The substantia nigra pars reticulata mediates the enhancement of startle by the dopamine D<Subscript>1</Subscript> receptor agonist SKF 82958 in rats

Rational and objectives Several studies have shown that the substantia nigra pars reticulata (SNr) is a critical site of action mediating dopamine agonist effects on motor behaviors. Because dopaminergic and GABAergic mechanisms may interact in the SNr, we tested the contribution of both dopamine and GABA receptors in the SNr on the enhancement of startle by the dopamine D₁ agonist SKF 82958.Methods Male Sprague-Dawley rats were implanted with cannulae into the SNr and 1 week later infused with either the D₁ antagonist SCH 23390 (0.1, 1 µg) or the GABA_A antagonist bicuculline (0.1 µg), followed by a systemic challenge with the D₁ agonist SKF 82958 (1 mg/kg). Other rats were infused with the GABA_A agonist muscimol (0.1 µg) or SKF 82958 (0.1, 1, 5 µg).Results Both SCH 23390 and bicuculline infused into the SNr completely blocked the enhancement of startle by systemic SKF 82958. Muscimol infused into the SNr produced a significant increase in startle by itself, whereas SKF 82958 had no effect.Conclusions These results suggest that activation of D₁ receptors in the SNr is necessary for the enhancement of startle by SKF 82958, but that activation of these receptors alone is not sufficient to increase startle. These results also suggest that GABA transmission in the SNr may be involved in the enhancement of startle by SKF 82958. Based on these data, we propose that activation of striatonigral neurons by D₁ receptor agonists facilitates GABA release in the SNr to produce the observed enhancement of startle.     

Effects of NMDA and MK-801 injected into the substantia nigra pars reticulata on jaw movements evoked by dopamine D1-/D2 receptor stimulation in the ventrolateral striatum: studies in freely moving rats

The effects of NMDA and MK-801 injected into the substantia nigra pars reticulata on jaw movements evoked by dopamine D1/D2 receptor stimulation in the ventrolateral striatum were examined in freely moving rats, by using a magnet-sensing system combined with intracerebral drug microinjection technique. Bilateral injections of a mixture of SKF 82958 (5 microg) and quinpirole (10 microg), agonist at dopamine D1 and D2 receptors respectively, into the ventrolateral striatum elicited repetitive jaw movements. Bilateral injections of NMDA (0.01 and 0.05 microg/0.2 microl in each side) into the substantia nigra pars reticulata, which alone did not produce jaw movements, reduced the repetitive jaw movements evoked by the dopamine D1/D2 receptor agonist mixture in a dose-dependent manner. Injection of the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.5 microg/0.2 microl in each side), into the substantia nigra pars reticulata, which alone did not produce jaw movements, prevented the dopaminergic jaw movements in a dose-dependent manner. Moreover, other behaviors such as grooming, rearing, yawning, vacuous chewing, and locomotor activity that occurred after injections of the dopamine receptor agonist mixture were not significantly altered by the bilateral injections of NMDA or MK-801 into the substantia nigra pars reticulata. Given our previous results showing that both agonist and antagonist of GABA(A) receptors injected into the substantia nigra pars reticulata inhibit the jaw movements elicited by dopamine D1/D2 receptor stimulation in the ventrolateral striatum, the present results suggest that there are complex functional interactions between NMDA and GABA(A) receptors within the substantia nigra pars reticulata that may be responsible for the common profiles in the effects of NMDA and GABA(A) receptor agents.     

A comparison of the effects of the D1 receptor antagonists SCH 23390 and SCH 39166 on suppression of feeding behavior by the D1 agonist SKF38393

