Effect of combined administration of afobazole and 5-HT2b/2c receptor antagonist SB-200646A on neurochemical profile of brain structures in C57Bl/6 and BALB/c mice.

The effects of combined administration of afobazole and 5-HT(2b/2c)receptor antagonist SB-200646A on the content of monoamines and their metabolites in brain structures of C57Bl/6 and BALB/c mice were studied by the methods of HPLC with electrochemical detection. Combined administration of afobazole and SB-200646A increased the content of epinephrine in the striatum of BALB/c mice (to 230% of the control) and in the hippocampus of both mouse strains. The content of dihydroxyphenylacetic and homovanillic acids and parameters of dopamine metabolism in these structures were reduced. The content of dopamine in the hypothalamus and amygdala was elevated in C57Bl/6, but not in BALB/c mice. These findings attest to the involvement of monoamine systems of the brain in the mechanism of afobazole action and suggest that the enhanced anxiolytic effect of afobazole combination with SB-200646A can be interpreted as a positive modulation of the effect of anxiolytic determined by blockade of 5-HT(2)serotonin receptors.

Modeling of presymptomatic and symptomatic stages of parkinsonism in mice.

A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.

Anxiety and predisposition to audiogenic epilepsy in rats of different genotypes.

We studied plus-maze behavior of inbred Krushinskii-Molodkina, Wistar, and black-hooded rats (originating from the Long-Evans outbred strain) differing by predisposition to audiogenic seizures. The severity of audiogenic seizures partially correlated with anxiety and negatively correlated with the total level of locomotor activity in the elevated plus-maze. The anxiety parameters in Krushinskii-Molodkina rats were evaluated after injection of anticonvulsant levetiracetam and anxiolytic afobazol. Levetiracetam and afobazol somewhat stimulated locomotor activity.

Dopamine synthesis by non-dopaminergic neurons expressing individual complementary enzymes of the dopamine synthetic pathway in the arcuate nucleus of fetal rats.

This study was aimed to test our hypothesis about dopamine (DA) synthesis by non-DAergic neurons expressing individual complementary enzymes of the DA synthetic pathway in cooperation, i.e. L-dihydroxyphenylalanine (L-DOPA) synthesized in tyrosine hydroxylase (TH)-expressing neurons is transported to aromatic L-amino acid decarboxylase (AADC)-expressing neurons for conversion to DA. The mediobasal hypothalamus of rats at the 21st embryonic day was used as an experimental model because it contains mainly monoenzymatic TH neurons and AADC neurons (>99%) whereas the fraction of bienzymatic (DAergic) neurons does not exceed 1%. The fetal substantia nigra containing DAergic neurons served as a control. DA and L-DOPA were measured by high performance liquid chromatography in: (1) cell extracts of the cell suspension prepared ex tempora; (2) cell extracts and incubation medium after the static incubation of the cell suspension with, or without exogenous L-tyrosine; (3) effluents of the incubation medium during perifusion of the cell suspension in the presence, or the absence of L-tyrosine. Total amounts of DA and L-DOPA in the incubation medium and cell extracts after the static incubation were considered as the indexes of the rates of their syntheses. L-Tyrosine administration caused the increased L-DOPA synthesis in the mediobasal hypothalamus and substantia nigra. Moreover, L-tyrosine provoked an increase of DA synthesis in the substantia nigra and its decrease in the mediobasal hypothalamus. This contradiction is most probably explained by the L-tyrosine-induced competitive inhibition of the L-DOPA transport to the monoenzymatic AADC-neurons after its release from the monoenzymatic TH neurons. Thus, this study provides convincing evidence of cooperative DA synthesis by non-DAergic neurons expressing TH or AADC in fetal rats at the end of the intrauterine development.

Effects of acute toxic doses of psychostimulants on extracellular levels of excitatory amino acids and taurine in rats: comparison of d-amphetamine and sydnocarb.

