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.     

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.     

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

  Rationale: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. Objective: This rodent model was used to characterize the putative antiparkinsonian effects of the full D₁ dopamine receptor agonist, SKF 82958. Methods: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. Results: SKF 82958 (0.5–2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D₁ dopamine receptor antagonist SCH 23390 (0.025–0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D₂ antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 μg/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. Conclusions: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D₁ receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D₁ agonists. Received: 9 June 1998 / Final version: 10 October 1998     

The impact of a competitive and a non-competitive NMDA receptor antagonist on dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra

The study compares effects of the competitive and non-competitive NMDA receptor antagonists, CGP 40116 and MK-801 respectively, on the metabolism of dopamine and on the density of D-1 and D-2 dopaminergic receptors in the rat ventral tegmental area and substantia nigra. The effects of CGP 40116 were tested in a range of doses which either were devoid of or had locomotor- or stereotypy-stimulating effects. It was found that (1) CGP 40116 given in a dose of 5 mg/kg enhanced the locomotor activity of rats and evoked a stereotypy-like activity; doses of 1.25 and 2.5 mg/kg were devoid of such effects; (2) CGP 40116 (5 mg/kg) enhanced the concentrations of dopamine, DOPAC and HVA in the ventral tegmental area, whereas the lowest dose, 1.25 mg/kg was without effect; a dose of 2.5 mg/kg increased the concentration of dopamine only; the only effect of CGP 40116 (5 mg/kg) observed in substantia nigra, was an increase in dopamine concentration; its doses of 1.25 and 2.5 mg/kg were ineffective. (3) MK-801 (0.2 and 0.4 mg/kg) enhanced the concentrations of dopamine, DOPAC and HVA in both structures. A dose of 0.1 mg/kg increased the dopamine concentration only. The effects of MK-801 in substantia nigra were quantitatively weaker than those observed in ventral tegmental area. (4) Both CGP 40116 (5 mg/kg) and MK-801 (0.4 mg/kg) evolved alterations in the density of dopaminergic receptors. D-2 receptors, were up-regulated by MK-801 in ventral tegmental area and subregions of substantia nigra, i.e. pars compacta and pars reticulata, whereas CGP 40116 evoked similar effects in ventral tegmental area only. D-1 receptors in pars compacta and pars reticulata of substantia nigra were down-regulated after administration of either drug.It is concluded that competitive NMDA receptor antagonists in doses which evoke hyperlocomotion and stereotypy-like activity, may have a substantial impact on the dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra, similar to that described for MK-801, a non-competitive NMDA receptor antagonist. The obtained results may suggest that CGP 40116 and, possibly, other competitive NMDA antagonists may have dopaminomimetic properties, and that their clinical potentials may be limited by the risk of evoking dopamine-dependent psychotomimetic and abusing effects, similar to those described for MK-801.     

Role of GABA(A) receptors in the retrorubral field and ventral pallidum in rat jaw movements elicited by dopaminergic stimulation of the nucleus accumbens shell

The role of gamma-aminobutyric acid (GABA)(A) receptors in the retrorubral field in the production of rat repetitive jaw movements was examined, as this nucleus receives a GABAergic, inhibitory input from the nucleus accumbens and is connected with the parvicellular reticular formation, a region that is directly connected with the orofacial motor nuclei. The GABA(A) receptor antagonist bicuculline (150 ng/0.2 microl per side) significantly produced repetitive jaw movements when injected bilaterally into the retrorubral field, but not the ventral pallidum. 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, into the nucleus accumbens shell. Nevertheless, bilateral injections of muscimol (10 ng, 25 ng and 50 ng/0.2 microl per side) into the retrorubral field significantly inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation in the nucleus accumbens shell. Bilateral injections of bicuculline (50 ng and 150 ng/0.2 microl per side) also reduced the dopamine D1/D2 receptor-mediated jaw movements. Essentially similar effects were obtained when muscimol and bicuculline were given into the ventral pallidum, a region that is also known to receive GABAergic inhibitory inputs from the nucleus accumbens. In conclusion, GABA(A) receptor blockade in the retrorubral field elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region as well as in the ventral pallidum modulate the accumbens-specific, dopamine D1/D2 receptor-mediated jaw movements.     