The hypophagic effect of the D₁ receptor agonist SKF 38393 is not dose-dependently antagonized by the D₁ antagonist SCH 23390. Moreover, the receptor specificity of this interaction remains in question, since SCH 23390 has significant activity at both 5-HT₂ and 5-HT_1C receptors, and SKF 38393 also interacts with 5-HT_1C receptors. To determine the relative significance of these actions, a comparison was made between the anorectic effects in rats of SCH 23390 (0.1–1.0 mg/kg) and the benzonaphthazepine SCH 39166 (0.1–3.0 mg/kg), a D₁ antagonist with negligible affinity for 5-HT sites. Both compounds inhibited food-intake dose-dependently, with SCH 23390 being approximately twice as potent as SCH 39166. Behaviorally inactive and active doses of both antagonists were tested in combination with the D₁ agonist SKF 38393 (10–56 mg/kg). Neither antagonist was able to produce more than a marginal attenuation of the agonist-induced hypophagia. This demonstrates that previous failures to reverse the behavioral actions of SKF 38393 by SCH 23390 were not due to specific actions of this particular antagonist. Finally, like SCH 23390, SCH 39166 (0.3 mg/kg) was able to attenuate fully the anorectic effects of the D₁ agonist SKF 82958 (1.0 and 3.0 mg/kg), demonstrating that neither compound is intrinsically unable to block D₁ receptor-mediated hypophagia. The results demonstrate the generality of the D₁ antagonist-mediated effect on feeding and call into question the use of SKF 38393 as a D₁ agonist in studies of feeding, and perhaps in other contexts as well.     

Dopaminergic and cholinergic stimulation of the ventrolateral striatum elicit rat jaw movements that are funnelled via distinct efferents

It has been reported that two distinct types of jaw movements can be elicited by bilateral injections of drugs into the ventrolateral striatum: (1) dopamine receptor-mediated jaw movements that are elicited by a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), and (2) acetylcholine receptor-mediated jaw movements that are elicited by carbachol (2.5 microg). In the present study, electromyographic analysis was used to characterise these movements: the dopamine receptor-mediated jaw movements were marked by a dominant digastric activity during jaw opening and a dominant masseter activity during jaw closing (digastric/masseter type), whereas the acetylcholine receptor-mediated jaw movements were marked by a dominant digastric activity during jaw opening without any significant change in masseter activity during jaw closing (digastric type). The main goal was to (in)validate the hypothesis that these two types of jaw movements are funnelled via distinct gamma-aminobutyric acid (GABA)ergic output channels. Bilateral injections of both muscimol (25 and 50 ng/0.2 microl per side) and bicuculline (50 and 150 ng/0.2 microl per side) into the ventral pallidum, entopeduncular nucleus or dorsolateral part of the substantia nigra pars reticulata essentially inhibited dopamine receptor-mediated jaw movements to various degrees. In contrast, acetylcholine receptor-mediated jaw movements were inhibited by muscimol given into the entopeduncular nucleus and dorsolateral part of the substantia nigra pars reticulata, whereas these movements were enhanced by bicuculline. The acetylcholine receptor-mediated jaw movements were not affected by muscimol injections into the ventral pallidum, but were inhibited by bicuculline injections. Studies on such injections into the ventral pallidum, entopeduncular nucleus or dorsolateral part of the substantia nigra pars reticulata of naive rats revealed that jaw movements of the digastric/masseter type were elicited either by muscimol injections into the dorsolateral part of the substantia nigra pars reticulata or by combined injections of muscimol and bicuculline into the entopeduncular nucleus, and that jaw movements of the digastric type were elicited only by combined injections of muscimol and bicuculline into the entopeduncular nucleus. Together, the data allow the conclusion that dopamine receptor-mediated and acetylcholine receptor-mediated jaw movements are two distinct types of jaw movements that are funnelled via separate GABAergic output channels. It is suggested that the three different profiles of responses to GABAergic drugs in animals showing either dopamine receptor-mediated or acetylcholine receptor-mediated jaw movements reflect the involvement of three distinct types of output neurons of the striatum, namely: type I neurons with collateralised axons to the ventral pallidum, entopeduncular nucleus and dorsolateral part of the substantia nigra pars reticulata, mediating the dopamine receptor-mediated jaw movements; type II neurons with collateralised axons to the globus pallidus that, in turn, project to the entopeduncular nucleus and the dorsolateral part of the substantia nigra pars reticulata, mediating directly the acetylcholine receptor-mediated jaw movements; and type III neurons with a single axon to the ventral pallidum, mediating indirectly the acetylcholine receptor-mediated movements. It is evident that future studies are required to provide direct evidence in favour of the latter hypothesis.     

