose dependently decreased the release, metabolism and synthesis of dopamine in both brain areas. The potency of 7-OH-DPAT to decrease dopamine release was found to be higher in the nucleus accumbens than in the dorsal striatum (ED50 for nucleus accumbens 0.0096 mg/kg, i.p.; for dorsal striatum 0.068 mg/kg, i.p.). Dopamine metabolism, assessed by measuring 3,4-dihydroxyphenylacetic acid extracellular levels, and dopamine synthesis, determined as 3,4-dihydroxyphenylalanine output following perfusion with the L-aromatic acid decarboxylase inhibitor 3-hydroxybenzylhydrazine (10(-5) M), were decreased at higher dose ranges of 7-OH-DPAT (ED50 for decrease of 3,4-dihydroxyphenylalanine output in nucleus accumbens 0.124 mg/kg, i.p.; in dorsal striatum 0.101 mg/kg, i.p.). The hypomotility of rats induced by 7-OH-DPAT in doses of 0.002-0.25 mg/kg, i.p., was shown to correlate with the decreased dopamine release in the nucleus accumbens. Pretreatment of animals with 7-OH-DPAT at the putative dopamine D3 receptor 'selective' dose of 0.05 mg/kg, i.p., was found to prevent the increase of dopamine release but not the increase in metabolism in the dorsal striatum of freely moving rats induced by (+)-AJ76, cis (+)-(1S,2R)-5-methoxy-1-methyl-1-2-(n-propylamino)tetralin HCI (7 mg/kg, i.p.) and haloperidol (0.1 mg/kg, i.p.). Local application of 7-OH-DPAT by addition into the perfusing medium also resulted in a preferential decrease of dopamine release in the nucleus accumbens as compared with the dorsal striatum (EC50 for nucleus accumbens 1.9 nM; for dorsal striatum 11.3 nM). The present results give further support to the hypothesis that the dopamine D3 autoreceptor is preferentially involved in the presynaptic regulation of dopamine release, while the D2 autoreceptor controls dopamine synthesis.

Simultaneous monitoring of dopamine, its metabolites and trans-isomer of atypical neuroleptic drug carbidine concentrations in striatal dialysates of conscious rats.

1. Transcerebral microdialysis was used to monitor dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and trans-isomer of atypical neuroleptic drug carbidine concentrations in the dialysates from dorsal striatum of freely moving rats following i.p. administration of the drug at doses 0.5, 1,5 and 25 mg/kg. The changes in locomotor activity as well as catalepsy in rats following transcarbidine administration were also evaluated. 2. The microdialysis "point of no net flux" method was used to measure interstitial free concentration (IFC) of trans-carbidine in the dorsal striatum of freely moving rats following i.p. administration of the drug at dose 5 mg/kg. The maximal IFC of trans-carbidine was found to be approximately 1 mu M 20-40 min after injection. 3. The drug at doses up to 1 mg/kg produces elevation of dopamine release not affecting sufficiently its metabolite dialysate levels. IFC of the drug calculated for these doses will not exceed 0.24 pM. At the dose 5 mg/kg, i.p., elevation of both dopamine release and metabolism was observed and dopamine release increased slightly more than DOPAC dialysate levels. 4. Stimulatory action of trans-carbidine on locomotor activity of non-operated rats has been observed at doses 0.2 and 0.5 mg/kg, i.p.. 5. Only the dose 25 mg/kg of trans-carbidine (maximal calculated IFC 4.53 mu M) was found to be cataleptogenic. The drug at this dose failed to increase DA release but induced a marked increase of DOPAC and HVA output. 6. It is concluded that trans-carbidine in in vivo neurochemical and behavioural studies demonstrates the preferential antagonistic action on dopamine release-regulating autoreceptors.

Regulation of dopamine release and metabolism in rat striatum in vivo: effects of dopamine receptor antagonists.

1. The acute effects of some of typical and atypical antipsychotic drugs on the dopamine release and metabolism in the dorsal striatum of freely moving rats were studied using transcerebral microdialysis technique. 2. Classical neuroleptic drugs haloperidol (0.05, 0.1 and 0.2 mg/kg), thioproperazine (0.1, 0.2 and 0.4 mg/kg) and spiperone (0.02, 0.04 and 0.07 mg/kg) administered i.p. induced pronounced elevation of extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) up to 250-300% to basal level while producing less increase in that of dopamine (DA) (up to 150-170%). 3. Atypical neuroleptics clozapine and thioridazine (both 2, 5 and 20 mg/kg) increased striatal DA release and DOPAC level approximately at the same degree (maximally up to 200% and 160%, respectively). 4. Dopamine D3 receptor and autoreceptor preferring antagonists (+)-UH232 and (+)-AJ76 (both 4, 7 and 14 mg/kg) more potently increased DA release in comparison with DOPAC dialysate level (+)-AJ76 elevated DA level maximally up to 330%, DOPAC-up to 250%). 5. The features of typical and atypical neuroleptics in preferential action on DA release or DOPAC output were observed in all doses of the drugs studied. 6. The ability of the drugs to affect preferentially DA release or DOPAC extracellular level in rat striatum correlates to their relative affinities at D3 and D2 DA receptors. 7. It is concluded that typical and atypical antipsychotic drugs might be clearly distinguished on the basis of their ability to affect preferentially DA synthesis/metabolism or release in rat dorsal striatum in vivo.