Decreased postsynaptic dopaminergic and cholinergic functions in the ventrolateral striatum of spontaneously hypertensive rat

Dopamine and acetylcholine receptor functions in spontaneously hypertensive rats (SHR) and in control progenitor Wistar-Kyoto (WKY) rats were assessed, using dopamine D1-like/D2-like receptor-mediated and acetylcholine receptor-mediated jaw movements as readout parameters. Spontaneous behaviours such as locomotor activity, vacuous chewing, grooming, sniffing and rearing occurred significantly more in SHR than in WKY rats. In the anaesthetised rats, a mixture of SKF 38393 (5 micrograms), a dopamine D1-like receptor agonist, and quinpirole (10 micrograms), a dopamine D2-like receptor agonist, readily produced repetitive jaw movements in WKY rats, but not SHR, when bilaterally injected into the ventrolateral striatum; such injections into the nucleus accumbens shell were ineffective in each strain. Bilateral injections of carbachol (2.5 micrograms each side), an acetylcholine receptor agonist, into the ventrolateral striatum elicited repetitive jaw movements in both SHR and WKY rats, but to a far less degree in SHR. The present study demonstrates that spontaneous behaviours are enhanced in SHR, and that postsynaptic dopamine D1-like/D2-like receptors and acetylcholine receptors in the ventrolateral striatum of SHR are hyposensitive when compared to those of WKY rats.     

Prefrontal,accumbal [shell] and ventral striatal mechanisms in jaw movements and non-cyclase-coupled dopamine D1-like receptors

The effect on jaw movements of intracerebral injections of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), SK&F 38393 ([R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and of injections of the dopamine D2-like receptor agonist quinpirole into the ventrolateral striatum, accumbens shell or prefrontal cortex were studied. SK&F 38393 and SK&F 83959 injected into the ventrolateral striatum synergised with i.v. quinpirole; in the shell of accumbens, SK&F 38393 evidenced weaker synergism with quinpirole, while SK&F 83959 did not synergise with it; neither agent synergised with quinpirole in the prefrontal cortex. Co-injection of SCH 23390 or SK&F 83959 into the prefrontal cortex antagonised jaw movements induced by injection of SK&F 83959 into the ventrolateral striatum in combination with i.v. quinpirole. Injection of SK&F 83959 + quinpirole into the ventrolateral striatum, but not into the accumbens shell, resulted in synergism. These findings indicate a primary, but not exclusive, role for ventral striatal, non-cyclase-coupled dopamine D1-like receptors in the induction of jaw movements. These processes appear to require tonic activity of prefrontal cyclase-linked dopamine D1A [and/or D1B] receptors.     

Role of AMPA and NMDA receptors in the nucleus accumbens shell in turning behaviour of rats: interaction with dopamine receptors

The role of AMPA and NMDA receptors in the shell of the nucleus accumbens in turning behaviour of rats was investigated. Unilateral injection of the AMPA receptor agonist, AMPA (0.25, 0.4, 0.5 and 1 microg), into the shell of the nucleus accumbens dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping, while injection of AMPA (0.5 microg) into the core produced only a marginal effect. This shell-specific AMPA effect was dose-dependently inhibited by the AMPA receptor antagonist, NBQX (1 and 10 ng), which alone did not produce turning behaviour. The AMPA-induced pivoting was also dose-dependently inhibited by the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.5 microg). Neither MK-801 (0.1, 0.5 and 5 microg) nor the NMDA receptor agonist, NMDA (0.5 and 1 microg), injected unilaterally into the shell, produced turning behaviour. Unilateral injection of a mixture of dopamine D(1) (SKF 38393, 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the shell has been found to elicit contraversive pivoting. The dopamine D(1)/D(2) receptor antagonist, cis-(Z)-flupentixol (1 and 10 microg), injected into the shell, in doses known to block dopamine D(1)/D(2) receptor-mediated pivoting, also significantly inhibited AMPA (0.5 microg)-induced pivoting. Moreover, both NBQX (1 and 10 ng) and MK-801 (0.1 and 0.5 microg), injected into the shell, significantly inhibited dopamine D(1)/D(2) receptor-mediated pivoting. It is therefore concluded that unilateral stimulation of AMPA receptors in the shell of the nucleus accumbens can elicit contraversive pivoting, and that both AMPA and dopamine D(1)/D(2) receptors play a critical role in shell-specific pivoting in contrast to NMDA receptors that at best play only a modulatory role.     

