GABAA and μ-opioid receptor binding in the globus pallidus and entopeduncular nucleus of animals symptomatic for and recovered from experimental Parkinsonism

The expression of parkinsonian motor symptoms may be partly attributed to an increase in GABAergic neurotransmission from hyperactive GABA/enkephalinergic striatopallidal efferents. The present study measured pallidal GABA(A) and mu-opioid receptor binding in normal cats and cats symptomatic for and recovered from MPTP-induced parkinsonism. GABA(A) receptor binding was significantly decreased in the globus pallidus (GP) in symptomatic cats and returned to normal levels in spontaneously recovered cats. Mu-opioid receptor binding in the GP was significantly decreased in symptomatic cats and remained significantly decreased in recovered cats. These results suggest that GABA(A) but not mu-opioid receptor binding may correlate with the expression of parkinsonian motor deficits and may reflect increased pallidal GABA and ENK release in parkinsonian animals. Upon recovery from experimental parkinsonism, however, pallidal GABA(A) receptor binding returns to normal levels while mu-opioid receptor binding reflecting enkephalin release remains elevated.     

GABA(A) and mu-opioid receptor binding in the globus pallidus and endopeduncular nucleus of animals symptomatic for and recovered from experimental Parkinsonism

The expression of parkinsonian motor symptoms may be partly attributed to an increase in GABAergic neurotransmission from hyperactive GABA/enkephalinergic striatopallidal efferents. The present study measured pallidal GABA_A and μ-opioid receptor binding in normal cats and cats symptomatic for and recovered from MPTP-induced parkinsonism. GABA_A receptor binding was significantly decreased in the globus pallidus (GP) in symptomatic cats and returned to normal levels in spontaneously recovered cats. Mu-opioid receptor binding in the GP was significantly decreased in symptomatic cats and remained significantly decreased in recovered cats. These results suggest that GABA_A but not μ-opioid receptor binding may correlate with the expression of parkinsonian motor deficits and may reflect increased pallidal GABA and ENK release in parkinsonian animals. Upon recovery from experimental parkinsonism, however, pallidal GABA_A receptor binding returns to normal levels while μ-opioid receptor binding reflecting enkephalin release remains elevated.     

Striatal preprotachykinin gene expression reflects parkinsonian signs

Striatal preprotachykinin (PPT) gene expression was measured in MPTP-treated cats when symptomatic and during various stages of recovery from parkinsonism using in situ hybridization histochemistry. Animals expressing severe (1 week post-MPTP) or moderate (3 weeks post-MPTP) parkinsonian sensorimotor deficits had significantly reduced striatal PPT mRNA expression. In contrast, fully recovered animals (6 weeks post-MPTP) had striatal PPT mRNA levels that were not significantly different from normal. Thus, PPT gene expression in the striatum appears to reflect presence or absence of sensorimotor deficits in MPTP-treated cats.     

Alterations in expression of messenger RNAs encoding two isoforms of glutamic acid decarboxylase in the globus pallidus and entopeduncular nucleus in animals symptomatic for and recovered from experimental Parkinsonism

Glutamic acid decarboxylase (GAD65, GAD67) mRNA expression was measured in the globus pallidus (GP) and entopeduncular nucleus (ENTO) of normal, and MPTP-lesioned cats symptomatic for and recovered from MPTP-induced Parkinsonism. In the ENTO of symptomatic cats, GAD65 and GAD67 mRNA expression were both significantly increased, while only GAD67 gene expression was increased in the GP. Levels of gene expression for both isoforms were normal in the GP and ENTO of spontaneously recovered animals. Increased expression of GAD65/67 mRNA in the ENTO corresponded with expression of Parkinsonian signs, suggesting a contribution of both isoforms to ENTO functioning and perhaps a greater contribution of GAD67 expression to GP functioning.     

Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: potential contributors to spontaneous recovery from experimental Parkinsonism

1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-exposed cats develop severe Parkinsonism that spontaneously resolves in 4-6 weeks. The present study examined the extent to which compensatory changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene and protein expression may underlie this behavioral recovery. In normal cats, TH and DAT protein levels were higher in the dorsal vs. ventral striatum. Expression of DAT and TH mRNA was higher in substantia nigra pars compacta (SNc) than in the ventral tegmental area (VTA). In symptomatic parkinsonian animals, DAT and TH protein levels were significantly decreased in all striatal areas studied. TH and DAT mRNA expression in residual SNc neurons were decreased a mean 32% and 38%, respectively. DAT gene expression in residual VTA neurons in symptomatic animals was decreased 30% whereas TH gene expression was unaffected. In spontaneously recovered cats, TH protein levels were significantly higher than the levels in symptomatic cats only in the ventral striatum, whereas no increase in DAT protein levels were observed in any striatal area. Residual neurons in most ventral mesencephalic regions of recovered cats had increased TH mRNA expression but not increased DAT gene expression, compared with symptomatic animals. Thus, increased TH protein and mRNA and suppression of DAT protein and mRNA expression in the striatum and ventral mesencephalon were associated with functional recovery from MPTP-induced parkinsonism.     

Striatal enkephalin gene expression does not reflect parkinsonian signs

Loss of striatal dopamine has been associated with an increase in striatal enkephalin expression. However, the relationship between increased striatal enkephalin expression and the manifestation of parkinsonian motor deficits is not clear. Administration of MPTP to cats produces a severe parkinsonian condition from which the animals spontaneously recover. Using in situ hybridization histochemistry, preproenkephalin (PPE) mRNA expression was examined in the striatum of cats when normal, symptomatic for or spontaneously recovered from MPTP-induced parkinsonism. In all areas of the striatum, PPE mRNA levels were significantly elevated in animals exhibiting severe parkinsonian motor deficits and remained elevated even after recovery of gross motor functioning. These results show that striatal PPE gene expression and parkinsonian motor deficits are not directly correlated.     

Changes in striatal dopamine D2 receptors in relation to expression of and recovery from experimental parkinsonism

Changes in dopamine D₂ receptor number in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cats during various stages of experimental parkinsonism were examined. In the normal adult cat, D₂ receptors were expressed throughout the striatum. In symptomatic cats (assessed 7 days after the last MPTP administration), there was a slight elevation of D₂ receptors in all striatal regions. At 2 weeks after MPTP (animals still grossly symptomatic), D₂ receptor number was increased 60–75% above normal. At 3 weeks after MPTP (partial functional recovery), D₂ receptor number remained elevated at a level slightly less than that observed at 2 weeks. At 6 weeks after MPTP (full functional recovery), D₂ receptor levels were back to normal. Changes in D₂ receptor mRNA expression in the striatum essentially mirrored the changes in receptor number. Increases in D₂ receptor number and mRNA expression did not coincide with the onset of parkinsonian signs and peaked after the parkinsonism was established. Permanent reduction of parkinsonian signs corresponded to normalization of D₂ receptor number.     

Alterations in dopamine uptake sites and D1 and D2 receptors in cats symptomatic for and recovered from experimental parkinsonism

The administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult cats severely disrupts the dopaminergic innervation of the striatum. Animals display a parkinson-like syndrome, consisting of akinesia, bradykinesia, postural instability, and rigidity, which spontaneously recovers by 4–6 weeks after the last administration of MPTP. In this study we used quantitative receptor autoradiography to examine changes in DA uptake sites and DA receptors in the basal ganglia of normal, and symptomatic and recovered MPTP-treated cats. Consistent with the destruction of the nigrostriatal DA pathway, there was a severe loss of DA uptake sites, labeled with [³H]-mazindol, in the caudate nucleus (64–82%), nucleus accumbens (44%), putamen (63%), and substantia nigra pars compacta (SNc, 53%) of symptomatic cats. Following behavioral recovery, there were no significant changes in DA uptake site density. Significant increases of [³H]-SCH 23390 binding to D1 DA receptors were observed in the dorsal caudate (>24%; P < 0.05) of symptomatic cats and in all regions of the caudate-putamen (>30%; P < 0.05) of recovered animals. [³H]-SCH 23390 binding in tree substantia nigra pars reticulata was half of that in the striatum and showed no changes in symptomatic or recovered animals. No alterations in the binding of [¹²⁵1]-epidepride to D2 receptors was observed in any region of the striatum in either, symptomatic or recovered animals. [¹²⁵1]-Epidepride binding in the SNc was decreased by >36% (P < 0.05) following MPTP treatment. These data show that cats made parkinsonian by MPTP exposure have a significant decrease in the number of DA reuptake sites throughout the striatum and that recovery of sensorimotor function in these animals is not correlated with an increase in the number of striatal reuptake sites. Behavioral recovery, however, does seem to be correlated with a general elevation of Dl receptors throughout the striatal complex. The present data also show that direct correlations between changes in DA receptor regulation after a large DA depleting lesion and behavioral deficits or recovery from those deficits are difficult and that the relationships between DA receptors/transporters and behavior require further study. © 1995 Wiley-Liss, Inc.     

