Behavioral effects of RO 41-9067: A novel D2 dopamine receptor agonist

The behavioral effects of a novel putative D2 dopamine (DA) receptor agonist, RO 41-9067 (RO), were investigated in the mouse and compared with those of the classic D2 agonist LY 171555 (LY) at equimolar doses. Both RO and LY dose-dependently increased defensive behavior in naive mice interacting with nonaggressive conspecifics at doses higher than 0.2 and 0.16 mg/kg, respectively. Moreover, low and intermediate doses of RO and LY decreased locomotor activity in mice tested individually in an automated apparatus. Finally, coadministration of the D1 selective agonist SKF 38393 and high doses of RO or LY induced the hyperactive response classically induced by high doses of the mixed D1/D2 agonist apomorphine in the mouse while the inhibitory effects of the lowest doses of RO or LY were not affected by coadministration with SKF. These results indicate that RO induces behavioral effects characteristic of a D2 selective agonist when tested in intact mice and suggest that at high doses this compound activates postsynaptic D2 receptors which also cooperate with D1 receptors in the stimulation of DA-induced behaviors, while at low doses it selectively activates DA autoreceptors or inhibitory DA receptors of the D2 type. © 1992 Wiley-Liss, Inc.     

On the selectivity and specificity of the antagonism of apomorphine-induced suppression of exploration by sulpiride

Ten behavioural variables were recorded by means of an automatic holeboard apparatus. The behaviour of rats placed for the first time in the apparatus was recorded for 10 min. The suppression of this exploratory behaviour by the dopamine agonist apomorphine (0.01–0.1 mg/kg) was shown to bereversible in a surmountable fashion by the dopamine antagonist sulpiride (2 and 4 mg/kg). Suppression of exploration induced by clonidine (0.05 0.2 mg/kg) or diazepam (2 mg/kg) was not antagonised by sulpiride (10 and 50 mg/kg, respectively). The partial dopamine D1-agonist SKF 38393 (2–20 mg/kg) also suppressed exploration but neither sulpiride (20 mg/kg) nor the D1-antagonist SCH 23390 (0.02 mg/kg) could antagonise this effect. The data show that dopamine agonist induced suppression of exploration display pharmacological characteristics of a receptor-mediated response and the data support our previous suggestion that these receptors may be pharmacologically distinct from other dopamine D2-receptors.     

Microiontophoretic studies of the effects of D-1 and D-2 receptor agonists on type I caudate nucleus neurons: lack of synergistic interaction.

Several lines of evidence have suggested there may be a physiologically relevant form of synergistic interaction between D-1 and D-2 dopamine (DA) receptors located on postsynaptic neurons in the forebrain that receive a dopaminergic innervation. Because of the theoretical importance of such an interaction with respect to understanding the normal physiology of dopaminergic systems, we evaluated effects of D-1 and D-2 selective agonists, applied microiontophoretically, on the spontaneous electrical activity of a single, identifiable subpopulation of neurons within the caudate nucleus, the type I striatal neuron, in locally anesthetized, gallamine-paralyzed rats. It was observed that the D-2 receptor agonist quinpirole (QUIN) produced biphasic effects on cell firing rate. Low ejection currents significantly increased firing rate, while higher currents produced an inhibition. Similar effects were observed for the D-1 agonists SKF 38393; however, the overall excitations observed at low ejection currents were far less than those observed for QUIN. When these two agonists were applied concurrently, a simple additive effect (but not synergism) was always observed. The acute reduction of striatal levels of DA, by as much as 84% (with pretreatment with alpha-methyl-p-tyrosine, AMPT), did not alter the responsiveness of type I striatal neurons to the DA receptor agonists applied alone or in combination. These observed effects were not altered either by chloral hydrate anesthesia (in which glutamate-driven activity was studied) or by a more severe depletion of striatal DA levels (98% depletion produced by combined pretreatment with AMPT and reserpine).     

Development of selective dopamine receptor agonists as novel cardiovascular drugs

Benzazepine and ergoline derivatives represent two chemical classes from which orally effective dopamine receptor agonists have been developed. The benzazepines SK&F 38393 and SK&F 82526 increase renal and mesenteric blood flow as a consequence of regional vasodilation mediated by vascular (DA₁) dopamine receptor stimulation. Renal vasodilation produced by acute administration of SK&F 38393 and SK&F 82526 is associated with variable diuresis and natriuresis, and minimal change in arterial blood pressure and cardiac rate. Pergolide and LY141865 are chemically related to ergoline and inhibit neurogenic release of norepinephrine by stimulating neuronal (DA₂) dopamine receptors. As a result of this action, pergolide and LY141865 produce generalized cardiovascular alterations that are characterized by reduced systemic vascular resistance, arterial blood pressure, and cardic rate. SK&F 38393 and pergolide lack beta receptor agonist activity, although each produces alpha receptor mediated vasoconstriction at or slightly above doses activating dopamine receptors. SK&F 82526, LY141865, and LY171555 (the levo enantiomer of LY141865) are more selective DA₁ and DA₂ dopamine receptor agonists, respectively, since each is devoid of adrenergic effects over an extended dose range. Potential clinical utilities of DA₁ dopamine receptor agonists include the treatment of renal insufficiency and arterial hypertension. DA₂ dopamine receptor agonists may also be useful in treating arterial hypertension, as well as cardiac conditions where facilitation of stroke volume and reduction of myocardial work would be desirable.     

