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R B Mailman

Publications and source records attributed to R B Mailman.

At least 55 records · Page 3Linked to original sources
PubMed1994

Heterotypic sprouting of serotonergic forebrain fibers in the brindled mottled mutant mouse.

The brindled mottled mouse has a mutation on the X-chromosome which causes alterations in copper metabolism. One role for copper is as a cofactor for dopamine-beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine (NE). This may explain the fact that the hemizygous males have low concentrations of NE, as well as high concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the brainstem and forebrain. The present study quantified serotonin (5-HT) immunoreactive fibers in the cerebral cortex and striatum of hemizygous males and control littermates on postnatal (P) days 7, 10, 12 and 14. The density of 5-HT immunoreactive fibers was measured using a digitized imaging system in conjunction with darkfield microscopy. Measurements of 5-HT innervation showed an age-dependent increase in density of 5-HT immunoreactive fibers in all layers of the cerebral cortex, with fiber density in brindled mice approximately 70% greater than controls by P14. High performance liquid chromatography confirmed the increased concentrations of 5-HT and 5-HIAA, and the low concentration of NE, in several regions. We believe that these results are an example of heterotypic sprouting of 5-HT neurons, similar to that observed in neonatal rats given 6-hydroxydopamine (6-OHDA). If so, these data provide the first description of 5-HT heterotypic sprouting in mice, and the first description of 5-HT heterotypic sprouting resulting from a natural disease state, rather than an experimentally induced lesion.

Animals↗
PubMed1994

Social reactivity and D1 dopamine receptors: studies in mice selectively bred for high and low levels of aggression.

Robust individual differences in social behavior have been obtained by selectively breeding Institute for Cancer Research mice for high and low levels of aggression. As previously shown, when paired with a non-selected group-housed partner mouse, NC900 mice exhibit isolation-induced aggression. Conversely, NC100 mice fail to attack, freezing upon social contact. Previous studies have established that NC100 mice have lower dopamine concentrations in nucleus accumbens and caudate nucleus, with increased dopamine receptor densities in these same regions. Thus, we wished to determine the effect of administration of a dopamine receptor agonist on social behavior. Mice of both lines were administered 0, 1, 3, or 10 mg/kg (SC) of the full efficacy D1 receptor agonist dihydrexidine, and their behavior was assessed in a social interaction test. Dihydrexidine reduced aggression in NC900 mice and nonagonistic approach in NC100 mice in a dose dependent manner. In both cases, this resulted from induction of a marked reactivity to mild social stimulation as measured by increases in behaviors such as escape, reflexive kicking, and vocalizations. Dihydrexidine had no systematic effect on the freezing behavior characteristic of the low-aggressive line. In independent experiments, mice were pretreated with either the D1 antagonist SCH-23390 (.1 mg/kg) or the selective D2 antagonist remoxipride (1.0 mg/kg), after which they received dihydrexidine (10 mg/kg) and were tested as above. The effects of dihydrexidine on social reactivity in mice of both lines were significantly antagonized by SCH-23390 but not attenuated by remoxipride.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1993

Dopamine D1 receptors: efficacy of full (dihydrexidine) vs. partial (SKF38393) agonists in primates vs. rodents.

Although partial efficacy dopamine D1 receptor agonists have little therapeutic benefit in parkinsonism, the first high potency, full efficacy dopamine D1 receptor agonist dihydrexidine recently has been shown to have profound antiparkinsonian effects. One reason for the greater antiparkinsonian effects of dihydrexidine vs. SKF38393 might be that SKF38393, while a partial dopamine D1 receptor agonist in rodent striatal preparations, has virtually no agonist activity in monkey striatum (Pifl et al., 1991, Eur. J. Pharmacol. 202, 273). To explore this hypothesis, we compared the dopamine D1 receptor affinity and efficacy of dihydrexidine and SKF38393 in striatum from rat and monkey. In vitro binding studies using membranes from putamen of adult rhesus monkeys demonstrated that dihydrexidine competed for dopamine D1 receptors (labeled with [3H]SCH23390) with high potency (IC50 = 20 nM vs. ca. 10 nM in rat brain). SKF38393 was about 4-fold less potent than dihydrexidine in both monkey and rat brain. The in vitro functional activity of these drugs was assessed by their ability to stimulate adenylate cyclase activity in tissue homogenates. Dihydrexidine was of full efficacy (relative to dopamine) in stimulating cAMP synthesis in both monkey and rat. SKF38393 was only a partial efficacy agonist in both rat striatum and monkey putamen, but contrary to the original hypothesis, it had the same efficacy (ca. 40% relative to dihydrexidine) in membranes from both species. Interestingly, greater between-subject variation was found in the stimulation produced by SKF38393 in primate compared to rat brain, although the basis for this variation is unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity.