We used microdialysis to study how acute toxic doses of d-amphetamine and sydnocarb [3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine], an original Russian psychostimulant, affect extracellular levels of glutamate, aspartate, and taurine in the neostriatum of halothane-anesthetized male Sprague-Dawley rats. The administration of d-amphetamine (5.0 mg/kg x 4 i.p.) caused gradual fivefold increases in the extracellular glutamate and taurine levels and moderate increases in the extracellular aspartate level. Sydnocarb administration (23.8 mg/kg x 4 i.p., a dose equimolar to 5.0 mg/kg d-amphetamine) elicited a marked increase in the extracellular aspartate level and a small increase in the extracellular level of glutamate. The extracellular taurine level increased only after the last (fourth) injection. We conclude that a massive increase in extracellular taurine reflects hyperactivation of glutamatergic neurotransmission elicited by acute toxic dose of d-amphetamine. Sydnocarb seems to be less neurotoxic than d-amphetamine, because it elicits lesser changes in the extracellular levels of glutamate and taurine.

Effects of amphetamine and sydnocarb on dopamine release and free radical generation in rat striatum.

Microdialysis technique was used to compare the effects of four repeated intraperitoneal administrations of two psychostimulant drugs, D-amphetamine and sydnocarb, at the equimolar doses 5 and 23.8 mg/kg, respectively, on the extracellular level of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and hydroxyl radicals (.OH) in the dorsal striatum of freely moving 3-month-old male Wistar rats 250-300 g in weight. D-amphetamine caused immediate increase of DA concentration up to 950% with quick decline towards baseline values thereafter, followed by much less increase after further injections. Sydnocarb elicited moderate elevation in DA level achieving 400% after the fourth injection. D-amphetamine induced deep decrease in DOPAC concentration, while sydnocarb caused its increase after the first and second dosing. Both drugs enhanced generation of .OH, the effect of D-amphetamine was more pronounced. D-Amphetamine induced more intensive stereotyped behavior in rats compare to sydnocarb. It is concluded that the psychostimulant action of sydnocarb is accompanied by facilitation of the central dopaminergic transmission in rat neostriatum and followed by less pronounced neurotoxic effect than that of D-amphetamine.

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.

Novel synthetic analogue of ACTH 4-10 (Semax) but not glycine prevents the enhanced nitric oxide generation in cerebral cortex of rats with incomplete global ischemia.

This work investigates whether nitric oxide production and lipid peroxidation contribute to the pathophysiology of ischemia and whether glycine and a novel Russian compound, Semax are neuroprotective via a mechanism involving the regulation nitric oxide (NO) and lipid peroxidation. In brief, nitric oxide and indices of lipid peroxidation were elevated following global ischemia. While glycine proved ineffective in reducing NO levels or ameliorating the neurological deficits following global ischemia, Semax proved to be highly effective in abating the rise in nitric oxide and restoring neurologic functioning.

Effects of sydnocarb and D-amphetamine on the extracellular levels of amino acids in the rat caudate-putamen.

The neurotoxic effects of psychostimulants at high dosages limit their clinical applicability but the mechanism of neurotoxicity is still unsettled. We now studied by microdialysis how acute and subchronic (four times at 2-h intervals) administrations of D-amphetamine and sydnocarb [3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine], an original novel Russian psychostimulant, affected the extracellular levels of amino acids in the caudate-putamen of halothane-anesthetized male Sprague-Dawley rats. Acute D-amphetamine administration (5.0 mg/kg, i.p.) produced a moderate accumulation of extracellular glutamate and aspartate. Sydnocarb (23.8 mg/kg, i.p., a dose equimolar to 5.0 mg/kg D-amphetamine) also increased extracellular glutamate and alanine. Subchronic D-amphetamine administration (5.0 mg/kg x 4, i.p.) caused gradual fivefold increases in the glutamate and taurine levels and moderate increases in the aspartate and alanine levels. Subchronic sydnocarb administration (23.8 mg/kg x 4, i.p.) elicited a marked increase in the aspartate level and a small increase in the level of glutamate. The alanine level increased temporarily after each administration of sydnocarb, while the taurine level increased only after the last injection. We conclude that the mode of action of sydnocarb differs from that of D-amphetamine. Sydnocarb also seems to be less neurotoxic than D-amphetamine, since it elicits lesser changes in the extracellular level of glutamate.