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.     

Ventral striatal vs. accumbal (shell) mechanisms and non-cyclase-coupled dopamine D(1)-like receptors in jaw movements.

This study compared the effects of intracerebral injections of the dopamine D(1)-like receptor agents 3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 83959) and [R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) into the ventrolateral striatum or the shell of the nucleus accumbens on the synergistic induction of jaw movements by intravenous (i.v.) co-administration of [R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 38393) or SK&F 83959 with the dopamine D(2)-like receptor agonist, quinpirole. In the ventrolateral striatum, SCH 23390 and SK&F 83959 each blocked jaw movements induced by i.v. SK&F 38393 with quinpirole, while only SCH 23390 blocked i.v. SK&F 83959 with quinpirole. SCH 23390 was less effective in the accumbens shell than in the ventrolateral striatum, and SK&F 83959 was ineffective to block i.v. SK&F 38393 with quinpirole, while neither SCH 23390 nor SK&F 83959 blocked i.v. SK&F 83959 with quinpirole. As SK&F 83959 inhibits the stimulation of adenylyl cyclase via dopamine D(1A) receptors but acts as an agonist at a putative dopamine D(1)-like receptor site not linked to cyclase, an important role is indicated for non-cyclase-coupled dopamine D(1)-like receptor sites as well as dopamine D(1A) receptors in the regulation of jaw movements via dopamine D(1)-like/D(2)-like receptor synergism, particularly in the ventrolateral striatum.     

Rotation following intranigral injections of a selective D1 or a selective D2 dopamine receptor agonist in rats

Injections of various nonselective dopamine agonists into the substantia nigra, pars reticulata (SNpr), have been reported to produce contralateral rotation in rats. Since a number of recent dopamine receptor distribution studies have indicated a preponderance of D1 compared to D2 dopamine receptor subtypes within the SNpr, we examined the relative behavioral functions of these two subtypes within the nigra by studying rotation following unilateral, local injections of a D1 (SKF38393) and D2 (quinpirole) agonist, Significant, dose-dependent contralateral rotation was observed following injections of R,S-SKF38393. This effect was found to be stereoselective to the R- enantiomer, suggesting that the effect is receptor mediated. In contrast, quinpirole (LY171555) produced significant, dose-dependent ipsilateral rotation following nigral injection. These results suggest that the rotation seen following intranigral injections of nonselective dopamine agonists is due to the simulation of the D1 dopamine receptor, and that nigral D1 and D2 dopamine receptors may play opposite roles in the control of behavior.     

Substantia nigra pars reticulata is a highly potent site of action for the behavioral effects of the D1 antagonist SCH 23390 in the rat

