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C A Altar

Publications and source records attributed to C A Altar.

At least 73 records · Page 4Linked to original sources
PubMed1988

Rotational behavior induced by 8-hydroxy-DPAT, a putative 5HT-1A agonist, in 6-hydroxydopamine-lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (5HT) agonist drugs. The 5HT-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3-3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative 5HT-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal 5HT levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending 5HT-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗
PubMed1988

Heterogeneous rotational responsiveness in 6-hydroxydopamine-denervated rats: pharmacological and neurochemical characterization.

Qualitative differences in pharmacological responsiveness to various types of dopamine agonists have been reported in rats that have undergone unilateral 6-hydroxydopamine (6-OHDA)-induced denervation of the nigro-striatal pathway. The present experiments further characterize these differences, pharmacologically and neurochemically. Rats were classified as having high rotational sensitivity (0.03 mg/kg SC apomorphine sufficient to induce more than 100 rotations/20 min) or low sensitivity (0.3 mg/kg SC apomorphine required to meet this criterion). High sensitivity rats showed marked contralateral rotational behavior (approximately 150 rotations/20 min) in response to apomorphine (ED50 = 0.08 mg/kg IP), CGS 15855A (ED50 = 0.07 mg/kg), CGS 15873A (ED50 = 0.43 mg/kg), (+)-3-PPP (ED50 = 2.3 mg/kg), (-)-3-PPP (ED50 = 0.87 mg/kg) and quinpirole (peak effective dose, 0.03 mg/kg). In low sensitivity rats, 3- to 10-fold higher doses of apomorphine induced a maximal rate of rotational behavior, but only partial effects were produced by quinpirole, CGS 15855A, CGS 15873A, (+)-3-PPP, and (-)-3-PPP (40-80 rotations/20 min). Because apomorphine is a nonselective D1 and D2 agonist, it is proposed that activation of either D1 or D2 receptors suffices to induce high rates of rotation in high sensitivity rats, whereas in low sensitivity rats, D1 or D2 agonism alone induces submaximal rotation rates. The ipsilateral rotational behavior induced by d-amphetamine was more pronounced and occurred at lower doses in the high-sensitivity rats. Striatal dopamine depletion on the lesioned side did not differ between the groups, but low sensitivity rats showed two-fold higher DOPAC/DA ratios on the lesioned side than did high-sensitivity rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Presynaptic inhibition of nigrostriatal dopamine release in the mouse: lack of cross tolerance between apomorphine, GBL and CGS 10746B.

Acute parenteral injections of apomorphine, gamma-butyrolactone (GBL) and CGS 10746B decreased dopamine release in the mouse nigrostriatal pathway as evidenced by decreases in striatal 3-methoxytyramine levels. In a 7 day treatment paradigm, the effects of acute apomorphine, GBL and CGS 10746B were unaltered in animals treated b.i.d. with GBL (500 mg/kg, i.p.). In contrast, the actions of acute CGS 10746B expressed a complete tolerance in mice treated b.i.d. with CGS 10746B (20 mg/kg, i.p.), while the actions of acute apomorphine or GBL were similar in the chronic saline and chronic CGS 10746 groups. These data show that the inhibition of striatal dopamine release by CGS 10746B is susceptible to tolerance. In addition, the lack of cross tolerance between GBL, apomorphine and CGS 10746B suggests independent sites of action for these agents in inhibiting dopamine release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Inhibition of climbing and mossy fiber input to mouse cerebellar Purkinje cells by cholecystokinin.