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958

  Rationale: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D₁ and D₂ receptors. Objectives: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D₁ receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D₁ and D₂ receptor using a varied range of startle-eliciting intensities. Methods: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D₁ receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D₁ or D₂ receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). Results: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. Conclusions: These data suggest that dopamine D₁ receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D₁/D₂ receptor interaction whereby D₂ receptor activation is necessary for the full expression of the D₁ receptor-mediated enhancement of startle. Received: 10 October 1998 / Final version: 11 January 1999     

Conditional neural knockout of the adenosine A2A receptor and pharmacological A2A antagonism reduce pilocarpine-induced tremulous jaw movements: Studies with a mouse model of parkinsonian tremor

Tremulous jaw movements are rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus. In rats, tremulous jaw movements can be induced by a number of conditions that parallel those seen in human parkinsonism, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Moreover, tremulous jaw movements in rats can be attenuated using antiparkinsonian agents such as L-DOPA, dopamine agonists, muscarinic antagonists, and adenosine A_2A antagonists. In the present studies, a mouse model of tremulous jaw movements was established to investigate the effects of adenosine A_2A antagonism, and a conditional neuronal knockout of adenosine A_2A receptors, on cholinomimetic-induced tremulous jaw movements. The muscarinic agonist pilocarpine significantly induced tremulous jaw movements in a dose-dependent manner (0.25–1.0 mg/kg IP). These movements occurred largely in the 3–7.5 Hz local frequency range. Administration of the adenosine A_2A antagonist MSX-3 (2.5–10.0 mg/kg IP) significantly attenuated pilocarpine-induced tremulous jaw movements. Furthermore, adenosine A_2A receptor knockout mice showed a significant reduction in pilocarpine-induced tremulous jaw movements compared to littermate controls. These results demonstrate the feasibility of using the tremulous jaw movement model in mice, and indicate that adenosine A_2A receptor antagonism and deletion are capable of reducing cholinomimetic-induced tremulous jaw movements in mice. Future studies should investigate the effects of additional genetic manipulations using the mouse tremulous jaw movement model.     

Self-administration of the D1 agonist SKF 82958 is mediated by D1, not D2, receptors

We have previously reported that two D₁ dopamine agonists, SKF 82958 and SKF 77434, are readily self-administered by rats. However, due to the limited selectivities of these agents, it was not possible to attribute their reinforcing effects exclusively to their D₁ actions. To assess the relative involvement of D₁ and D₂ receptors in SKF 82958 reinforcement, rats were pretreated 30 min before self-administration sessions with either the D₁-selective antagonist (+)SCH 23390 or the D₂-selective antagonist raclopride. The D₁ antagonist (+)SCH 23390 (5–20 µg/kg, SC) produced significant, dose-related (compensatory) increases in SKF 82958; in contrast, the D₂ antagonist raclopride (25–400 µg/kg, SC) did not significantly increase SKF 82958 self-administration, although raclopride did increase cocaine self-administration. Compensatory increases in self-administration rates are thought to reflect antagonist-induced reductions in drug reinforcement. Hence, we conclude that SKF 82958 self-administration depends on activation of a D₁-regulated reinforcement substrate.This work was supported by U.S.P.H.S. grants DA-05107, DA-05379, and DA-07747. All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH pub. no. 86-23, revised 1985).     

The superior colliculus contains a discrete region involved in the control of jaw movements: role of GABAA receptors