Spontaneous functional recovery from parkinsonism is not due to reinnervation of the dorsal striatum by residual dopaminergic neurons

Cats exposed to MPTP experience severe motor deficits that spontaneously recover after 4–6 weeks. This recovery occurs despite a persistent deficit (approximately 95%) in dorsal striatal DA levels. To determine whether residual DA neurons that previously did not innervate the dorsal caudate nucleus (CD) have innervated this area in recovered MPTP-treated animals, HRP was injected into the dorsal lateral and dorsal medial CD and the locations of retrogradely labeled neurons in ventral mesencephalon were mapped in normal and recovered MPTP-treated cats. Tyrosine hydroxylase (TH) positive cells were also counted in ventral mesencephalic DA-containing cell groups in normal, symptomatic, and recovered MPTP-treated cats. Results showed no difference in the pattern of HRP labeling in normal and recovered cats except for the loss of labeled substantia-nigra pars compacta (SNc) cells in MPTP-treated cats. Cell counts revealed no significant difference in the degree of TH-positive cell loss in all ventral mesencephalic areas studied in both symptomatic and recovered cats. The results suggest that spontaneous recovery of gross motor function in MPTP-treated cats is most likely not dependent upon reinnervation of the dorsal striatum from residual DAergic neurons.     

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.     

Differential expression of dopamine D2 and D4 receptor and tyrosine hydroxylase mRNA in mice prone, or resistant, to chronic high-fat diet-induced obesity

The present study examined brain dopamine D2 and D4 receptor and tyrosine hydroxylase (TH) mRNA expression in chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Twenty-eight mice were fed a high-fat diet (HF: 40% of calories from fat) for 6 weeks and then classified as cDIO (n = 8) or cDR (n = 8) mice according to the highest and lowest body weight gainers, respectively. Seven mice were fed a low-fat diet (LF: 10% of calories from fat) and used as controls. After 20 weeks of feeding, visceral fat per gram of initial body weight was significantly higher in the cDIO group (ratio: 0.25, 0.09, and 0.04; P < 0.01 cDIO vs. cDR and LF, respectively). Using quantitative in situ hybridization techniques, the levels of D2 and D4 receptor and tyrosine hydroxylase (TH) mRNAs were measured in multiple brain sections. The cDIO mice had a significantly higher level of D2 receptor mRNA expression in the core of the nucleus accumbens (AcbC, +16%) and ventral parts of caudate putamen (CPu, 21% and 24%) compared to the cDR and LF mice. The levels of D2 receptor mRNA expression in the AcbC and ventromedial part of the CPu were positively related to the final body weight. This study is the first to systematically examine the D4 mRNA expression in the mouse brain using in situ hybridization method. D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60%; P < 0.05). TH mRNA expression was significantly higher in the ventral tegmental area (+17%, P 相似文献   

Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments

The mesolimbic dopaminergic system is a neuroanatomical key structure for reward and motivation upon which previous studies indicated that antidepressant drugs exert a stimulatory influence, via still unknown neurobiological mechanisms. Here we examined the effects of chronic administration of antidepressants of several classes (amitriptyline, desipramine, imipramine, fluoxetine and tranylcypromine) and repeated electroconvulsive shock treatments (ECT) on dopamine D3 receptor expression in the shell of the nucleus accumbens, a major projection area of the mesolimbic dopaminergic system. Short-term drug treatments had variable effects on D3 receptor mRNA expression. In contrast, treatments for 21 days (with all drugs except fluoxetine) significantly increased D3 receptor mRNA expression in the shell of nucleus accumbens; D3 receptor binding was also significantly increased by amitriptyline or fluoxetine after a 42-day treatment. ECT for 10 days increased D3 receptor mRNA and binding in the shell of nucleus accumbens. D1 receptor and D2 receptor mRNAs were increased by imipramine and amitriptyline, but not by the other treatments. The time-course of altered D3 receptor expression, in line with the delayed clinical efficiency of antidepressant treatment, and the fact that various antidepressant drugs and ECT treatments eventually produced the same effects, suggest that increased expression of the D3 receptor in the shell of nucleus accumbens is a common neurobiological mechanism of antidepressant treatments, resulting in enhanced responsiveness to the mesolimbic dopaminergic system.     

