Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q.

Dopa-responsive dystonia (DRD) is an autosomal-dominant neurological disorder which appears to result from a genetically determined deficiency of striatal dopamine. Pathological evidence suggests that this may be due to the establishment of a reduced number of dopaminergic nerve terminals in the striatum, or to an excessive reduction (pruning) of these terminals in early development. We have mapped the DRD gene to chromosome 14 by linkage analysis in 3 families with a maximum 2-point lod score of 4.67 at 8.6 centiMorgans from D14S63; maximum multipoint lod scores > 6 were obtained for the intervals D14S47-D14S52 and D14S52-D14S63. The flanking loci D14S47 and D14S63 define a region of about 22 cM as containing the DRD gene.

Distribution of D1 and D2 dopamine receptors in the basal ganglia of the cat determined by quantitative autoradiography.

The patterns of dopamine D1 and D2 receptors were examined in the corpus striatum and related structures in the cat brain by quantitative autoradiography after in vitro radioligand binding with [3H]SCH23390 (D1 antagonist) and [3H]spiperone (D2 antagonist). Highly specific binding for both radioligands occurs in striatal structures known to receive dopaminergic input: the caudate nucleus, putamen, nucleus accumbens, and olfactory tubercle. However, the density of binding varies from one structure to another, and the density distribution within striatal nuclei is heterogeneous. In all but one portion of the striatum, the concentration of bound D1 radioligand ranges from 46 to 230% more than that of the D2 radioligand. The exception to this difference occurs at caudal putamenal levels where the two radioligands bind in equal concentrations (approximately equal to 220 fmol/mg tissue wet-weight). The highest density of both D1 and D2 radioligand binding occurs in irregular zones in the head and body of the caudate nucleus. Such high-density zones of D2 radioligand binding appear mainly in the dorsolateral part of the caudate's head. For the D1 radioligand, the high-density zones are more widespread throughout the caudate nucleus, nucleus accumbens, and putamen. The D2 radioligand binding (but not the D1) also exhibits low-density zones at more caudal levels of the caudate nucleus, and these are often in register with the high-density zones of D1 radioligand binding. In the putamen, inverted concentration gradients exist for the two radioligands: the [3H]SCH23390 gradient runs from higher levels rostrally to lower levels caudally. The lowest levels of bound [3H]spiperone in the striatum occur in the nucleus accumbens-olfactory tubercle area, whereas the lowest binding of [3H]SCH23390 occurs in the caudal putamen. Pallidal and nigral structures show marked disparities in binding of the two different radioligands. The D2 radioligand binding in the globus pallidus (80 +/- 8 fmol/mg tissue wet-weight) is about twice that in the entopedunuclear nucleus and pars reticulata of the substantia nigra, the latter two having equal levels (35 +/- 3 fmol/mg). No specific binding of the D2 radioligand occurs in the ventral pallidum. In contrast, D1 radioligand binding is highest in the entopeduncular nucleus (217 +/- 6 fmol/mg) and in the pars reticulata of the substantia nigra (198 +/- 2 fmol/mg) and moderate in the ventral pallidum (135 +/- 15 fmol/mg). In the globus pallidus, no detectable D1 radioligand binding occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease.

BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.

Clinical correlates of sleep benefit in Parkinson's disease.

The phenomenon of sleep benefit, a period of lessened disability or feeling "on" upon awakening from sleep in the morning, has received scant attention in the literature on Parkinson's disease. We interviewed 162 consecutive patients regarding disease onset, medication history, and symptoms, evaluated them using the Unified Parkinson's Disease Rating Scale, and assessed them as to the presence or absence of sleep benefit. Thirty-three percent reported experiencing sleep benefit. Compared with patients not having sleep benefit, patients with sleep benefit tended to be younger at disease onset, have longer disease duration, take higher total daily doses of levodopa, have longer duration of levodopa treatment, and exhibit less cognitive and physical disability. The findings of this study suggest that sleep benefit is a common phenomenon that may be anticipated in a subgroup of patients with Parkinson's disease. The mechanisms underlying sleep benefit do not appear to be simple and may be multifactorial. Clinicians need to be aware of the authenticity of patients' reports of sleep benefit and consider the existence of this phenomenon when prescribing or adjusting patients' medication schedules.

Early morning dystonia in Parkinson's disease.