RATIONALE: Considerable evidence indicates that dopaminergic drugs, including drugs that act on D1 receptors, exert their effects by actions on forebrain dopamine terminal regions. Nevertheless, anatomical studies also have demonstrated that there is a high concentration of D1 receptors in the substantia nigra pars reticulata (SNr). The D1 receptors in SNr are located largely on the terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. The present studies were undertaken to determine whether the D1 antagonist SCH 23390 was effective if locally injected into SNr and to compare the results of SNr injections with those obtained from other brain sites. Fixed ratio 5 (FR5) lever pressing and open-field locomotion were used as the behavioral tests because these tasks are sensitive to systemic SCH 23390. METHODS: Rats received bilateral implantations of guide cannulae into either nucleus accumbens, neostriatum, SNr, or control sites in the cortex or brainstem. Rats in the FR5 study were trained prior to surgery. All rats received one of the following local injections (0.5 microl per side): vehicle, 0.25, 0.5, 1.0, or 2.0 microg SCH 23390. RESULTS: In the FR5 study, the SNr was by far the most potent site for suppression of lever pressing, with an ED50 (dose that produces half maximal response) of 0.33 microg per side. Nucleus accumbens and neostriatum injections were less potent than those in SNr, but more potent than injections into the control regions. With open-field locomotion, the SNr, nucleus accumbens, and neostriatum were approximately equipotent sites, and all three were more potent than the control sites. CONCLUSIONS: SNr was a very potent site for suppression of lever pressing and open-field locomotion. These data suggest that D1 antagonists have multiple sites of action, including not only the forebrain dopamine terminal regions but also the SNr. It is possible that blockade of SNr D1 receptors modulates GABA release from striatonigral neurons.     

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     

Neuronal localization and modulation of the D2 dopamine receptor mRNA in brain of normal mice and mice lesioned with 6-hydroxydopamine.

A novel oligonucleotide probe was designed, characterized and utilized to study the distribution and modulation of the mRNA encoding the D2 dopamine receptor in the brain of the mouse. Using in situ hybridization histochemistry, the highest levels of the D2 receptor mRNA were found in regions of the brain containing the cell bodies and the terminal projection fields of the nigrostriatal, mesolimbic and mesocortical dopaminergic systems. Particularly high levels of the D2 receptor mRNA were found in substantia nigra pars compacta, ventral tegmental area, caudate-putamen and olfactory tubercle. This distribution generally paralleled that of the D2 dopamine receptor. Some areas, not usually associated with dopaminergic systems, also contained significant levels of the D2 receptor mRNA signal. These areas included the hippocampus, certain thalamic nuclei, the inferior colliculus and the spinal trigeminal nucleus of the medulla and spinal cord. Lesioning the corpus striatum with 6-hydroxydopamine had little effect on the level of the D2 receptor mRNA in the striatum but greatly reduced the hybridization signal in the substantia nigra pars compacta and ventral tegmental area. Similarly, lesioning the substantia nigra, nearly abolished the signal in the pars compacta but failed to substantially alter the D2 receptor mRNA signal in the striatum. These results suggest that the D2 receptor mRNA in the substantia nigra pars compacta was localized largely to dopaminergic cell bodies, the terminal projections of which lie in the striatum and codes for D2 autoreceptors and that the D2 receptor mRNA of the striatum is in non-dopaminergic cell bodies that are intrinsic to the striatum and probably codes for post-synaptic D2 receptors. Further, the evidence that lesions of striatum and substantia nigra induced with 6-hydroxydopamine greatly reduced the D2 receptor mRNA signal in the substantia nigra, without concomitantly increasing the D2 receptor mRNA in the striatum, suggests that the increase in dopamine receptor binding in the striatum that is ipsilateral to the lesion with 6-hydroxydopamine and the enhanced behavioral sensitivity to dopaminergic agonists, cannot be accounted for solely by an increase in D2 receptor mRNA.     

Rotation induced by intranigral injections of GABA agonists and antagonists: Zone-specific effects

Recent investigations of the function of the strionigral pathway have utilized the intranigral injection of γ-aminobutyric acid (GABA) agonist and antagonist drugs. While the unilateral application of these substances typically produces rotational behavior, the direction of this turning (ipsilateral or contralateral to the injected hemisphere) differs in several reports. The present study determines whether the direction of this drug-induced turning depends upon the locus of nigral stimulation. Picrotoxin and bicuculline methiodide were injected into either the pars compacta or the pars reticulata of the substantia nigra at several anterior-posterior levels. Injection of these drugs into the pars compacta resulted in ipsilateral turning while injection into the pars reticulata produced contralateral rotation. Both of these effects were dose-dependent and were elicited by similar threshold doses of picrotoxin. Prior 6-hydroxydopamine treatment abolished the ipsilateral but not the contralateral rotation. In contrast, muscimol injections produced contralateral turning in dependent of whether they were made into the pars compacta or pars reticulata. However, 6-hydroxydopamine treatment only attenuated the contralateral turning produced by pars compacta injections. These findings provide a histological basis for understanding the different types of turning behavior elicited by the intranigral injection of GABA agonists and antagonists. In addition, they suggest that GABA receptors mediate at least two independent actions in substantia nigra.     