Cholecystokinin (CCK)-8S was found both to decrease basal and to antagonize harmaline-dependent increases in cerebellar cyclic GMP (cGMP) in the mouse. These actions were not blocked by parenteral pretreatment with naloxone, proglumide or CR-1409, indicating a central-type CCK receptor activation with no involvement of opioid systems. These data were further confirmed by the greater potency (200x) of intraventricular relative to s.c. doses for CCK-8S. The intraventricular administration of CCK-4, t.BOC.CCK-4 and CCK-8US also resulted in decreased cerebellar cGMP levels, consistent with a central-type CCK receptor action. Direct administration of CCK-8S into the cerebellum failed to alter either basal or harmaline-stimulated cerebellar cGMP levels, indicating that the actions of this peptide on cerebellar cGMP are not directly at the level of the cerebellum. The convulsants, picrotoxin and pentylenetetrazol, elevated cerebellar cGMP with no antagonism by pretreatment with s.c. CCK-8S. In marked contrast, the increases in cerebellar cGMP induced by treatment with amphetamine, apomorphine, DN 1417, oxotremorine and harmaline were all antagonized by pretreatment with s.c. CCK-8S. These data are consistent with CCK receptor involvement in the regulation of climbing and mossy fiber input to the cerebellum. These actions apparently involve the central-type CCK receptor that resides outside of the cerebellum proper. The exact site(s) of action for CCK-8S remain(s) to be defined.

Animals↗
PubMed1988

Dopamine release and metabolism after chronic delivery of selective or nonselective dopamine autoreceptor agonists.

The metabolism and release of dopamine by rat mesostriatal and mesolimbic dopamine neurons were determined after 2 or 14 days of subcutaneous administration via Alzet minipumps of a selective (CGS 15855A) or nonselective (apomorphine) dopamine autoreceptor agonist. Bioassays and high performance liquid chromatography assays showed that each drug was accurately delivered for the 2- and 14-day periods. CGS 15855A levels in the plasma and brain increased with increases in the daily dose given, although plasma levels of CGS 15855A at 14 days were less than those at 2 days for each dose. Striatal dopamine metabolism and release, assessed with dihydroxyphenylacetic acid and 3-methoxytyramine concentrations, respectively, were suppressed by 2-day treatments of 50-200 micrograms/day CGS 15855A or 250 micrograms/day apomorphine. These suppressions were potentiated by acute challenge with 1 mg/kg intraperitoneally of CGS 15855A or 2 mg/kg subcutaneously of apomorphine. In contrast, dopamine metabolism and release were unchanged after 14 days of administration of 40-400 micrograms/day of CGS 15855A or 250 micrograms/day of apomorphine, even when plasma levels of drug were as high as at 2 days. Dopamine release was decreased in only one of six groups 30 min after an additional acute injection of the agonist given for 14 days, whereas dopamine metabolism was decreased in five of six groups. Striatal dopamine levels were increased 20-57% after 14 but not 2 days of cgs 15855A followed by acute challenge with the vehicle or CGS 15855A injections. Thus, the responsiveness of dopamine neurons to the release-suppressing properties of dopamine autoreceptor agonists is mostly attenuated between 2 and 14 days of treatment. The ability of chronic CGS 15855A treatments to increase dopamine levels and, with acute CGS 15855A, to decrease DOPAC levels, indicates that autoreceptor control of dopamine metabolism is partly retained after chronic autoreceptor agonism.

Animals↗
PubMed1987

Topography of substantia nigra innervation by D1 receptor-containing striatal neurons.

Iodinated SCH 23390, [125I]SCH 23982, saturably binds in brain to D1 receptors that mostly reside on striatal and striatonigral neurons. [125I]SCH 23982 autoradiography was used to determine the topography of D1 receptor-containing striatal inputs to subregions of the substantia nigra. The concentration of D1 sites was greatest in the pars reticulata of the substantia nigra and exceeded by over 50% the equal concentrations of D1 sites in the lateral substantia nigra, caudate-putamen, nucleus accumbens, and olfactory tubercle. D1 receptors were uniformly concentrated throughout the caudate-putamen and were absent in the pars compacta of the substantia nigra and ventral tegmental area. Injections into the rostral striatum of the axon-sparing neurotoxin, quinolinic acid, depleted the concentration of D1 sites in the rostral caudate-putamen by 98% and the concentration of D1 sites in the medial substantia nigra by up to 74%. Quinolinic acid-induced losses of the D1 sites in the central striatum of up to 85% were associated with 87% losses of D1 sites in the central nigra. D1 losses of 91% in the caudal striatum were associated with D1 losses of 85% in the lateral nigra. Thus, most D1 sites in the striatum reside on neurons that are intrinsic to that brain region, and the vast majority of D1 sites in the substantia nigra are on the terminals of striatonigral neurons. These D1 receptor-containing striatonigral neurons have a rostral, central, or caudal origin in the striatum and a corresponding medial, central, or lateral termination in the nigra. This topographical organization of striatal inputs to the substantia nigra indicates that substance P or dynorphin B-containing striatonigral neurons may have D1 receptors on their terminals.