The role of GABA(A) receptors in the superior colliculus in the production of rat repetitive jaw movements was examined, as this nucleus receives tonic GABAergic inhibitory inputs from the dorsolateral part of the substantia nigra pars reticulata and the entopeduncular nucleus. Both regions are also connected with the ventrolateral striatum where stimulation of either dopamine or acetylcholine receptors has been found to elicit distinct types of jaw movements in rats. The GABA(A) receptor antagonist bicuculline (50 and 150 ng/0.2 microl per side) dose-dependently produced repetitive jaw movements only when injected bilaterally into a circumscribed region (A 3.0) of the lateral deeper layers of the superior colliculus; this region is known to receive input predominantly from the dorsolateral part of the substantia nigra pars reticulata. The effects of bicuculline were GABA(A) receptor specific because the effects were abolished by muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline-induced jaw movements differed qualitatively from those elicited by injection of a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), agonist at dopamine D1 and D2 receptors, respectively, or carbachol (2.5 microg), an acetylcholine receptor agonist, into the ventrolateral striatum. Nevertheless, injection of muscimol into the lateral deeper layers of the superior colliculus (A 3.0) inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation. Conversely, the jaw movements evoked by acetylcholine receptor stimulation were enhanced by injection of muscimol into the superior colliculus. In conclusion, GABA(A) receptor blockade in a circumscribed region (A 3.0) of the lateral deeper layers of the superior colliculus elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region modulate the dopamine D1/D2 receptor-mediated and acetylcholine receptor-mediated jaw movements in an opposite manner.     

Effects of kappa receptor agonists on D1 and D2 dopamine agonist and antagonist-induced behaviors

Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entoped uncular nucleus. These neurons mainly express dopamine (DA) D₁ receptors and thus dynorphin system stimulation might be expected largely to influence D₁ receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D₁ and D₂ drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D₁ and D₂ DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D₁ agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D₂ agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D₂ receptor and decreased D₁ receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D₁ antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D₁ antagonist-induced catalepsy, but had no effect on D₂ antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D₁ receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.     

Differential antagonism of the effects of dopamine D1-receptor agonists on feeding behavior in the rat

A series of experiments was conducted to examine the effects of dopamine D₁ receptor agonists on food intake in rats. In the first experiment, the D₁ agonist SKF 38393 (3.0–30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D₁ agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 > SKF 77434 > SKF 38393 (ED₅₀ values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D₁ antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1–10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D₁ antagonist. The effects of SKF 82958 were also antagonized by the D₂ receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D₁ receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D₁ receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D₁ agonist. The results also demonstrate the need for comparisons among several compounds in studies of D₁ mediated behavioral effects.     

Interactions between dopamine D1 receptors and γ-aminobutyric acid mechanisms in substantia nigra pars reticulata of the rat: neurochemical and behavioral studies

RATIONALE: Several studies have shown that dopamine D1 agonists act on forebrain dopamine terminal regions to exert many of their behavioral effects. Yet, there is also a large number of D1 receptors in the substantia nigra pars reticulata (SNr), and these receptors are located mainly on terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. OBJECTIVE: The present studies were undertaken to determine the behavioral and neurochemical effects of local administration of the D1 agonist SKF 82958 and to study the interactions between D1 and GABA mechanisms in SNr. METHODS: Microdialysis methods were used to characterize the effect of SKF 82958 on extracellular GABA, and several experiments studied the effects of nigral D1 stimulation on motor activity and investigated the behavioral significance of D1/GABA interactions in SNr. RESULTS: Local infusion of 10(-6) M SKF 82958 increased extracellular levels of SNr GABA, and this effect was blocked by co-infusion of the D1 antagonist SCH 23390. Bilateral SNr injections of SKF 82958 increased locomotor activity, and this effect was blocked by the GABA-A antagonist bicuculline. Intranigral bicuculline reduced motor activity, while the GABA-A agonist muscimol increased various motor activities in a manner similar to SKF 82958. CONCLUSIONS: The present results suggest that the D1 agonist SKF 82958 acts on D1 receptors in SNr to increase extracellular levels of GABA, and the increase in motor activity produced by nigral D1 stimulation is dependent on stimulation of GABA-A receptors. D1/GABA interactions in SNr are important for the modulation of basal ganglia output, which may have important implications for Parkinson's disease.     

