Biomedical subjects

W C Boyar

Publications and source records attributed to W C Boyar.

12 recordsLinked to original sources

PubMed1990

Discriminatory roles for D1 and D2 dopamine receptor subtypes in the in vivo control of neostriatal cyclic GMP.

The D1 and D2 subtypes of the dopamine receptor have been distinguished by their opposing effects on levels of neostriatal cyclic adenosine monophosphate (cAMP). The studies reported here show that the content of cyclic guanosine monophosphate (cGMP) in the mouse neostriatum is modulated by dopaminergic drugs in a manner which also discriminates D1 and D2 receptors. D1 receptor stimulation with SKF 38393 produced up to 90%, dose-related increases in neostriatal cGMP, whereas D1 antagonism with SCH 23390 decreased cGMP by 30% and blocked the increase induced by SKF 38393. D2 receptor stimulation with quinpirole did not alter cGMP levels whereas D2 antagonism increased cGMP by 40-60% after haloperidol and by up to 100% after sulpiride. The increases in neostriatal cGMP levels following D1 agonism were potentiated in an additive manner by haloperidol. Thus, neostriatal cGMP content is positively controlled by D1 agonism and negatively controlled by or unlinked to the D2 receptor. The reciprocal control of neostriatal cGMP levels by D1- and D2-selective compounds may contribute to the separate as well as combined actions of D1 and D2 ligands.

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

PubMed1989

Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin.

The sulfated octapeptide of cholecystokinin (CCK-8S) and CCK fragments were administered to mice to determine the subtype and central versus peripheral location of the CCK receptor that modulates dopamine release in the neostriatum. Dopamine release was decreased when unsulfated CCK (CCK-8U) or the butoxycarbonyl tetrapeptide of CCK (t-boc-CCK-4) was infused into the brain ventricles but not when injected subcutaneously. These CCK fragments bind to the brain-type (CCK-B) but not alimentary-type (CCK-A) receptor. Centrally or peripherally administered CCK-8S also lowered dopamine release and this action was not blocked by the selective CCK-A receptor antagonist, L 364,718. The increase in dopamine release following amphetamine administration was attenuated by central injections of t-boc-CCK-4, CCK-8U, or CCK-8S, and this action of CCK-8S was not prevented by L 364,718. These data are the first to demonstrate that CCK-B receptors in brain mediate the suppression of dopamine release by cholecystokinin, especially when release is augmented. CCK-B receptor agonists should be useful for the treatment of psychiatric conditions that result from hyperactive dopamine neurons.

Amphetamines↗

PubMed1989

Inhibition of nigrostriatal release of dopamine in the rat by adenosine receptor agonists: A1 receptor mediation.

The stable analogues of adenosine, N-ethylcarboxamidoadenosine (NECA), R-phenylisopropyladenosine (R-PIA) and cyclohexyladenosine (CHA), dose-dependently decreased levels of 3-methoxytyramine (3-MT) in the striatum and antagonized pargyline-dependent accumulation of 3-methoxytyramine. These agents were equipotent with ED25 values of approximately 1 mg/kg, (p.o.) in inhibiting pargyline-dependent accumulation of 3-methoxytyramine. Since CHA and R-PIA are relatively selective for A1 receptors and NECA is almost equipotent at A1 and A2 sites, the data of undifferentiated potency for these 3 agents on release of dopamine (levels of 3-MT) would argue in favor of mediation of A1 receptors in this phenomenon. This conclusion was further supported by experiments with the A1-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPDX), which antagonized the actions of CHA. Similar antagonism of CHA-dependent decreases in levels of cyclic GMP in the cerebellum, an action known to be mediated by A1 receptors, was also observed. These data support previous studies which indicated an adenosine receptor-mediated modulation of nigrostriatal release of dopamine. In addition, the present data indicate that this is an action on A1 receptors.

Adenosine↗

PubMed1988

Cholecystokinin attenuates basal and drug-induced increases of limbic and striatal dopamine release.