We interviewed 383 patients with PD regarding disease onset and medication history and evaluated them using the Unified Parkinson's Disease Rating Scale. Sixteen percent of the sample reported the occurrence of early morning dystonia (EMD). Patients with EMD had been taking levodopa for a longer time, were taking higher daily levodopa doses, demonstrated more disability in carrying out their activities of daily living, exhibited dystonia more often before initiation of levodopa treatment, and experienced more peak-dose and diphasic dyskinesias with levodopa therapy.

Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family.

We examined 106 members of a family affected with dopa-responsive dystonia (DRD), a subset of idiopathic dystonia. Ten members had unequivocal dystonia; 8 of these had generalized dystonia and the other 2 had focal dystonias (writer's cramp and spastic dysphonia). Twenty members had lesser dystonic signs and symptoms suggestive of a diagnosis of dystonia. Five members, including 1 with dystonia, had prominent parkinsonism that became symptomatic in late adulthood. All members affected with dystonia or parkinsonism had increased muscle tone (rigidity), which may represent the minimal clinical expression of DRD. Gene penetrance in families with DRD may be greater than previously suspected.

Oral phenylalanine loading in dopa-responsive dystonia: a possible diagnostic test.

To determine if there is abnormal phenylalanine and biopterin metabolism in patients with dopa-responsive dystonia (DRD), we measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1, 2, 4, and 6 hours after an oral phenylalanine load (100 mg/kg). Seven adults with DRD, two severely affected children with DRD, and nine adult controls were studied. All patients had phenylalanine and tyrosine concentrations within the normal range at baseline. In the adult patients, phenylalanine levels were higher than in controls at 2, 4, and 6 hours post-load (p < 0.0005); tyrosine concentrations were lower than control levels at 1, 2, and 4 hours post-load (p < 0.05). Phenylalanine to tyrosine ratios were elevated in patients at all times post-load (p < 0.0005). Biopterin levels in the patients were decreased at baseline and 1, 2, and 4 hours post-load (p < 0.005). Pretreatment with tetrahydrobiopterin (7.5 mg/kg) normalized phenylalanine and tyrosine profiles in two adult patients. In the children with DRD, phenylalanine to tyrosine ratios were slightly elevated at baseline. Following phenylalanine loading, the phenylalanine profiles were similar to those seen in the adult patients but there was no elevation in plasma tyrosine. Baseline biopterin levels were lower in the children with DRD than in the adult patients or the controls and there was no increase in biopterin post-load. In both the children and adults with DRD, neopterin concentrations did not differ from control values at baseline or after phenylalanine load. The results are consistent with decreased liver phenylalanine hydroxylase activity due to defective synthesis of tetrahydrobiopterin in patients with DRD. The findings show that a phenylalanine load may be useful in the diagnosis of this disorder.

Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia.

We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.

The dopamine agonist, PHNO ((+)-4-propyl-9-hydroxynaphthoxazine), inhibits cyclic adenosine 3',5'-monophosphate formation and prolactin release from anterior pituitary cells.

In cultured rat anterior pituitary cells incubated for 30-180 min, PHNO caused a concentration-dependent inhibition of prolactin release (IC50 approximately 0.5 nM) with maximal suppression at 5 nM. Forskolin increased cyclic adenosine 3',5'-monophosphate (cAMP) generation by stimulating adenylate cyclase and PHNO inhibited this effect with the same concentration profile as for inhibition of prolactin release. Inhibitory effects of 0.5 nM PHNO on prolactin release and cAMP generation were abolished by coincubation with 10 nM haloperidol, a D2 dopamine receptor antagonist. Within 30 min, 0.5 nM PHNO blunted the stimulation of prolactin release due to 10 nM thyrotropin-releasing hormone (TRH) or angiotensin II (AII). Thus, PHNO appears to activate the D2 dopamine receptor to inhibit the formation of cAMP and the secretion of prolactin.

The effects of L-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra.