[The effect of bromantane on the dopamin- and serotoninergic systems of the rat brain]. / Vliianie bromantana na dofamin- i serotoninergicheskie sistemy mozga krys.

The effect of acute and chronic administration (50 mg/kg, p.o.) of a new immunostimulator, bromantan exhibiting psychostimulant features on the content of NE, DA and 5-HT, and their metabolites are studied. Bromantan induced a significant increase in the 5-HT and 5-HIAA content in the frontal cortex and delayed an increase in their content in subcortical brain regions. A stable decrease in the 5-HT and 5-HIAA levels in the cerebellum is observed. The drug also affected the DA parameters of the brain thus suggesting an important role of dopaminergic system in the mechanism of pharmacological effects of the drug.

Estimation of the interstitial free concentration of the putative dopamine D3 receptor selective agonist 7-OH-DPAT in the dorsal striatum of freely moving rats.

Using the quantitative microdialysis 'point of no net flux' method, we estimated the interstitial free concentration (IFC) of (+/-)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT) in the dorsal striatum of freely moving rats after i.p. administration of the drug at the dose of 18.3 mumol/kg. The maximal IFC of 7-OH-DPAT was found to be 1.61 microM 20 min after the injection. Due to the approximately linear relationship between dose and dialysate concentration observed, it may be inferred that the behaviourally active 7-OH-DPAT dose of 0.12 mumol/kg should give an IFC which does not exceed 10 nM. It is concluded that in vivo effects observed following 7-OH-DPAT i.p. administration at doses lower than 0.12 mumol/kg might be considered as mediated by the dopamine D3 receptor.

Dopamine D2 and D3 receptor preferring antagonists differentially affect striatal dopamine release and metabolism in conscious rats.

Classical neuroleptic drugs with high affinity for dopamine D2 receptors in comparison to D3 ones (haloperidol, thioproperazine and spiperone) administered i.p. acutely (0.2, 0.2 and 0.07 mg/kg, respectively) induced a pronounced increase in the extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and only a modest rise in that of dopamine in the dorsal striatum of conscious rats studied by transcerebral microdialysis. Atypical neuroleptics, clozapine and thioridazine (both 20 mg/kg), demonstrating relatively higher affinity for dopamine D3 receptor than typical ones, as well as the dopamine D3 receptor and autoreceptor preferring antagonists, cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(di-n- propylamino)tetralin HCl ((+)-UH232) and cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin HCl ((+)-AJ76) (both 14 mg/kg), were equally effective or even more potent in increasing dopamine release than DOPAC. It is concluded that the dopamine D2/D3 receptor relative potencies of typical and atypical neuroleptics appear to correspond to their ability to affect preferentially dopamine metabolism or release in rat dorsal striatum in vivo.

[Effects of N-acetylasparaginic acid during frontal lobectomy in the rat: antiamnestic action and effect on monoamine level]. / Effekty N-atsetilasparaginovoi kisloty pri frontal'noi lobéktomii mozga krys: antiamnesticheskoe deistvie i vliianie na soderzhanie monoaminov.

Effects of N-acetyl-aspartic acid (NAA) on the behaviour models "open field", passive avoidance test and content of monoamines and their metabolites in the brain areas on the 9-th day after frontal decortication were studied. NAA (50 mg/kg), i.p., daily, 9 days) exerted antiamnestic effect in decorticated rats, evaluated in passive avoidance test. Corresponding changes in concentration of serotonin and 5-hydroxyindolacetic acid in the brain of decorticated rats were also seen.

[Changes in the activity of angiotensin converting enzyme in the structures of the rat brain after frontal lobectomy]. / Izmeneniia aktivnosti angiotenzinprevrashchaiushchego fermenta v strukturakh mozga krys posle frontal'noi lobéktomii.

The functional state of the angiotensin system (the activity of the angiotensin converting enzyme--ACE) was studied in different rat brain regions during disturbance of the integrative activity of CNS after frontal lobectomy. The most prominent increase of the ACE activity (in four times) on the ninth day after lobectomy was detected in crown cortex and hippocamp. Considerable differences were discovered in striatum, thalamus and hypothalamus also. The variations of the ACE activity were not shown in the medulla oblongata and midbrain. It is possible to conclude, that ACE activity alternations have regional disposition and functional dependence.

[Role of monoamines in the recovery of the conditioned reflex activity of rats following extirpation of the frontal cortex]. / Rol' monoaminov v vosstanovlenii uslovnoreflektornoi deiatel'nosti krys posle ékstirpatsii lobnoi kory.

The influence of frontal cortex extirpation on the amount of monoamines in the brain structures was investigated in chronic experiments on rats trained according to the method of motor feeding reflexes with bilateral reinforcement. Monoamine levels were measured by high performance liquid chromatography with electrochemical detection. By the ninth day after the ablation serotonin (5-HT) and dopamine (DA) levels were significantly reduced in the cortex and the striatum, respectively, while noradrenaline ++ (NA), 5-HT, dihydroxyphenylacetic and 5-hydroxyindoleacetic acid levels in raphe nuclei and locus coeruleus were increased. The level of conditioned reflex reproduction was 39% on the light and 33% on the sound stimulus. The involvement of monoamines in the recovery of conditioned reflexes after frontal cortex extirpation is discussed.