Certain novel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 microM concentrations in rodent brain tissue. This effect on TH was blocked by the putative sigma-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory sigma-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (+/-)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene ([3H](+/-)-4). trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known sigma or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known sigma or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(-)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates sigma-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.

Animals↗
PubMed1993

Hexahydrobenzo[a]phenanthridines: novel dopamine D3 receptor ligands.

We report that certain substituted hexahydrobenzo[a]phenanthridines are novel high affinity ligands selective for the dopamine D3 receptor. These data demonstrate that substitutions on the heterocyclic nitrogen and the pendant phenyl ring of this nucleus cause a marked increase in both affinity and selectivity for dopamine D3 vs. D2 receptors. Thus, these compounds represent important new tools to study the pharmacology of dopamine D3 receptors, and may also provide an opportunity for the synthesis of new radioligands for dopamine D3 receptors.

Animals↗
PubMed1993

A rapid and efficient method for the radiosynthesis and purification of [125I]SCH23982.

The radiosynthesis of (1R)-(+)-1-phenyl-3-methyl-7-[125I]iodo-8-hydroxy- 2,3,4,5-tetrahydro-1H-3-benzazepine (commonly referred to as SCH23982) and its use as a high affinity D1 dopamine antagonist ligand have been reported previously. We now provide a simple and inexpensive protocol for the rapid and efficient synthesis of this radioligand based on the Cloramine-T-catalyzed reaction between the commercially available precursor (R)-(+)-1-phenyl-3-methyl- 8-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine and carrier-free sodium [125I]iodide. [125I]SCH23982 is separated rapidly (within 20 min) from the precursor and reaction byproducts (e.g., chlorinated precursor, SCH23390) by reverse-phase HPLC on a C-8 column. The major iodinated product has been identified as SCH23982 based on co-chromatography with authentic SCH23982, UV spectral characteristics, and biological activity. The chromatographic effluent containing the active product is adsorbed on a C-18 Sep-Pak cartridge to remove mobile-phase constituents and permit it to be eluted and diluted to the desired concentration; this technique is used also for periodic repurification. Our synthesis protocol results in final purified product that incorporates ca. 50% of the initial 125I (tested using starting quantities of 1-10 mCi Na125I); the final product has a specific activity of ca. 2500 +/- 350 Ci/mmol. Data from in vitro receptor autoradiographic and homogenate studies with this radioligand are consistent with previously reported values in terms of expected receptor distribution, affinity, and density (KD of 1.0 nM, Bmax of 1400 fmol/mg protein in rat striatal membranes).

Animals↗
PubMed1993

Postmortem stability of dopamine D1 receptor mRNA and D1 receptors.

The effects of postmortem interval on dopamine D1 mRNA and D1 receptors were assessed in rat striatum under conditions simulating the handling of human brain tissue at 0, 6, 12, and 24 h postmortem. The amount of D1 mRNA was measured by both in situ hybridization film and emulsion autoradiography with [35S]dATP-labeled oligonucleotide probes. D1 receptor density was determined by autoradiography with [125I]SCH 23982. Neither the total amount of D1 mRNA in the striatum nor the frequency distribution of striatal cells expressing D1 mRNA varied with the postmortem interval. There was a modest but significant decrease (ca. 10%) in D1 receptors over the 24 h postmortem interval; this decrease occurred within the first 6 h postmortem, with no further decreases up to 24 h postmortem. These findings suggest that the effects of postmortem interval on D1 mRNA and receptors are minimal and should not limit an examination of possible alterations in dopamine D1 receptor mRNA and D1 receptors in the postmortem brains of humans with neuropsychiatric disease.