Using [14C]2-deoxyglucose autoradiography, we have studied the effects of systemically administered L-DOPA (10, 25 and 50 mg/kg s.c.) on regional cerebral glucose utilization (RCGU) in rats with unilateral substantia nigra lesions. In comparison with lesioned rats treated with saline, the lesioned-DOPA treated rats demonstrated contralateral turning and RCGU changes in both ipsilateral and contralateral brain regions. L-DOPA treatment markedly increased RCGU in the ipsilateral entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), cell groups that receive direct striatal input and function as major outflow pathways of corpus striatal activity. In contrast, L-DOPA did not alter RCGU in the globus pallidus (GP), supporting the thesis that dopamine (DA) has different effects on striatal outflow to the GP compared with outflow to both the EP and SNr. Moderate RCGU increases were observed in the ipsilateral subthalamic nucleus (STN), lateral midbrain reticular formation (LMRF), and deep layers of the superior colliculus (DLSC), all regions which receive direct projections from the GP, EP or SNr. L-DOPA decreased RCGU in the ipsilateral lateral habenular nucleus (LHN) and increased RCGU in the contralateral LHN, changes that we suggest are mediated via altered neuronal activity in the striatum and EP. The results suggest that systemically administered L-DOPA, after conversion to DA in the brain, interacts with supersensitive DA receptors in the DA-depleted striatum to selectively activate efferent pathways. Furthermore, the data suggest that the LMRF and DLSC are functionally activated during L-DOPA induced turning and support the hypothesis that nigroreticular and nigrocollicular projections are of physiologic significance in the expression of striatal activity.

D1 dopamine agonist and antagonist effects on regional cerebral glucose utilization in rats with intact dopaminergic innervation.

The effects of stimulation and blockade of the D1 dopamine receptor on regional cerebral glucose utilization (RCGU) were studied using quantitative [14C]2-deoxyglucose autoradiography in naive rats. Systemic administration of the selective D1 antagonist, SCH 23390 (0.5 mg/kg), lowered glucose utilization by 24-28% in the globus pallidus, entopeduncular nucleus, subthalamic nucleus, substantia nigra pars reticulata (SNr), and motor cortex, suggesting that stimulation of the D1 receptor by endogenous dopamine contributes to basal metabolism in these regions. Administration of SCH 23390 increased RCGU in the lateral habenula, as do selective D2 antagonists. The selective D1 agonist, SKF 38393 (30 mg/kg), increased RCGU in the SNr (up 22%) without affecting the other brain regions which were examined. This modest increase contrasts with the large increase in RCGU (up 100-200%) in the SNr elicited by similar doses of SKF 38393 in rats with acute or chronic dopamine depletion. Systemic administration of amphetamine (5.0 mg/kg), a dopamine releasing agent, increased RCGU in the caudate-putamen (up 33%), globus pallidus (up 23%), subthalamic nucleus (up 46%), entopeduncular nucleus (up 78%), and SNr (up 72%) and lowered RCGU in the lateral habenula (down 43%). All of these amphetamine effects were blocked by pretreatment with either SCH 23390 (0.5 mg/kg) or eticlopride (2.0 mg/kg, a selective D2 antagonist). These results suggest that endogenous dopamine stimulates both D1 and D2 receptors in vivo and provide metabolic evidence to support the concept of a functional linkage of D1 and D2 receptor systems in animals with intact dopaminergic innervation.

Dose-related effects of continuous levodopa infusion in rats with unilateral lesions of the substantia nigra.

Preclinical studies in rats have demonstrated markedly different effects of intermittent and continuous levodopa administration on many biochemical and functional parameters yet the dose regimens employed have not been fully evaluated. In this study, rats with unilateral 6-hydroxydopamine nigral lesions were administered levodopa (0-1200 mg/kg/day) and benserazide (25 mg/kg/day) subcutaneously via osmotic minipump and studied 20-22 h later for rotational behavior, striatal dopamine concentration, and regional cerebral glucose utilization (RCGU). Levodopa infusion at 100 mg/kg/day resulted in minimal rotation and minimal striatal dopamine replacement but did increase RCGU in the subthalamic nucleus and decrease RCGU in the lateral habenula, consistent with a selective inhibition of the striatopallidal GABAergic (indirect striatal output) pathway. Levodopa infusion at 100 mg/kg/day did not significantly increase RCGU in the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), as does the acute injection of levodopa (25-50 mg/kg), indicating that this levodopa dose elicits only part of the spectrum of metabolic effects elicited by acute levodopa injection. Higher doses of levodopa (400-1200 mg/kg/day) resulted in moderate rates of rotation, dose-dependent increases in striatal dopamine, and increased RCGU in the EP and SNr, consistent with activation of the striatonigral GABAergic (direct striatal output) pathway. In the EP and SNr, the two major output nuclei of the basal ganglia, levodopa infusion at 800 and 1200 mg/kg/day reproduced the metabolic effects elicited by acute injection of levodopa. These results demonstrate, for the first time, dose-dependent effects of levodopa on distinct populations of striatal output neurons which may be relevant to the pathogenesis of levodopa-induced dyskinesias in Parkinson's disease. The minimal dopamine replacement and partial functional effects elicited by levodopa infusion at 100 mg/kg/day indicate the need for caution in the interpretation of prior studies of continuous levodopa infusion which employed this dose.