Effect of d-amphetamine and sydnocarb on the extracellular level of dopamine, 3,4-dihydroxyphenylacetic acid, and hydroxyl radicals generation in rat striatum.

d-AMPH and its congeners are able to produce several neurotoxic effects, including behavioral evidences of dopaminergic dysfunction, enhanced generation of reactive oxygen species, and depletion of endogenous DA. As has been shown, Sydnocarb produces a slow and gradual increase of the parameters of dopaminergic dysfunction. Present investigations report that Sydnocarb, the original Russian psychostimulant, at a dose of 23.8 mg/kg (equimolar to 5 mg/kg d-AMPH) elicited a moderate increase in the extracellular level of DA. We found that Sydnocarb increased OH generation in less degree than that by d-AMPH. Sydnocarb was also able to elicit stereotyped behavior, but to a less extent than d-AMPH. Differences between the mode of action of this drug were previously observed. In our study, the DOPAC extracellular level was significantly decreased after the fourth injection of Sydnocarb, unlike with d-AMPH treatment. Taken together, this finding probably reflects less neurotoxic potential of the novel, original psychostimulant Sydnocarb with good clinical efficaciousness in comparison to the amphetamine.

Lamotrigine and carbamazepine affect differently the release of D-[3H]aspartate from mouse cerebral cortex slices: involvement of NO.

The effects of lamotrigine and carbamazepine on the release of preloaded D-[3H]aspartate and the involvement of nitric oxide were studied with mouse cerebral cortical slices in a superfusion system. Lamotrigine inhibited the veratridine-evoked release, whereas the K+-stimulated release was attenuated more strongly by carbamazepine than by lamotrigine. These effects were accentuated by the N-methyl-D-aspartate receptor antagonist L-2-amino-5-phosphonovalerate and the nitric oxide synthase inhibitor L-nitroarginine, but diminished by the nitric oxide donor sodium nitroprusside. The results show that in addition to the blockade of voltage-sensitive Na+ (and Ca2+) channels, NO-mediated mechanisms are probably involved in the anticonvulsant actions of carbamazepine and, in particular, those of lamotrigine.

Effect of tolcapone, a catechol-O-methyltransferase inhibitor, on striatal dopaminergic transmission during blockade of dopamine uptake.

To examine the mechanisms of tolcapone in the central nervous system (CNS), we analyzed alterations in parameters of striatal dopamine transmission induced by this drug (30 mg/kg) co-administered with the selective dopamine uptake inhibitor, GBR 12909 (10 mg/kg). Using microdialysis in freely moving rats, it was determined that combined administration of tolcapone with GBR 12909 resulted in a further increase of dopamine levels over that obtained without the catechol-O-methyltransferase inhibitor, while tolcapone alone failed to change dopamine levels. Fast-scan cyclic voltammetric monitoring of electrically evoked dopamine did not show any changes in dopamine release after the combination of the drugs, but there was a pronounced decrease in the rate of dopamine clearance after GBR 12909 alone and when co-administered with tolcapone. These data indicate that in rat striatum, a tolcapone-induced increase in extracellular dopamine is not observed because of the presence of uptake. These results also support the hypothesis that under normal conditions, uptake, rather than metabolism, control extracellular levels of dopamine.

Nitric oxide in mechanisms of brain damage induced by neurotoxic effect of glutamate.

Nitric oxide (NO) is a gaseous chemical messenger which plays the role of a universal modulator of various physiological functions of animals including the nervous system, i.e., interneuronal communications, synaptic plasticity, memory formation, receptor functions, intracellular signal transmission, release of neurotransmitters. The possible role of NO is considered in some basic diseases of the central nervous system which are associated with the neurotoxic effect of glutamate (ischemia, stroke, convulsive disorders, etc.). NO is believed to be a key pathophysiological factor of these diseases. The production of NO in the brain cortex of rats was found to significantly increase during convulsions of various origin.

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.

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.