Subcutaneous administration to mice of the sulfated octapeptide of cholecystokinin (CCK; 0.2-1 mg/kg) lowered dopamine release and metabolism in the caudate-putamen and frontal cortex in a dose- and time-related manner. Twelve-fold higher doses of CCK were required to lower dopamine release and metabolism in the olfactory tubercle. Amphetamine-induced increases in dopamine release but not metabolism in the caudate-putamen and olfactory tubercle were attenuated in a dose-related manner by CCK. Increases in dopamine release and metabolism following haloperidol were also attenuated by CCK. These data are consistent with the potential antipsychotic action of CCK receptor agonists. CCK appears to be a suppressor of striatal, limbic and cortical dopamine release, especially when release is augmented.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Dopamine neurochemical profile of atypical antipsychotics resembles that of D-1 antagonists.

The release and metabolism of dopamine in the mouse caudate-putamen were determined after the oral administration of antipsychotic drugs at doses equal to or sixfold greater than the ED50 dose for their inhibition of apomorphine-induced climbing. Dopamine release was equated with concentrations of 3-methoxytyramine (3-MT) and metabolism was equated with concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Like the D-1 antagonists SCH 23390 and SKF 83566, most antipsychotic agents with an atypical preclinical profile suggestive of low extrapyramidal symptomatology (CGS 10746B, flumezapine, CL 77328, rimcazole, clozapine, RMI 81582, and fluperlapine) never increased dopamine release and produced variable increases in dopamine metabolism. Other atypical antipsychotics (thioridazine, mesoridazine, melperone) increased dopamine release at only one dose tested but increased dopamine metabolism at most doses. Antipsychotic agents associated with extrapyramidal side effects (setoperone, perlapine, haloperidol, chlorpromazine, and metoclopramide) increased dopamine release and metabolism at almost every dose tested. Thus, atypical antipsychotics increase the metabolism but not release of dopamine at behaviorally effective doses. The resemblance of these minimal effects on dopamine release to those obtained with D-1 antagonists that also have an atypical preclinical profile suggests that a mechanism related to D-1 receptor antagonism may contribute to the action of atypical antipsychotics.

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

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

Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist.

CGS 12066B is a novel pyrroloquinoxaline with selectivity for the serotonin-1B (5HT1B) recognition site as assessed by binding, biochemical and electrophysiological studies. The compound had an IC50 value of 51 nM at the 5HT1B recognition site as determined using the binding of [3H]5HT in the presence of 1 microM spiperone. At the 5HT1A receptor the compound had an IC50 value of 876 nM, providing a 5HT1A/5HT1B ratio of 17 in contrast to the putative 5HT1B selective agent trifluoromethylphenylpiperazine (TFMPP) which had a corresponding ratio of 3.6. The compound had minimal affinity for alpha 1-, alpha 2- and beta-adrenoceptors and for dopamine D-1 and D-2 receptors. CGS 12066B, in contrast to TFMPP, which was inactive, was found to inhibit dorsal raphe cell firing with an ED50 value of 358 nmol/kg i.v. The corresponding values for the 5HT1A selective agonists 8-OH-DPAT and ipsapirone were 1.3 and 33 nmol/kg. CGS 12066B was also effective in decreasing rat brain 5-HTP concentrations and inhibiting in vitro 5HT release. The data obtained indicate that CGS 12066B is a reasonably active 5HT1B site agonist, which due to its selectivity as compared to compounds such as TFMPP, will be a useful tool for evaluating the physiological role of such receptors in the mammalian CNS.

5-Hydroxytryptophan↗

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

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

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

125I-LSD autoradiography confirms the preferential localization of caudate-putamen S2 receptors to the caudal (peripallidal) region.

The in vitro binding of 125I-lysergic acid diethylamide (LSD) to horizontal sections of rat brain was quantified with computer-assisted autoradiography. Specific binding of 125I-LSD to D2 and S2 sites, defined with 5 microM (+)-butaclamol, was 65-94% of the total binding. Identification of S2 sites with 50 nM ketanserin showed that over 90% of the butaclamol-displaced 125I-LSD binding in the frontal, cingulate and parietal neocortex was to S2 sites (22-55 fmol/mg protein). 125I-LSD also labeled a dense population of S2 sites (16 fmol/mg protein) in the caudal caudate-putamen at the level of the globus pallidus which exceeded by 5-fold the concentration of S2 sites (3 fmol/mg protein) in more rostral portions of the caudate-putamen. The peripallidal distribution of S2 sites was identical to that observed previously with the less selective S2 label, [3H]spiperone. The dense concentration of S2 sites in the caudal caudate-putamen and their overlap with D2 binding sites indicates that the peripallidal neostriatum may play an important role in interactions between dopamine and serotonin.

Animals↗