A68930: a potent agonist selective for the dopamine D1 receptor.

A68930, (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent (EC50 = 2.5 nM), partial (intrinsic activity = 66% of dopamine) agonist in the fish retina dopamine-sensitive adenylate cyclase model of the D1 dopamine receptor. In the rat caudate-putamen model of the D1 dopamine receptor, A68930 is a potent (EC50 = 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3920 nM) full agonist in a biochemical model of the dopamine D2 receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the dopamine D1 receptor. A68930 also displays weak alpha 2-agonist activity but the molecule is virtually inactive at the alpha 1- and beta-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (greater than 20 h) contralateral turning that is antagonized by dopamine D1 receptor selective doses of SCH 23390 but not by D2 receptor selective doses of haloperidol. In this lesioned rat model, A68930 increases 2-deoxyglucose accumulation in the lesioned substantia nigra, pars reticulata. When tested in normal rats, A68930 elicits hyperactivity and, at higher doses, produces a forelimb clonus.

D1/D2 actions of dopaminergic drugs studied with [14C]-2-deoxyglucose autoradiography.

1. To define the neural circuits activated by dopaminergic stimulation in rat models of parkinsonism, the author studied the effects of L-dopa and selective D1 and D2 agonists on RCGU in rats with unilateral 6-OHDA substantia nigra lesions. 2. Systemic administration of L-dopa markedly increased RCGU in the EP and SNr ipsilateral to the nigral lesions; it is suggested that this represents metabolic activity primarily in axon terminals of GABAergic striatal projection neurons. These effects were reproduced by selective D1, but not D2, dopamine agonists, and were blocked completely by a D1 antagonist, indicating their critical dependence on D1 stimulation. L-dopa moderately increased RCGU in the STN; this effect was reproduced by D1 and D2 agonists and was blocked completely only by combined D1 and D2 antagonist pretreatment. 3. The RCGU data support a direct stimulatory action of dopamine, formed from L-dopa, on D1 receptor-bearing striatal GABAergic neurons projecting to the EP and SNr as well as a net stimulatory action on the GP output to the STN. 4. The marked D1-mediated RCGU increase in the SNr ipsilateral to the dopamine depletion contrasts with the modest increase seen on the contralateral side and in naive rats, suggesting that the enhanced RCGU response to D1 stimulation is an index of dopaminergic supersensitivity. The stimulatory effect of the D1 agonist SKF 38393 on RCGU in the SNr is enhanced 6-12 hours after acute dopamine depletion with reserpine/AMPT indicating that supersensitive responses develop within this rapid time frame. 5. The RCGU data indicate that D1 receptor stimulation contributes importantly, in an anatomically selective manner, to the effects of L-dopa on basal ganglia circuits and that the response to D1 stimulation is rapidly modifiable by dopamine depletion.

Reversal of reserpine-induced catalepsy by selective D1 and D2 dopamine agonists.

To gain insight into the antiparkinsonian effects of selective D1 and D2 dopamine receptor stimulation, we examined the ability of D1 (SKF 38393) and D2 (quinpirole) agonists to reverse catalepsy induced by the combined administration of reserpine and alpha-methyl-p-tyrosine (AMPT) in rats. Catalepsy, the failure to correct an externally imposed posture, is a measure of akinesia and was assessed using the bar test. Rats injected with reserpine alone (2.5 mg/kg i.p.) developed akinesia and ptosis within 60-90 min. The D1 agonist SKF 38393 (30 mg/kg i.v.) rapidly reversed ptosis and restored near-normal mobility when administered 24 h after reserpine and AMPT; catalepsy was reversed for 90 min, after which the drug effect wore off. Quinpirole (1 mg/kg i.v.) reversed catalepsy for the duration of the test period (4 h) but did not consistently reverse ptosis or promote normal mobility; the rats continued to exhibit kyphotic postures with little spontaneous locomotion. These results indicate that selective D1 stimulation is sufficient to reverse reserpine-induced akinesia and highlight the need for the development of potent selective D1 agonists for clinical trial in Parkinson's disease. In severe dopamine depletion, D2 stimulation alone appears to be insufficient to restore normal movement. Quinpirole, but not SKF 38393, elicited paroxysmal limb/body jerking in reserpine-AMPT-treated rats, providing further evidence that atypical jerking can be elicited by D2 stimulation in the complete absence of D1 stimulation. This laboratory observation suggests that some jerking dyskinesias seen in treated parkinsonian patients may be mediated by an imbalance in D1-D2 receptor stimulation.