Electromyographical differentiation of the components of perioral movements induced by SKF 38393 and physostigmine in the rat

Facial electromyography (EMG) coupled with visual observation was used to investigate spontaneous and drug induced perioral movements in freely moving rats. Four separate perioral behaviours were identified; facial tremor, purposeless chewing, gaping and yawning. Facial tremor, yawning and gaping but not purposeless chewing produced characteristic EMG signals. Normal rats displayed a low level of purposeless chewing, occasional bursts of facial tremor but not gaping or yawning. Each burst of facial tremor was accompanied by a transient increase in purposeless chewing. Administration of the D₁ agonist SKF 38393 induced a dose related increase in bursts of facial tremors and consequently an increase in the total number of purposeless chews. Gaping and yawning were not induced by SKF 38393 administration. Administration of the cholinesterase inhibitor physostigmine (0.1–0.4 mg/kg) induced a dose related increase in the total number of purposeless chews, but primarily these were not associated with facial tremor. Administration of physostigmine also increased gaping and yawning. Administration of the D₁ antagonist SCH 23390 almost abolished facial tremor in normal treated rats but only partially reduced that induced by SKF 38393 and physostigmine. SCH 23390 reduced purposeless chewing in SKF 38393 treated rats but not in normal or physostigmine treated animals. Administration of the cholinergic antagonist atropine almost abolished facial tremor in normal and physostigmine treated rats, but only reduced by 46% that induced by SKF 38393. Atropine reduced purposeless chewing in normal, physostigmine and SKF 38393 treated animals. Physostigmine induced gaping and yawning were abolished by atropine administration. Combined administration of SKF 38393 and physostigmine did not alter the total number of facial tremor bursts and purposeless chews compared to those observed in rats treated with physostigmine alone. Administration of SKF 38393 with physostigmine reduced physostigmine-induced yawning. The EMG technique described allows assessment of the different profiles of perioral movement induced by SKF 38393 and physostigmine, and the relationship that exists between the different components. The results suggest that it is necessary to individually assess each individual perioral behaviour. Assessment of only one component in isolation, or of an amalgamation of several behaviours will add to the confusion that exists over the origins of perioral movement.     

Individual differences in behavior following amphetamine,GBR-12909, or apomorphine but not SKF-38393 or quinpirole

Subjects that respond more to a novel environment show a greater locomotor response to drugs of abuse such as cocaine and amphetamine. The current study was performed to examine differences between high (HR) and low (LR) responding rats to a novel environment following administration of amphetamine, a selective dopamine uptake blocker (GBR-12909), a nonselective dopamine agonist (apomorphine), and selective dopamine D₁ and D₂/D₃ agonists. A behavioral checklist and a rating scale were used to determine the behavioral arousal caused by administration of amphetamine (0, 0.5, 2.0, and 8.0 mg/kg), GBR-12909 (0, 1.25, 5.0, and 20.0 mg/kg), apomorphine (0, 0.1, 0.3, and 1 mg/kg), SKF 38393 (0, 2.5, 10, and 40 mg/kg), or quinpirole (0, 0.05, 0.5, and 5.0 mg/kg). The five drugs produced behavioral activation profiles distinct from each other. Following amphetamine administration, both HR and LR subjects showed dose dependent increases in behavioral arousal. The behaviors primarily affected were sniffing, locomotor activity, rearing, and oral activity. HR rats showed a greater overall behavioral response to amphetamine administration compared with LR rats and there were differences in specific behaviors between the two groups. Following GBR-12909 administration, all subjects showed dose dependent increases in sniffing, locomotor activity, and rearing. Differences between HR and LR were observed in sniffing, locomotor activity, and rearing behaviors. HR and LR both showed dose dependent increases in behavior following apomorphine administration. HR showed greater behavioral activation after apomorphine than LR. SKF 38393 produced pronounced increases in the amount of sniffing, grooming, and intense grooming, in addition to increasing the overall behavioral rating of all subjects, while quinpirole produced increases in sniffing, locomotor activity, and oral movements. However, the behavioral effects of SKF 38393 and quinpirole did not differ between HR and LR. These results suggest that activation of the dopamine system but probably not only one type of dopamine receptor is sufficient to produce behavioral differences between high and low responding subjects.     