Animals↗
PubMed1987

Dopamine autoreceptor agonists including CGS 15855A decrease dopamine release and metabolism in mouse brain.

The ability of dopamine autoreceptor agonists to suppress the in vivo release or metabolism of dopamine in mouse brain was determined by measuring steady state levels of 3-methoxytyramine (3-MT) or dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), respectively. These experiments provide the first neurochemical evidence for dopamine autoreceptors in the mouse. (-)N-n-propylnorapomorphine, apomorphine, (+)-3-PPP, TL-99, and the novel dopamine autoreceptor agonist CGS 15855A each decreased 3-MT levels at doses that approximated their potency in the gamma-butyrolactone model. CGS 15855A suppressed dopamine release and metabolism to the same extent in the rat and mouse neostriatum. Generally, agonist-induced decreases in 3-MT levels were obtained to a greater extent or with lower doses than were changes in DOPAC or HVA. The autoreceptor efficacy of CGS 15855A was confined to the (+) and not the (-) optical isomer. Consecutive injections of CGS 15855A did not induce an acute tolerance to its actions but instead prolonged for at least 3.5 h the suppression of dopamine metabolism and release. The release and metabolism of dopamine in mouse limbic and striatal regions is regulated by autoreceptors with a pharmacological specificity that is similar to autoreceptors of the rat.

Animals↗
PubMed1987

Injections of deuterated tryptamine into the nucleus accumbens of the rat: effects on locomotor activity and monoamine metabolism.

Previous studies have shown that the systemic injection of tryptamine stimulates locomotion in rats and that the nucleus accumbens, a region involved in locomotion, contains the largest concentrations of binding sites for tryptamine in the brain of the rat. The present study examined the behavioral and neurochemical effects of bilateral injections into the accumbens of a deuterated analog of tryptamine, a,a-[2H]tryptamine. Injections of 25 micrograms a,a-[2H]tryptamine increased movements in rats at 25-70 min after injection and increased vertical (rearing) activity at 25-40 min. Injections of 50 micrograms of a,a-[2H]tryptamine produced a transient suppression of movement and vertical activity at 5-15 min, followed by increases in these activities at 40-65 min after injection that were comparable to the increases elicited by 10 micrograms of d-amphetamine. At 30 min after the injection of 50 micrograms a,a-[2H]tryptamine the concentration of dopamine in the nucleus accumbens was increased by 87%, and was preceded by a transient decrease in the level of the metabolite of dopamine homovanillic acid. The levels of 5-hydroxytryptamine and its major metabolite, 5-hydroxyindoleacetic acid in the nucleus accumbens were not changed. Thus, a,a-[2H]tryptamine may interact with tryptamine receptors in the nucleus accumbens to modulate locomotor behavior through mesolimbic dopamine neurons.

Animals↗
PubMed1987

Quantitative autoradiography of brain binding sites for the vesicular acetylcholine transport blocker 2-(4-phenylpiperidino)cyclohexanol (AH5183).