MK801 influences L-DOPA-induced dopamine release in intact and hemi-parkinson rats

In vivo microdialysis was used to investigate the influence of dizocilpine (MK801) on basal and levodopa (L-DOPA)-induced extracellular dopamine levels in striatum and substantia nigra of intact and 6-hydroxydopamine-lesioned rats. In lesioned rats, extracellular dopamine was decreased in striatum but not in substantia nigra. L-DOPA (25 mg/kg i.p. after benserazide 10 mg/kg i. p.) increased the dopamine levels in striatum and substantia nigra of intact and dopamine-depleted rats. This increase was significantly higher in dopamine-depleted compared to intact striatum. Pretreatment with MK801 (0.1 and 1.0 mg/kg i.p.) dose-dependently attenuated the L-DOPA-induced dopamine release in substantia nigra of intact rats. In dopamine-depleted striatum, MK801 enhanced L-DOPA-induced dopamine release. The present results indicate that the influence of MK801 on L-DOPA-induced dopamine release in striatum and substantia nigra depends on the integrity of the nigrostriatal pathway. In Parkinson's disease, NMDA receptor antagonists could be beneficial by enhancing the therapeutic efficacy of L-DOPA at the level of the striatum.     

Changes in muscle tone are regulated by D1 and D2 dopamine receptors in the ventral striatum and D1 receptors in the substantia nigra.

Muscle rigidity associated with antipsychotic drug treatment is believed to result from reduced striatal dopamine neurotransmission. In the current study the regulatory roles of dopamine D1 and D2 receptor subfamilies in the dorsal (DSTR) and ventral striatum (VSTR) and substantia nigra (SN) were investigated on muscle tone, assessed as increases in tonic electromyographic (EMG) activity. Rats were injected with the irreversible D1/D2 antagonist N-ethoxycarbonyl-2-ethoxy, -1,2-dihydroquinoline (EEDQ), the reversible D1 antagonist SCH23390, or D2 antagonist sulpiride. Increased EMG activity was observed following injection of EEDQ and SCH23390 into the SN or VSTR, and sulpiride into the VSTR. Mapping, using quantitative autoradiographic analysis of dopamine receptor occupancy after striatal injections, showed D1 and D2 receptors in discrete ventral sites were associated with EMG increases. Overall the results support roles for dopamine D1 and D2 receptors in the ventral striatum, and D1 receptors in the substantia nigra, in the regulation of muscle tone.     

Behavioural and neurochemical effects of cholinergic and dopaminergic agonists administered into the accumbal core and shell in rats.

The first goal of this study was to investigate whether turning behaviour elicited by unilateral injections of the cholinergic agonist carbachol into the shell of the nucleus accumbens differs from that elicited by similar injections into the core of this nucleus, and to compare the behavioural effects with the known effects of such injections of the mixture of the dopamine D1 and D2 receptor agonists SKF 38393 (5 microg) and quinpirole (10 microg). The second goal was to investigate whether these injections of carbachol produce neurochemical alterations in the ventrolateral striatum that differ from similar injections of the mixture of the dopamine D1 and D2 receptor agonists into these brain regions. Injections of carbachol into the shell produced predominantly (a) contralateral circling marked by normal stepping and running in wide circles during the initial 50 min and (b) postural asymmetry during the following 75 min; similar injections into the core produced (a) contralateral pivoting, namely pathological head-to-tail turning marked by abnormal hindlimb stepping during the initial 50 min and (b) postural asymmetry during the next 75 min. The postural asymmetry seen after the carbachol injections was closely associated with the drug-induced increase in the dopamine release measured by microdialysis in the ipsilateral striatum. Injections of the mixture of dopamine agonists into the shell, but not core, also produced pivoting. These shell injections increased the dopamine release in the ipsilateral striatum, and decreased it in the contralateral striatum. The relative increase in the ipsilateral striatum was closely associated with the drug-induced pivoting. The data show that stimulation of cholinergic and dopaminergic receptors in the shell and core elicit effects that vary according to the subregion of the nucleus accumbens. It is concluded that the accumbens-specific, cholinergic effects are mediated via substrates that differ from those involved in the shell-specific, dopaminergic effects.     