Loss of D3 receptors in the zitter mutant rat is not reversed by L-dopa treatment

In Parkinson's disease (PD) and animal models of parkinsonism the destruction of nigrostriatal (NSB) system results in a marked loss of the dopamine D(3) receptor and mRNA in the islands of Calleja (ICj) and the nucleus accumbens shell (NAS). In animal models, it has been reported that both measures are elevated by repeated intermittent administration of L-dopa. However, a large proportion of PD cases are resistant to L-dopa-induced elevation of D(3) receptor number. The zitter mutant (Zi/Zi) rat replicates the slow progressive degeneration of the NSB observed in PD and also exhibits a loss of D(3) receptor number in the NAS or ICj. To test if this could be reversed with subchronic L-dopa treatment, injections of carbidopa (10 mg/kg i.p.) were followed an hour later with injection of L-dopa (100 mg/kg i.p.) twice a day for 10 days. In control Sprague-Dawley (SD) and zitter heterozygote (Zi/-) rats that do not show a loss of D(3) receptors with vehicle treatment, L-dopa produced no change in D(3) receptor number or in DA terminal density as measured by dopamine transporter (DAT) binding and tyrosine hydroxylase immunoautoradiography (TH-IR). There was a marked loss of DAT and TH-IR in caudate-putamen (CPu) and NA, as well as D(3) receptors in NAS and ICj in Zi/Zi rats but no further change with L-dopa treatment. To determine if the resistance to L-dopa-induced increase in D(3) receptor was due to a deficiency in expression of cortical BDNF or its receptor, TrkB, in CPu and NAS, we examined BDNF mRNA by ISHH in frontal cortex and TrkB mRNA in frontal cortex, CPu, and NA. The loss of the NSB in the Zi/Zi did not alter levels of BDNF or TrkB mRNA, nor did L-dopa administration alter levels BDNF or TrkB mRNA. Thus, unlike in 6-hydroxydopamine-treated rats, in Zi/Zi rats administered L-dopa does not reverse the loss of BDNF mRNA or lead to an elevation of D(3) receptor number.     

Dysfunction of the cortico-basal ganglia-cortical loop in a rat model of early parkinsonism is reversed by metabotropic glutamate receptor 5 antagonism

This study examined the cellular correlates of the akinetic deficits produced in Wistar rats by discrete bilateral 6-hydroxydopamine (6-OHDA) striatal infusions in the dorsolateral striatum, mimicking the preferential denervation of the motor striatal territory in early symptomatic stage of Parkinson's disease (PD). Intraneuronal gene expression of cytochrome oxidase subunit I (COI), a metabolic index of neuronal activity, was increased in the subthalamic nucleus, substantia nigra pars reticulata and decreased in frontal cortical areas, but paradoxically unchanged in the striatum, globus pallidus, entopeduncular nucleus and ventrolateral thalamic nucleus. Neither preproenkephalin A nor preprotachykinin mRNA expression, markers of striatal projection neurons, were modified in the denervated striatal area despite 90% loss of dopamine (DA) terminals. Preproenkephalin A mRNA expression was however, decreased in the nondepleted striatal region, suggesting compensatory increase of dopamine tone from those spared areas. A chronic treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), which alleviated the akinetic disorders produced by the lesion, reversed the lesion-induced variations of COI gene expression, moderately increased this marker in the structures unaffected by the lesion and did not modify the striatal neuropeptides gene expression. These data suggest that the expression of akinetic deficits in early parkinsonism is associated with focused metabolic changes in the cortico-basal ganglia-cortical loop downstream of the striatum and pallidal complex.     

Involvement of 5-HT1B receptors within the ventral tegmental area in ethanol-induced increases in mesolimbic dopaminergic transmission