2-(4-Phenylpiperidino)cyclohexanol (AH5183) is a noncompetitive and potent inhibitor of high-affinity acetylcholine transport into cholinergic vesicles. It is reported here that [3H]AH5183 binds specifically and saturably to slide-mounted sections of the rat forebrain (Kd = 1.1 to 2.2 X 10(-8) M; Bmax = 286 to 399 fmol/mg of protein). The association and dissociation rate constants for [3H]AH5183 binding are 8.6 X 10(6) M-1 X min-1 and 0.18 min-1, respectively. Bound [3H]AH5183 can be displaced by nonradioactive AH5183 and by the structural analog (2 alpha,3 beta,4A beta,8A alpha)-decahydro-3-(4-phenyl-1-piperidinyl)-2- naphthalenol but not by 10 microM concentrations of the cholinergic drugs acetylcholine, choline, atropine, hexamethonium, eserine, or hemicholinium-3 or by the structurally related compounds 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridine, (+/-)-N-allylnormetazocine (SKF 10,047), levoxadrol, or dexoxadrol. Quantitative autoradiography reveals that [3H]AH5183 binding sites are distributed heterogenously throughout the rat forebrain and are highly localized to cholinergic nerve terminal regions. At the level of the caudate nucleus-putamen, the highest concentrations of saturable [3H]AH5183 binding (713-751 fmol/mg of protein) are found in the vertical limb of the diagonal band and the olfactory tubercle, with lesser amounts (334-516 fmol/mg of protein) in the caudate-putamen, nucleus accumbens, superficial layers of the cerebral cortex, and the primary olfactory cortex. At day 7 after transsection of the left fimbria, [3H]AH5183 binding and choline acetyltransferase activity in the left hippocampus were reduced by 33 +/- 6% and 61 +/- 7%, respectively. These findings indicate that [3H]AH5183 binds to a unique recognition site in rat brain that is topographically associated with cholinergic nerve terminals.

Acetylcholine↗
PubMed1987

Time course of adaptations in dopamine biosynthesis, metabolism, and release following nigrostriatal lesions: implications for behavioral recovery from brain injury.

Alterations in neostriatal dopamine metabolism, release, and biosynthesis were determined 3, 5, or 18 days following partial, unilateral destruction of the rat nigrostriatal dopamine projection. Concentrations of dopamine and each of its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) were markedly decreased in the lesioned striata at 3, 5, or 18 days postoperation. The decline in striatal high-affinity [3H]dopamine uptake closely matched the depletion of dopamine at 3 and 18 days postoperation. However, neither DOPAC, HVA, nor 3-MT concentrations were decreased to as great an extent as dopamine at any time following lesions that depleted the dopamine innervation of the striatum by greater than 80%. In these more severely lesioned animals, dopamine metabolism, estimated from the ratio of DOPAC or HVA to dopamine, was increased two- to four-fold in the injured hemisphere compared with the intact hemisphere. Dopamine release, estimated by the ratio of 3-MT to dopamine, was more increased, by five- to sixfold. Importantly, the HVA/dopamine, DOPAC/dopamine, and 3-MT/dopamine ratios did not differ between 3 and 18 days postlesioning. The rate of in vivo dopamine biosynthesis, as estimated by striatal DOPA accumulation following 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibition with NSD 1015, was increased by 2.6- to 2.7-fold in the surviving dopamine terminals but again equally at 3 and 18 days postoperation. Thus, maximal increases in dopamine metabolism, release, and biosynthesis occur rapidly within neostriatal terminals that survive a lesion. This mobilization of dopaminergic function could contribute to the recovery from the behavioral deficits of partial denervation by increasing the availability of dopamine to neostriatal dopamine receptors. However, these presynaptic compensations are not sufficient to account for the protracted (at least 3-week) time course of sensorimotor recovery that has been observed following partial nigrostriatal lesion.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

In vivo assessment of dopamine and norepinephrine release in rat neocortex: gas chromatography-mass spectrometry measurement of 3-methoxytyramine and normetanephrine.