Interaction between dopamine and glutamate receptors following treatment with NMDA receptor antagonists

Interactions between dopamine and glutamate neurotransmission have been reported to play an important role in a number of different systems. We were interested in examining the effects of sub-chronic treatment with NMDA receptor antagonists (dizocilpine [MK-801], and 3-carboxy-piperazin-propyl phosphonic acid [CPP]) on dopamine D(1)-like, dopamine D(2)-like, as well as glutamate receptors of the NMDA and AMPA receptor subtypes in the neostriatum and substantia nigra of rats that had received a massive dopamine denervation at 3 days of age. Using quantitative ligand binding autoradiography, we demonstrated that the two NMDA receptor antagonists did not have different profiles of action. Furthermore, while we found a significant negative relationship between NMDA receptors and dopamine receptors (both dopamine D(1)-like and D(2)-like receptor subtypes) in the neostriatum, AMPA receptors were positively correlated with dopamine D(1)-like binding sites in all regions investigated. These findings suggest that the interrelationship between dopamine and glutamate receptors is highly controlled and that the nigrostriatal dopamine systems play an important role in this interaction.     

Antagonism of the effects of (+)-PD 128907 on midbrain dopamine neurones in rat brain slices by a selective D2 receptor antagonist L-741,626.

1. The ability of PD 128907 to activate dopamine receptors in the ventral tegmental area, substantia nigra pars compacta, and striatum was investigated by use of in vitro electrophysiological recording and fast cyclic voltammetry. The affinity of a novel D2 selective antagonist L-741,626 for receptors activated by this agonist was measured to determine if its effects were mediated by D2 or D3 receptors. 2. The active (+) enantiomer of PD 128907 bound with high affinity and selectivity to rat D3 dopamine receptors. The Ki values for (+)-PD 128907 were 620 nM at D2, 1 nM at D3 and 720 nM at D4 receptors. 3. (+)-PD 128907 inhibited cell firing in both the ventral tegmental area and substantia nigra pars compacta with EC50 values of 33 nM (pEC50 = 7.48 +/- 0.10, n = 10) and 38 nM (pEC50 = 7.42 +/- 0.15, n = 5), respectively. No effects of (+)-PD 128907 (100 nM) were observed on glutamate or GABA-mediated synaptic potentials elicited by focal bipolar stimulation. 4. L-741,626 antagonized these effects of (+)-PD 128907 in a concentration-dependent and surmountable manner with an affinity, determined from Schild analysis, of 20 nM (pKB = 7.71 +/- 0.14) in the ventral tegmental area and 11 nM (pKB = 7.95 +/- 0.18) in the substantia nigra pars compacta. 5. (+)-PD 128907 also inhibited dopamine release in the caudate-putamen with an EC50 of 66 nM (n = 5). The affinity of L-741,626 for these nerve terminal autoreceptors (pKB = 7.71 +/- 0.06; = 20 nM) was identical to that observed on midbrain dopamine neurones. 6. These data demonstrate that the D3 receptor ligand (+)-PD 128907 is a potent agonist on rat midbrain dopamine neurones. However, its lack of regional selectivity, and the high affinity of the selective D2 receptor antagonist L-741,626 for receptors activated by (+)-PD 128907, was more consistent with an action on D2 autoreceptors rather than upon a D3 dopamine receptor subtype.