Evidence suggests that 5-hydroxytriptamine-1B (5-HT1B) receptors play a role in modifying ethanol's reinforcing effects and voluntary intake, and that 5-HT1B receptors within the ventral tegmental area (VTA) are involved in regulation of mesolimbic dopaminergic neuronal activity. Since increased mesolimbic dopaminergic transmission has been implicated in ethanol's reinforcing properties, this study was designed to assess the involvement of VTA 5-HT1B receptors in mediating the stimulatory effects of ethanol on VTA dopaminergic neurons. Dual-probe microdialysis was performed in freely moving adult Sprague-Dawley rats with one probe within the VTA and the other within the ipsilateral nucleus accumbens (NACC). Dopamine (DA) levels in dialysates from both areas, as the index of the activity of mesolimbic DA neurons, were measured simultaneously. The results showed that intraperitoneal injection of ethanol at the doses of 1 and 2 g/kg increased extracellular DA concentrations in both the VTA and the NACC, suggesting increased DA neuronal activity. These ethanol-induced increases of the DA release in the VTA and the NACC were significantly attenuated by intra-tegmental infusion of SB 216641 (a 5-HT(1B) receptor antagonist), but not BRL 15572 (a 5-HT(1D/1A) receptor antagonist) or WAY 100635 (a 5-HT1A receptor antagonist). Administration of ethanol at the same doses did not significantly alter extracellular levels of GABA in the VTA. The results also showed that intra-tegmental infusion of CP 94253, a 5-HT1B receptor agonist, significantly prolonged the effects of ethanol on NACC DA. The results suggest that blockade and activation of VTA 5-HT1B receptors attenuates and potentiates the neurochemical effects of ethanol, respectively, and support the suggestion that VTA 5-HT(1B) receptors may be involved in part in mediating the activating effects of ethanol on mesolimbic DA neurons.     

Nandrolone decanoate administration dose-dependently affects the density of kappa opioid peptide receptors in the rat brain determined by autoradiography

The kappa opioid receptor ligand [³H]CI-977 was used to autoradiographically determine the density of kappa opioid receptors in the male rat brain following chronic treatment with the anabolic androgenic steroid nandrolone decanoate at two different doses. As compared to controls, significantly lower densities of the kappa opioid receptor were encountered after two weeks of high dose nandrolone decanoate (15 mg/kg) in the nucleus accumbens shell (16%), lateral hypothalamic area (36%), ventromedial hypothalamic nucleus (37%), dorsomedial hypothalamic nucleus (49%), central amygdaloid nucleus, capsular part (28%), lateral globus pallidus (35%) and in the stria terminalis (24%). Furthermore, an up-regulation of the receptor level was observed in the caudate putamen (18%) and in the dorsal endopiriform nucleus (23%). These alterations in the kappa opioid receptor expression are possibly attributed to a previously observed pronounced impact of nandrolone decanoate on the dynorphinergic system and could also include involvement of the dopaminergic reward system.     

Enhanced accumbal dopamine release following 5-HT2A receptor stimulation in rats pretreated with intermittent cocaine

This study was conducted to determine whether dopamine (DA) release in the nucleus accumbens (NACC) following 5-HT_2A receptor stimulation is potentiated by intermittent cocaine. Rats received daily injections of either saline or cocaine (30 mg/kg, s.c.) for 14 days. At the 7th day after withdrawal, microdialysis was performed in the NACC. Infusion of (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 50 μM), a 5-HT₂ receptor agonist, into the NACC produced greater and longer-lasting increases in extracellular DA in the rats pretreated with cocaine than in the rats pretreated with saline. The DOI-induced increases in NACC DA were attenuated by co-perfusion with ketanserin (50 μM), a 5-HT_2A receptor antagonist. The results are consistent with the concept that intermittent cocaine may cause enhanced sensitivity of 5-HT_2A receptors within the NACC.     

Implication of the GABA(B) receptor in gamma vinyl-GABA's inhibition of cocaine-induced increases in nucleus accumbens dopamine

Previously, we demonstrated that gamma vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-induced increases in dopamine (DA) concentrations in both the rodent and primate brain. Furthermore, it abolishes cocaine self-administration and conditioned place preference, while having no effect on locomotor activity or drug delivery to the brain. In an effort to better understand the mechanisms underlying this inhibition, we examined the effect of the selective GABA(B) receptor antagonist SCH 50911 on the GVG-induced decrease in cocaine's elevation of extracellular DA concentrations in the nucleus accumbens (NACC). Cocaine administration alone (20 mg/kg i.p.) produced a 480% increase in extracellular NACC DA levels. GVG (300 mg/kg i.p.) significantly reduced this increase by 25% (P<0.01). In sharp contrast, extracellular DA levels increased to 550% after the sequential administration of SCH 50911 (3 mg/kg i.p.), GVG, and cocaine. This increase is significantly different than GVG and cocaine (P<0.05) but similar to cocaine alone. These results demonstrate that the GABA(B) antagonist SCH 50911 was able to completely abolish GVG's inhibition of cocaine-induced increases in DA in the NACC and implicates the GABA(B) receptor in the mechanism underlying this inhibition.