A new method with the sensitivity and specificity required to measure regional levels of 3-methoxytyramine (3-MT) and normetanephrine (NMN) in the rat cortex is described. The method utilizes a liquid ion exchanger to isolate the parent amines, dopamine (DA) and norepinephrine (NE), along with their methylated metabolites. These samples are derivatized and analyzed by negative ion gas chromatography-mass spectrometry. Using this method, we examined a number of drug actions on steady-state levels as well as pargyline-induced increases in 3-MT and NMN. In the prefrontal cortex, cingulate cortex, striatum, and olfactory tubercle, nomifensine was found to increase 3-MT steady-state levels and accumulation rates. Similar actions of this drug were observed in the cingulate and prefrontal cortices with NMN. In contrast, clonidine decreased cortical NMN levels and accumulation. A unique action was observed with haloperidol, in that both 3-MT levels and accumulation after pargyline were increased in the nigrostriatal and mesolimbic dopaminergic projections, whereas only the accumulation rates were accelerated in the mesocortical projections. In summary, our data indicate that this new assay is a useful approach for the in vivo evaluation of DA and NE release in cortical regions of the rat. This approach is unique in that no surgery, restraint, or anesthetic is required, thereby permitting more complicated experimental paradigms to be utilized.

Animals↗
PubMed1987

Modulation of in vivo dopamine release by D2 but not D1 receptor agonists and antagonists.

The capacity of D1 and D2 agonists and antagonists to regulate the in vivo release and metabolism of dopamine (DA) in mesolimbic and nigrostriatal DA neurons of the mouse was determined using gas chromatographic and mass fragmentographic (GC-MF) analysis. DA release was inferred from levels of 3-methoxytyramine (3-MT) and DA metabolism was inferred from levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). DA release was increased by the D2 antagonists haloperidol and metoclopramide but not by the D1 antagonists SCH 23390 and SKF 83566. DA metabolism was increased by each of the four antagonists but to a greater extent with the D2 antagonists. The D2 agonists CGS 15855A and LY 171555 decreased DA release whereas the D1 agonist SKF 38393, at relatively high doses, only slightly affected DA release. Each of the three agonists decreased DA metabolism but again metabolism was more affected by the D2-selective drugs. The in vivo release of DA from mesolimbic and neostriatal DA neurons appears to be modulated by D2 but not by D1 receptors, whereas both receptor types can modulate DA metabolism.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Picomolar affinity of 125I-SCH 23982 for D1 receptors in brain demonstrated with digital subtraction autoradiography.

Iodinated SCH 23390, 125I-SCH 23982 (DuPont-NEN), was examined using quantitative autoradiography for its potency, selectivity, and anatomical and neuronal localization of binding to the dopamine D1 receptor in rat brain sections. 125I-SCH 23982 bound to D1 sites in the basal ganglia with very high affinity (Kd values of 55-125 pM), specificity (70-85% of binding was displaced by 5 microM cis-flupenthixol), and in a saturable manner (Bmax values of 65-176 fmol/mg protein). Specific 125I-SCH 23982 binding was displaced by the selective D1 antagonists SCH 23390 (IC50 = 90 pM) and cis-flupenthixol (IC50 = 200 pM) and the D1 agonist SKF 38393 (IC50 = 110 nM) but not by D2-selective ligands (I-sulpiride, LY 171555) or the S2 antagonist cinanserin. Compared with 3H-SCH 23390, the 5- to 10-fold greater affinity for the D1 site and 50-fold greater specific radioactivity of 125I-SCH 23982 makes it an excellent radioligand for labeling the D1 receptor. The concentrations of D1 sites were greatest in the medial substantia nigra and exceeded by over 50% the concentration of D1 sites in the lateral substantia nigra, caudoputamen, nucleus accumbens, olfactory tubercle, and entopeduncular nucleus. Lower concentrations of D1 sites were present in the internal capsule, dorsomedial frontal cortex, claustrum, and layer 6 of the neocortex. D1 sites were absent in the ventral tegmental area. Intrastriatal injections of the axon-sparing neurotoxin, quinolinic acid, depleted by 87% and by 46-58% the concentrations of displaceable D1 sites in the ipsilateral caudoputamen and medial and central pars reticulata of the substantia nigra, respectively. No D1 sites were lost in the lateral substantia nigra. Destruction of up to 94% of the mesostriatal dopaminergic projection with 6-hydroxydopamine did not reduce D1 binding nor, with one exception, increase striatal or nigral D1 receptor concentrations. 125I-SCH 23982 selectively labels D1 binding sites on striatonigral neurons with picomolar affinity, and these neurons contain the majority of D1 sites in rat brain.