Animals↗
PubMed1993

New sigma-like receptor recognized by novel phenylaminotetralins: ligand binding and functional studies.

Several novel phenylaminotetralins (PATs) cause functional changes in brain that are associated with binding to saturable, high affinity sites that are not identical to any known central nervous system receptor. These PATs were tested for their ability to cause receptor-mediated functional effects on tyrosine hydroxylase activity in corpus striatum from rat and guinea pig brain. (+/-)-(trans)-1-Phenyl-3-dimethylamino-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene (CI, OH-PAT) increased tyrosine hydroxylase activity (by approximately 30-40%) at 0.1 microM. Higher concentrations inhibited enzyme activity by indirect mechanisms that may include displacement of intraneuronal dopamine. The 6,7-unsubstituted congener (+/-)-(trans)-1-phenyl-3-dimethylamino-1,2,3,4- tetrahydronaphthalene stimulated tyrosine hydroxylase by as much as 50-60% over basal activity, without displacement of dopamine. Similarly to certain (+)-benzomorphan sigma receptor ligands, the effects of both PATs to activate tyrosine hydroxylase were blocked competitively by the putative sigma antagonist BMY-14802. Radiolabeled [3H]CI,OH-PAT bound saturably and with high affinity to guinea pig brain membranes (Kd = 31 pm, Bmax = 6.5 fmol/mg of protein). The pharmacological profile of these binding sites was inconsistent with those of known sigma 1, sigma 2, dopaminergic, serotonergic, adrenergic, opioid, N-methyl-D-aspartate, or several other characterized central nervous system recognition sites. Together, these data suggest that these PATs may be agonists at a novel sigma-like site that has neuromodulatory activity that results in increases of brain catecholamine synthesis via activation of tyrosine hydroxylase.

Animals↗
PubMed1992

Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist.

The present work provides a detailed pharmacological characterization of dihydrexidine (DHX) (trans-10,11-dihydroxy- 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine), the first high-potency, full efficacy, bioavailable D1 dopamine receptor agonist. DHX represents a new conformationally rigid structural class of dopamine receptor ligands. It competes stereoselectively and potently for D1 binding sites in rat striatal membranes labeled with [3H]SCH23390 with an IC50 of about 10 nM compared to about 30 nM for the prototypical D1 agonist SKF38393. Like other dopamine agonists, DHX has a shallow competition curve (nH = ca. 0.7) that can be fitted by a two-site model consisting of high-affinity (63%; KD = 3 nM) and low-affinity (37%; KD = 75 nM) sites. DHX was screened for activity against 40 other binding sites, and was inactive (IC50 greater than 10 microM) against all except D2 dopamine receptors (IC50 = 130 nM) and alpha 2 adrenoreceptors (IC50 = ca. 230 nM). Functionally, DHX is a full efficacy dopamine D1 agonist. In homogenates of rat striatum, DHX or dopamine doubles the rate of cyclic AMP synthesis, whereas SKF38393 only causes a maximal increase of about 50%. These effects of DHX are blocked by the selective D1 antagonist SCH23390, but are not affected by D2, 5-hydroxytryptamine2, muscarinic, or alpha or beta adrenergic antagonists. Because DHX is known to cause D2-like behavioral effects at high doses, the nature of its D2 activity was characterized using prolactin release as an end-point. DHX and the prototypical D2 agonist quinpirole both caused a significant inhibition of the prolactin release induced by 5-hydroxytryptophan. These effects of DHX are not due to "indirect" alterations at the presynaptic terminal, because DHX is essentially inactive at inhibiting the dopamine uptake system, and does not cause the release of dopamine. These data demonstrate the utility of DHX for probing the biochemistry and function of D1 dopamine receptors.

Adenylyl Cyclases↗
PubMed1991

Dopamine receptor 'supersensitivity' occurring without receptor up-regulation.