Rapid development of dopaminergic supersensitivity in reserpine-treated rats demonstrated with 14C-2-deoxyglucose autoradiography.

Dopaminergic denervation supersensitivity has been implicated in the pathogenesis of levodopa-induced dyskinesias, the most common and limiting side effect in the drug treatment of Parkinson's disease, yet the mechanisms that mediate altered drug sensitivity remain poorly understood. In animals models, one key component of denervation supersensitivity is the enhanced efficacy of selective D1 agonists to stimulate locomotion. In rats with chronic dopamine depletion induced by 6-hydroxydopamine nigral lesion, the increased ability of D1 agonists to stimulate regional cerebral glucose utilization (RCGU) in the substantia nigra pars reticulata (SNr) has provided a metabolic correlate to the heightened motor response. In this study, we used the stimulation of RCGU in the SNr as a sensitive in vivo assay of D1 agonist effect to examine the time course of development of supersensitivity in rats following acute dopamine depletion with single doses of reserpine (5.0 mg/kg, i.p.) and alpha-methyl-p-tyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory effect of the D1 agonist SKF 38393 (30 mg/kg) on RCGU in the SNr was first enhanced 6 hr after reserpine/AMPT injection and was maximally enhanced at 12-24 hr (relative 2-deoxyglucose uptake increased 32-51%; P less than 0.05). The response to SKF 38393 returned to control values 5 d after reserpine/AMPT injection. The single reserpine/AMPT injections depleted striatal dopamine to 1-2% of control values from 3-48 hr postinjection, whereas D1 and D2 dopamine receptor densities were unchanged at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions.

The relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration of SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not.(ABSTRACT TRUNCATED AT 250 WORDS)

D1/D2 dopamine receptor stimulation by L-dopa. A [14C]-2-deoxyglucose autoradiographic study.

In rats with unilateral 6-hydroxydopamine substantia nigra lesions, the effects of selective D1 and D2 dopamine receptor antagonists on L-DOPA-induced rotation and regional cerebral glucose utilization (RCGU) changes were examined. Contralateral rotation induced by L-DOPA (25 mg/kg) was effectively blocked by D1 (SCH 23390, 1.0 mg/kg) and D2 (eticlopride, 2.0 mg/kg) antagonists, in combination, but not by either antagonist alone. This suggests that in the dopamine-depleted rat, L-DOPA administration results in the stimulation of both D1 and D2 receptor systems, each capable of independently eliciting a full motor response, L-DOPA altered RCGU in the following brain regions ipsilateral to the lesion: entopeduncular nucleus (EP, + 105%), substantia nigra pars reticulata (SNr, + 121%), subthalamic nucleus (STN, + 32%), deep layers of the superior colliculus (DLSC, + 35%), and lateral habenula nucleus (LHN, -52%). The effects in the EP and SNr were blocked completely by D1 antagonist pretreatment but only partially attenuated by D2 antagonist pretreatment, indicating the critical dependence of these changes on D1 stimulation. In contrast, combined D1 and D2 antagonist pretreatment, but neither drug alone, blocked the L-DOPA-induced increases in the STN and DLSC. The effects of L-DOPA in the LHN were attenuated by either SCH 23390 or eticlopride, and blocked completely by the antagonist combination. These results provide evidence that dopamine formed following the decarboxylation of L-DOPA stimulates both D1 and D2 receptors in vivo and that stimulation of each receptor contributes uniquely to its physiological effects. Neural mechanisms of action of L-DOPA are discussed in the context of these findings.