Imipramine demethylation and norepinephrine storage in brain

Imipramine administered i.p. in rats following intraventricular administration of DL-NE-7³H decreases the amount of unchanged NE in the brain and leads to a significant increase of normetanephrine, methylated acid and methylated glycol. The results are the same if demethylation of imipramine is inhibited by pretreatment with SKF 525-A. According to current findings, imipramine itself has an effect on the storage capacity of brain tissue for NE.     

Stereospecific blockade of N-methyl-d-aspartate transmission by MK 801 prevents priming of SKF 38393-induced turning

In rats unilaterally lesioned with 6-hydroxydopamine, the D-1 agonist SKF 38393 (3 mg/kg SC) induced contralateral turning only after priming with a dopaminergic agonist such as apomorphine. Administration of the N-methyl-d-aspartate receptor antagonist (+) MK 801 (0.1 mg/kg IP) 15 min before apomorphine (0.1 mg/kg SC) prevented the ability of apomorphine to act as a primer while potentiating its acute contralateral turning effects. The inactive isomer (–) MK 801 was without effect. The results indicate that the N-methyl-d-aspartate receptor exerts a permissive role on priming.     

Observational studies of dopamine D1 and D2 agonists in squirrel monkeys

The behavioral effects of selective D₁ and D₂, nonselective, and indirectly acting dopamine agonists were compared in squirrel monkeys using continuous observation procedures. D₁ agonists including SKF 81297, SKF 82958, andR(+)-6-Br-APB produced dose-dependent increases in the frequencies of stationary postures and head movements and had little or no effect on either huddling or scratching. In contrast, SKF 75670 andR-SKF 38393, which are considered to be D₁ partial agonists, had effects comparable to those of the D₁ antagonist SCH 39166. That is, the D₁ partial agonists increased the duration of huddling without greatly altering the frequencies of stationary postures, head movements, or scratching. Unlike the D₁ agonists, the D₂ agonists (+)-PHNO, quinpirole, and bromocriptine increased the frequency of scratching, but did not consistently alter other observable behaviors. The indirect dopamine agonists cocaine, GBR 12909, andd-amphetamine and the nonselective D₁/D₂ agonist CY 208–243, but not (–)apomorphine, had effects comparable to those of D₁ agonists such as SKF 81297. That is, each of these drugs increased the frequencies of stationary postures and head movements with little or no effect on scratching or huddling. Additionally, effects of the D₁ agonist SKF 82958 and the indirect dopamine agonist cocaine were surmountably antagonized by the D₁ antagonist SCH 39166. The present results show that: 1) behavioral effects of D₁ and D₂ agonists in monkeys are qualitatively different; 2) D₁ agonists presumed to differ in intrinsic activity have dissimilar effects; and 3) effects of indirect dopamine agonists are comparable to those of D₁ agonists with presumably high intrinsic activity.Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education, and Welfare, Publication No. (NIH)85-23, revised 1985. This research was supported by USPHS grants DA03774, DA00499, MH07658. Facilities and services were provided by the New England Regional Primate Research Center (USPHS Division of Research Resources Grant RR000168). Portions of this work were presented at the Society for Neuroscience Meeting 18: A641.1 1992. This work was completed in partial fulfilment of the requirements for the doctor of philosophy degree for S.R.-L.     

Sigma-1 and Sigma-2 sites in rat brain: Comparison of regional,ontogenetic, and subcellular patterns

Radioligand binding assay conditions were established for the selective labeling of sigma-1 and sigma-2 sites in membrane homogenates of rat brain. Selective sigma-1 assays were conducted using 5 nM (+)[³H]SKF-10,047 in the presence of 300 nM dizocilpine (MK-801). Selective sigma-2 assays were conducted using 5 nM [³H]DTG in the presence of 1 μM (+)SKF-10,047. Distributions of sigma-1 and sigma-2 binding among brain regions were found to differ. While the brain stem yields the highest level of sigma-1 binding, it yields among the lowest levels of sigma-2 binding. The reverse is true in hippocampal membranes. Different ontogenetic patterns were also observed. Sigma-2 binding decreases substantially during brain development, whereas sigma-1 binding does not vary significantly. Patterns of distribution among subcellular fractions of rat brain homogenates were found to be similar. Both sigma-1 and sigma-2 sites are most enriched in microsomal fractions, and neither is enriched in synaptosomal or mitochondrial fractions. The present results suggest that sigma-1 and sigma-2 sites are distinct entities; they do not appear to be located on a common macromolecule, and they do not represent two different affinity states of a single type of binding site. While the precise subcellular locations (if sigma-1 and sigma-2) sites remain to be determined, we conclude that localization of either type of binding site to synaptic regions of plasma membrane or to mitochondria is highly unlikely © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such is in the public domain in the United States of America.