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the substantia nigra have been widely used to study various aspects of dopamine neurobiology, and to screen for antiparkinsonian drugs. This study examined the role of receptor alterations in the pharmacological supersensitivity seen in response to lesioning of central dopamine pathways in rats by intracisternal (IC) administration of 6-OHDA (200 micrograms), as well as by bilateral (BIL) or unilateral (UNI) infusion of 6-OHDA into the substantia nigra (8 micrograms/side). Both IC and BIL lesions resulted in permanent decreases in dopamine concentration in the striatum, the major terminal projection from the substantia nigra. When challenged with apomorphine (0.3 mg/kg), IC-lesioned rats exhibited bursts of rapid locomotion interspersed by rearing, whereas BIL-lesioned rats displayed intense grooming or gnawing and nose poking of the cage floor; these behaviors were not seen in respective sham (i.e. vehicle)-lesioned rats injected with apomorphine. Scatchard analysis of saturation isotherms of both D1 [( 3H]SCH23390 binding sites) and D2 [( 3H]spiperone binding sites) dopamine receptors in the striatum revealed no difference in either the maximum number of binding sites (Bmax), or the dissociation constant (Kd) of either receptor type when BIL and IC lesioned rats were compared to appropriate controls. Conversely, the UNI lesioned rats had, under identical conditions of analysis, the expected increase in the density of D2 receptors on the lesioned side. There was no change in dopamine-sensitive adenylate cyclase activity in the striata of supersensitive IC-lesioned rats, but there was a shift to the left in the dose-response curve in striata from rats bilaterally-lesioned in the substantia nigra, similar to what occurs in UNI lesioned rats. Together, these data clearly demonstrate that although increases in receptor density and changes in cAMP systems are seen in the UNI model, neither mechanism is a requirement for functional supersensitivity in response to 6-OHDA lesions. These data suggest that other cellular events (e.g. alterations in receptor interactions) may play a role in the response to insult, and raise questions about the utility of the unilateral model as a screen for antiparkinsonian drugs.

Adenylyl Cyclases↗
PubMed1991

Guanine nucleotide binding proteins and the regulation of cyclic AMP synthesis in NS20Y neuroblastoma cells: role of D1 dopamine and muscarinic receptors.

D1 dopamine receptors on NS20Y neuroblastoma cells stimulate adenylate cyclase activity, whereas muscarinic receptors on the same cells negatively regulate adenylate cyclase. To determine the mechanisms which underlie these processes, cyclic AMP accumulation was measured in intact cells following either cholera or pertussis toxin treatment. Pretreatment with pertussis toxin (100 ng/ml), which ribosylated greater than 95% of inhibitory quinine nucleotide binding protein (Gi), caused the complete loss of muscarinic induced inhibition. Conversely, pertussis toxin did not affect the ability of dihydrexidine (1 microM, a full efficacy D1 agonist), PGE1 (100 nM), or forskolin (1 microM, a direct activator) to stimulate cAMP accumulation. Both the dihydrexidine-induced stimulation and the carbachol-induced inhibition of cyclic AMP accumulation were unaffected by either removal of extracellular calcium, or increased intracellular calcium caused by the addition of the calcium ionophore A23187. Cholera toxin dose- and time-dependently induced large accumulations of cAMP. At low cholera toxin concentrations, the effects of dihydrexidine (300 nM) were additive with those of cholera toxin. At cholera toxin concentrations greater than 100 ng/ml, dihydrexidine became ineffective in stimulating further cAMP synthesis. Conversely, forskolin (1 microM) still caused marked increases in cAMP accumulation after all cholera toxin treatments. Dihydrexidine-stimulated cAMP accumulation was additive with forskolin-stimulated cAMP accumulation at low forskolin concentrations (10 nM-3 microM), but synergistic at high concentrations (3-100 microM). Additionally, forskolin was much more potent after cholera toxin treatment, suggesting that an activated stimulatory guanine nucleotide binding protein (Gs) may be required for full activation of adenylate cyclase by forskolin in this cell type.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylate Cyclase Toxin↗
PubMed1991

Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D2 receptors.