Action of intravenously administered talipexole on the rat striatal neurons receiving excitatory input from nigral dopamine neurons

Electrophysiological studies using rats anesthetized with chloral hydrate were performed to elucidate whether or not intravenously injected talipexole acted as a D₂ receptor agonist on the striatal neurons in comparison with the action of bromocriptine. The activities of the striatal neurons were extracellularly recorded using a glass microelectrode attached along a seven-barreled micropipette, each barrel of which was filled with talipexole, bromocriptine, SCH23390 (D₁ antagonist), domperidone (D₂ antagonist), glutamate or 2 M NaCl. These drugs were iontophoretically applied to the immediate vicinity of the target neuron being recorded. The effects of talipexole and bromocriptine were examined on the neurons, whose spikes (induced by the stimulation of the substantia nigra pars compacta) were inhibited by the iontophoretic application of domperidone. Iontophoretic application of talipexole or bromocriptine increased spontaneous firing of these neurons and this increase in firing was also inhibited by iontophoretically applied domperidone. In the same neurons, intravenously administered talipexole (0.01, 0.02 and 0.04 mg/kg) dose-dependently increased firing, and this increase was inhibited by microiontophoretically applied domperidone, but not by SCH23390. On the other hand, the intravenous injection of bromocriptine (0.1, 0.2 and 0.4 mg/kg) also increased the firing rate. However, the increase was not dose-dependent and fluctuated; the firing transiently decreased during the increase in firing with intravenously administered bromocriptine. However, the bromocriptine-induced increase in firing was also suppressed by domperidone, and decrease in firing was inhibited by SCH23390. These findings suggest that talipexole acts as a D₂ agonist on the striatal neurons receiving input from substantia nigra pars compacta and increases firing when intravenously applied. However, intravenously administered bromocriptine appears to act as both a D₂ agonist and probably as a D₁ agonist on the striatal neurons to increase and decrease firing, respectively.     

Effects of intranucleus accumbens shell administration of dopamine agonists and antagonists on cocaine-taking and cocaine-seeking behaviors in the rat

Rationale Dopamine signaling in the nucleus accumbens (NAc) plays an important role in regulating drug-taking and drug-seeking behaviors, but the role of D₁- and D₂-like receptors in this regulation remains unclear.Objectives Our objective was to study the role of NAc D₁- and D₂-like receptors in the reinstatement of cocaine-seeking behavior and the regulation of stabilized cocaine intake in rats.Methods Using a within-session reinstatement procedure, whereby animals self-administer cocaine (90 min) and extinguish responding (150 min) in a single session, we assessed the ability of NAc microinfusions of the D₁ agonist SKF 81297 and the D₂ agonist 7-OH-DPAT to reinstate extinguished cocaine seeking. The effects of the D₁ antagonist SCH 23390 and the D₂ antagonist eticlopride pretreatment on agonist- and cocaine-primed reinstatement were also measured. Similar agonist and antagonist treatments were tested for their ability to modulate stabilized cocaine and sucrose self-administration.Results Intra-NAc infusions of either SKF 81297 (0.3–3.0 μg) or 7-OH-DPAT (1.0–10.0 μg) dose-dependently reinstated cocaine seeking with greater efficacy in the medial core than in the shell subregion and at doses that also stimulated locomotor behavior. Intra-NAc shell infusions of SCH 23390 (1.0 μg) and eticlopride (3.0–10.0 μg) blocked cocaine-primed reinstatement (2.0 mg/kg, i.v.) and indiscriminately blocked reinstatement induced by either intra-NAc D₁ or D₂ agonists. Doses of agonists that triggered reinstatement failed to alter stabilized cocaine intake, whereas doses of antagonists that blocked reinstatement increased cocaine intake in the shell.Conclusions Both D₁ and D₂ receptors in the NAc play a prominent, and perhaps cooperative, role in regulating cocaine-taking and cocaine-seeking behaviors.     