Animals↗
PubMed1987

Dopamine autoreceptors modulate the in vivo release of dopamine in the frontal, cingulate and entorhinal cortices.

The regulation by autoreceptors of dopamine release in the rat neocortex was inferred from measurements of 3-methoxytyramine after the peripheral injection of a selective (CGS 15855A) or nonselective (apomorphine) dopamine autoreceptor agonist. Basal levels of dopamine release were greatly decreased in the frontal cortex and caudate putamen after the injection of CGS 15855A or apomorphine. The pargyline-induced accumulations of 3-methoxytyramine in the frontal cortex, cingulate cortex and caudate putamen were attenuated by 52 to 82% after the injection of either agonist. 3-Methoxytyramine accumulations in the entorhinal cortex were attenuated by 68% by apomorphine. Thus, as in the caudate putamen, dopamine autoreceptors modulate the in vivo release of dopamine in the frontal cortex and the turnover of the releasable dopamine pool in the frontal, cingulate and entorhinal cortices.

Animals↗
PubMed1986

1-Methyl-4-phenylpyridine (MPP+): regional dopamine neuron uptake, toxicity, and novel rotational behavior following dopamine receptor proliferation.

The regional uptake and subsequent dopaminergic toxicity, receptor proliferation, and rotational behavior pharmacology following intracerebral 1-methyl-4-phenylpyridine (MPP+) administration was determined in the rat. [3H]MPP+ was transported by the high-affinity dopamine uptake system equally in the caudate-putamen (CP), nucleus accumbens (NA) and olfactory tubercle (OT), and to a lesser extent in the substantia nigra. Consistent with the equivalent uptake of [3H]MPP+ by mesostriatal and mesolimbic dopamine neurons, dopamine concentrations of the ipsilateral CP and NA were decreased equally (83-98%) following a 10, 17.5 or 25 microgram injection of MPP+ along the left medial forebrain bundle (MFB). At four weeks after a 25 microgram injection of MPP+ into the MFB, the concentration (Bmax) of D2 receptors in the left CP was increased by 42% compared with the intact hemisphere. D2 receptors did not proliferate in the denervated nucleus accumbens. The affinity (Kd) of D2 receptors was not affected in either the CP or NA. The MPP+ injection, which was restricted to the region of striatonigral efferent fibers, also produced a 60% decrease in the GABA content of the substantia nigra. Ipsiversive rotational behavior was induced in MPP+-treated rats by systemic injections of d-amphetamine. Systemic injections of neither the dopamine agonist apomorphine nor agonist prodrug formulation of 1-DOPA and carbidopa induced contraversive rotation. These behavioral and neurochemical results are identical to those observed following concomitant destruction of striatonigral GABA and mesostriatal dopamine projections, and indicate that MPP+ may be toxic to GABAergic as well as to A10 and A9 dopaminergic neurons.

1-Methyl-4-phenylpyridinium↗
PubMed1986

CGS 10746B: an atypical antipsychotic candidate that selectively decreases dopamine release at behaviorally effective doses.

CGS 10746B, a benzothiadiazepine, has a behavioral profile in mice and monkeys similar to the atypical antipsychotic clozapine. Unlike clozapine, CGS 10746B suppresses dopamine neuron firing rates and, when administered at behaviorally effective doses by the oral or intraperitoneal route, decreases neostriatal dopamine release without changing dopamine metabolism or occupying D2 receptors. CGS 10746B is the first atypical antipsychotic candidate that selectively decreases dopamine release.

Action Potentials↗