A number of 2,3-dimethoxy-5-(fluoroalkyl)-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamides (with or without a 6-hydroxy group) were synthesized and evaluated as dopamine D2 receptor ligands. The parent acids were synthesized via the Claisen rearrangement of the appropriate O-allyl ethers, which were derived from o-vanillic acid or 2,3-dimethoxysalicylic acid. A decrease in reactivity was found to be characteristic of pentasubstituted benzoates, and difficulties were encountered with the introduction of fluorine onto the ethyl side chains. The (fluoroethyl)- and (fluoropropyl)salicylamides were 5 times more potent than the corresponding benzamides in inhibiting [3H]spiperone binding to the D2 receptor. These (fluoroalkyl)salicylamides are of potential value for in vivo positron emission tomography (PET) studies upon the basis of their relatively selective, high potency binding affinity for the D2 receptor.

Animals↗
PubMed1991

Neurochemical and immunocytochemical studies of catecholamine system in the brindled mouse.

The distribution of immunoreactive catecholamine neurons and fibers was investigated in brindled mottled mouse, a murine model of Kinky hair syndrome (KHS), using antisera against tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH). In all mice, including normal littermate controls, a transient increase of TH-immunoreactive neurons (TH-IN) was observed in the cerebral cortex during the second postnatal week. The numbers of TH-IN were more pronounced in hemizygous brindled males (MObr/y). In addition, TH-IN appeared and rapidly increased in number in the striatum of MObr/y after postnatal day 11 (P11). Striatal TH-IN were rarely detected in controls. After cupric chloride (CuCl2) treatment, TH-IN in the striatum of some of the MObr/y mice became less conspicuous. In the substantia nigra and ventral tegmental area where TH-IN are normally present, no differences either in the immunostaining of TH-IN or the pattern of TH immunoreactive fibers were detected between MObr/y and controls. In MObr/y, a superficial plexus of DBH immunoreactive fibers was more pronounced than in controls but there were no DBH immunoreactive neurons in the cerebral cortex or striatum in any of the mice examined. Neurochemical analysis revealed a marked decrease in norepinephrine levels and increase of serotonin and its metabolites in the brain in MObr/y. Together, these data suggest that the unusual expression of TH-IN in MObr/y represents perturbations of normal development of catecholamine neurons in this copper deficient mutant mouse.

Animals↗
PubMed1991

D1 dopamine receptors of NS20Y neuroblastoma cells are functionally similar to rat striatal D1 receptors.

Dopamine or agonists with D1 receptor potency stimulated cyclic AMP (cAMP) accumulation in whole cell preparations of NS20Y neuroblastoma cells. The accumulation of cAMP after D1 stimulation was rapid and linear for 3 min. Both dopamine and the novel D1 receptor agonist dihydrexidine stimulated cAMP accumulation two- to three-fold over baseline. The pseudo-Km for dopamine was approximately 2 microM, whereas for dihydrexidine it was approximately 30 nM. The effects of both drugs were blocked by either the D1-selective antagonist SCH23390 (Ki, 0.3 nM) or the nonselective antagonist (+)-butaclamol (Ki, 5 nM). Both (-)-butaclamol and the D2-selective antagonist (-)-sulpiride were ineffective (Ki greater than 3 microM). Forskolin (10 microM), prostaglandin E1 (1 microM), and adenosine (10 microM) also stimulated cAMP accumulation, but none were antagonized by SCH23390 (1 microM). Finally, muscarinic receptor stimulation (100 microM carbachol) inhibited both D1- and forskolin-stimulated increases in cAMP accumulation by 80%. The present results indicate that NS20Y neuroblastoma cells have D1 receptors that are coupled to adenylate cyclase, and that these receptors have a pharmacological profile similar to that of the D1 receptor(s) found in rat striatum.

Benzazepines↗
PubMed1991

The female brindled mouse as a model of Menkes' disease: the relationship of fur pattern to behavioral and neurochemical abnormalities.