GABA(B) receptor activation inhibits dopamine D1 receptor-mediated facilitation of [(3)H]GABA release in substantia nigra pars reticulata

GABA(B) receptors inhibit and dopamine D1 receptors stimulate the release of GABA from striatal terminals in the pars reticulata of the substantia nigra. Here we have studied the interaction between both classes of receptors by exploring the effect of GABA(B) receptors upon the stimulation of depolarization-induced [(3)H]GABA release induced by the activation of D1 receptors in slices of the pars reticulata of the rat substantia nigra. The activation of GABA(B) receptors with baclofen (100 microM) inhibited by 48+/-8% the evoked [(3)H]GABA release in normal slices but did not modify the release in slices from reserpine-treated rats, indicating that the inhibition was dependent on endogenous dopamine. The inhibitory effect of baclofen was also abolished by the D1 receptor antagonist SCH 23390 (1 microM), indicating a D1 receptor-dependence of the baclofen inhibition. Baclofen dose-dependently inhibited (IC(50)=3.6 microM) the stimulation of release induced by the D1 agonist SKF 38393 (1 microM). Baclofen also blocked the stimulation of release induced by forskolin but not that induced by 8-Br-cAMP, indicating that the inhibitory effect was exerted before cAMP synthesis. N-ethylmaleimide (NEM), a selective inactivator of PTX-sensitive G-proteins, abolished the baclofen inhibition of the SKF 38393-induced stimulation of the release without affecting the stimulation induced by the D1 agonist, suggesting that the baclofen effect was mediated by Galpha(i/o) proteins. These results might have relevance in the control motor disorders associated with D1 receptor supersensitivity.     

Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia nigra pars reticulata block tremulous jaw movements in rats: studies with a putative model of Parkinsonian tremor

Abstract Rationale. Atypical antipsychotics such as clozapine and olanzapine have a low liability for producing motor side effects. In addition to being D2 antagonists, these drugs have a complex binding profile that includes affinity for muscarinic, alpha, H1, and various serotonin receptors. Previous work in rats has shown that atypical antipsychotics suppress tremulous jaw movements induced by the anticholinesterase tacrine in rats. Cholinomimetic-induced jaw movements are a putative model of parkinsonian tremor, and the ability of antipsychotic drugs to suppress these movements in rats is correlated with motor side-effect liability in humans. Objective. The present work was undertaken to study the role of central serotonin receptors in the generation of cholinomimetic-induced jaw movements. Results. Systemic injections of the serotonin antagonist mianserin suppressed tacrine-induced jaw movements, with an ED₅₀ of 2.77 mg/kg. Local injections of mianserin directly into substantia nigra pars reticulata (SNr) also suppressed tacrine-induced jaw movements. Injections into ventrolateral neostriatum, or a control site dorsal to SNr, failed to have any effects on jaw movement activity. Conclusions. These studies suggest that atypical antipsychotics may act both on striatal muscarinic receptors and nigral serotonin receptors to suppress jaw movement activity. It is possible that the unique motor properties of atypical antipsychotics result from actions on multiple receptors in several brain areas. The precise serotonin receptor subtype involved in these effects is unknown, and future work will examine the effects of drugs that act selectively on 5-HT_2A and 5-HT_2C receptors. Electronic Publication     

Proconvulsant effect of SKF 38393 mediated by nigral D1 receptors

This study investigated the hypothesis that the proconvulsant action of systemically applied dopamine D1 receptor stimulants is mediated by D1 receptors in the substantia nigra. Rats were equipped with bilateral stainless steel guide cannulas under halothane anaesthesia, to allow drugs to be injected into both nigras of conscious, unrestrained animals 7-14 days later. Bilateral intranigral administration of saline, together with a subconvulsant dose of pilocarpine (200 mg/kg), produced no convulsions in 14 rats. By contrast, intranigral SKF 38393 (2.5 micrograms) and pilocarpine (200 mg/kg) caused 18/22 rats to convulse. This proconvulsant action of SKF 38393 was completely attenuated by pretreatment with SCH 23390 (0.25 mg/kg). SCH 23390 (1 microgram) delivered into both nigras reduced the number of rats convulsing in response to 600 mg/kg pilocarpine (7/15, one fatally) as compared to saline-injected controls (12/13, eight fatally). These results indicate that dopamine D1 receptors in the substantia nigra (pars reticulata) mediate a proconvulsant action of dopamine, which is opposite to the anticonvulsant effect of the amine at striatal D2 receptors.     

Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: a parallel dialysis and behavioural study in rats

Although dopaminergic mechanisms are known to modulate cognitive function and cholinergic transmission, their pharmacological characterization remains incomplete. Herein, the role of D1 sites was evaluated employing neurochemical and behavioural approaches. By analogy to the acetylcholinesterase inhibitor, galantamine (0.0025-0.63 mg/kg s.c.), the selective and high efficacy D1 receptor agonist, SKF 82958, dose-dependently (0.0025-0.63), robustly and potently enhanced extracellular levels of acetylcholine (ACh) in the frontal cortex and hippocampus of freely moving rats. A further agonist, SKF 81297 (0.04-0.63), mimicked this action whereas the selective antagonist, SCH 23390 (0.00063-0.63), decreased levels of ACh. In the presence of SCH 23390 (0.08), the facilitatory influence of SKF 82958 (0.04) upon ACh levels was abolished. In a model of social memory (recognition of a juvenile by an adult rat), galantamine (0.04-0.63), SKF 82958 (0.01-0.16) and SKF 81297 (0.001-0.16) dose-dependently abrogated amnesic effects of the muscarinic receptor antagonist scopolamine (1.25). Further, under conditions of spontaneous loss of recognition, mimicking the effects of galantamine (0.04-2.5), SKF 82958 (0.01-0.16) and SKF 81297 (0.04-1.25) dose-dependently and specifically facilitated social recognition. Conversely, SCH 23390 (0.0025-0.04) exerted a modest negative influence upon social recognition and, in its presence, the pro-cognitive properties of SKF 82958 were blocked. In conclusion, D1 receptors exert a tonic, facilitatory influence upon cholinergic transmission and social recognition. Although the relationship between these actions awaits further clarification, these data underpin the relevance of D1 receptors to CNS disorders in which cholinergic transmission and social cognition are disrupted.     

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of parkinson's disease — the differential effects of D1 dopamine antagonists in the primate

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D₁ DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine) and A66359 (1-[2-bromo-4, 5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4 tetrahydroisoquinoline), but not the D₂ DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D₁ DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3-CH₃ analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D₁ DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D₁ DA agonists. These findings demonstrate that the behavioural effects of benzazepine D₁ DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D₁ DA receptor sites, although in the primate, stimulation of D₂ DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D₁ DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D₁ DA antagonists may indicate the involvement of multiple D₁ DA receptor subtypes in mediating benzazepine D₁ DA agonist induced behaviours in the MPTP-treated marmoset.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Chronic treatment with the D1 receptor antagonist,SCH 23390, and the D2 receptor antagonist,raclopride, in cebus monkeys withdrawn from previous haloperidol treatment

The effects of chronic treatment with dopamine (DA) D₁ and D₂ receptor antagonists were evaluated in eightcebus apella monkeys with mild oral dyskinesia after previous haloperidol treatment. SCH 23390 (D₁ antagonist) was given daily to investigate the direct behavioural effect during long-term treatment and the subsequent supersensitivity to DA agonists. Raclopride (D₂ antagonist) was investigated for comparison. All drugs were given subcutaneously. SCH 23390 and raclopride induced dystonic syndromes, catalepsy, sedation and reduced locomotor activity. The monkeys developed marked tolerance to the dystonic effect of SCH 23390, while they showed increased sensibility to the dystonic effect of raclopride. Baseline oral dyskinesia (24 h after injection) remained unchanged during D₁ antagonist treatment, while it increased during D₂ antagonist treatment. SCH 23390 induced supersensitivity to the oral dyskinesia- and grooming-inducing effects of SKF 81297 (D₁ agonist) after 9 weeks, while the subsequent treatment with raclopride induced supersensitivity to the reactivity- and stereotypy-inducing effects of quinpirole (D₂ receptor agonist) after 3 weeks. Because of the possibility of a carry-over effect (SKF 81297-induced oral hyperkinesia and grooming), other changes in raclopride-induced behaviours cannot be ruled out. The development of tolerance to the dystonic effect of SCH 23390 and the unchanged baseline oral dyskinesia during SCH 23390 treatment indicate an advantageous profile of side effects of DA D₁ receptor blockade.