The brindled mottled mutant mouse, a model of Menkes' disease, has alterations in copper homeostasis which cause, among other sequelae, neuronal degeneration in selected areas of brain. This work examined the neurochemical changes at postnatal days (PND) 15, 30 and 60 in females heterozygous for the sex-linked brindled mutation. These data were compared to behavioral alterations and to fur coat color at these same time points. The brindled heterozygotic females had lower concentrations of norepinephrine (NE) in the cingulate cortex, and higher levels of dopamine or dopamine metabolites in the cingulate cortex, thalamus and hypothalamus across all ages, although the difference was greatest at PND 15. The brindled females were much less active than their normal littermates at PND 15, but the differences were no longer evident at PND 30 and 60. Mottling of the fur is believed to result from low tyrosinase activity caused by abnormalities in copper metabolism. The fur pattern and behavior of the brindled mice were highly correlated with NE levels in the cingulate cortex and thalamus. These data show that female brindled mice have neurochemical abnormalities similar to (if less severe than) the male hemizygotes, that these abnormalities are regionally specific, are most apparent prior to 30 days of age, and are linked to behavioral deficits. These data also show that the extent of such deficits can be predicted by a quantitative analysis of the fur pattern of these females.

Age Factors↗
PubMed1991

D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey.

Previous studies have revealed the involvement of a dopaminergic link in the regulation of spontaneous eye blink rate in primates. Based on the effect of dopamine D2 receptor-selective drugs and the anecdotal failure of the partial D1 agonist, SKF 38393, to alter blink rate in monkeys, it was assumed that D1 dopamine receptors did not control blink rate. The recent availability of dihydrexidine, a full D1 agonist, prompted us to reevaluate the role of D1 and D2 receptors in the regulation of blink rate. African green monkeys (n = 5) were used in all studies. Dihydrexidine produced a rapid and dose-dependent (up to 1 mg/kg, i.m.) increase in blink rate. The elevation in blink rate elicited by 0.3 mg/kg dihydrexidine was completely reversed by prior administration of a specific D1 antagonist, SCH 23390 (0.01 mg/kg, i.m.), but was unaffected by prior administration of a specific D2 antagonist, remoxipride (1 mg/kg, i.m.). Treatment with the specific D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine, led to a rapid and dose-dependent (up to 0.01 mg/kg, i.m.) increase in blink rate. The raised blink rate produced by (+)-4-propyl-9-hydroxynaphthoxazine (0.001 mg/kg) was abolished by pretreatment with remoxipride, but was not influenced by pretreatment with SCH 23390. These data indicate that spontaneous blink rate in the primate can be regulated by both D1 and D2 dopamine receptors. Furthermore, the receptor subtypes appear to affect blink rate in the same direction, yet function independently. Measurement of blink rate may provide a noninvasive method to assess the potency and selectivity of dopamine agonists and antagonists in primates.

Animals↗
PubMed1991

Behavioral effects in the rat of dihydrexidine, a high-potency, full-efficacy D1 dopamine receptor agonist.

Dihydrexidine (trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phena nthridine) was reported recently to be the first full efficacy, potent D1 receptor agonist, but one also having some potency for D2 receptors. This study reports the effects of dihydrexidine on behavior of the rat. In study 1, the dose-response relationships of dihydrexidine (0.3 to 30 mg/kg) to various behaviors were assessed using direct observations. The frequency of three behaviors (grooming, sniffing, and locomotion) was significantly increased by this drug. The dose-response curve for drug-induced grooming approximated an inverted U shape. Dihydrexidine increased locomotion at two of the higher doses (3 and 30 mg/kg), and increased sniffing at doses greater than or equal to 1.0 mg/kg. Other behavioral topographies, such as licking, gnawing, and rearing, were not systematically affected by drug administration. Also, there was no indication of convulsion in any dihydrexidine-treated rat. In study 2, rats were pretreated with either the selective D1 antagonist SCH23390 or the selective D2 antagonist remoxipride prior to receiving dihydrexidine. SCH23390 antagonized the effects of dihydrexidine on grooming, locomotion, and sniffing. Conversely, remoxipride blocked dihydrexidine-induced locomotion, but had no effect on dihydrexidine-induced grooming or sniffing. Numerous behaviors are believed to be mediated by the interactions of D1 and D2 receptors. These data indicate that dihydrexidine can be an important tool for characterizing both the behavioral actions of D1 receptors, and the nature of D1/D2 interactions in mammalian brain. In addition, its high potency and full efficacy at D1 receptors, coupled with its significant D2 properties, may provide specific utility in certain clinical situations.

Animals↗