Different plasticity changes in D1 and D2 receptors in rat striatal subregions following impairment of dopaminergic transmission

The precise topographical changes in striatal D1 and D2 dopamine receptor density that occurred after chronic treatment with haloperidol or SCH 23390 or after 6-hydroxydopamine-induced lesion of the mesostriatal dopaminergic pathway have been studied autoradiographically in the rat. Repeated treatment with SCH 23390 (0.5 mg/kg i.p., 21 days) caused an almost similar increase in [3H]SCH 23390 binding sites in the different striatal subregions whereas lesion of the dopaminergic pathway was ineffective. Subacute administration of haloperidol (2 mg/kg i.p., 18 days) or lesion of dopaminergic afferents provoked an increase in [3H]spiperone binding which was restricted to the ventro- and dorsolateral striatal sectors.     

Enhancement of stereotypy induced by nomifensine in rats during continuous chronic haloperidol treatment

Stereotyped behaviour induced by apomorphine (0.125 mg/kg s.c.) was inhibited in rats treated continuously for 20 months with haloperidol (1.4–1.6 mg/kg/day) while that induced by a higher dose of apomorphine (1.0 mg/kg s.c.) was enhanced. Stereotypy induced by nomifensine (3.125–25.0 mg/kg i.p.) was not inhibited at any dosage level in haloperidol-treated rats, and was enhanced by higher doses of nomifensine. The results indicate that the behavioural effects of endogenously released dopamine may not remain inhibited in rats undergoing chronic neuroleptic treatment.     

Muscarinic antagonists attenuate neurotensin-stimulated accumbens and striatal dopamine metabolism.

The effect of scopolamine and atropine upon the increase in extracellular 3,4-dihydroxyphenylacetic acid induced by central injection of neurotensin was examined in the nucleus accumbens and the striatum of anaesthetized rats using in vivo differential pulse voltammetry with carbon fibre electrodes. Scopolamine (1 and 3 mg/kg, i.p.) and atropine (20 micrograms, i.c.v.) did not alter the 3,4-dihydroxyphenylacetic acid level in the nucleus accumbens or the striatum, measured for 60 min after administration. Neurotensin (10 micrograms, i.c.v.) increased the 3,4-dihydroxyphenylacetic acid peak height in both regions. Pretreatment with scopolamine (1 mg/kg) 15 min before neurotensin injection blocked the increase in extracellular 3,4-dihydroxyphenylacetic acid in the striatum but not in the nucleus accumbens whilst scopolamine (3 mg/kg) partially attenuated the effect of neurotensin in the nucleus accumbens and blocked the increase in 3,4-dihydroxyphenylacetic acid in the striatum. Atropine partially attenuated the effect produced by neurotensin in the nucleus accumbens and blocked the increase in 3,4-dihydroxyphenylacetic acid induced by the peptide in the striatum. However, the increase in extracellular 3,4-dihydroxyphenylacetic acid induced by haloperidol (1 mg/kg, s.c.) was not altered by scopolamine (1 mg/kg) or atropine. Also, the increase in dopamine metabolism in the nucleus accumbens and the striatum after centrally injected haloperidol (10 micrograms, i.c.v.) was not altered by atropine (20 micrograms, i.c.v.). Together, the results demonstrate a functional interaction between muscarinic antagonists and neurotensin on in vivo dopamine metabolism in the nucleus accumbens and the striatum but with a greater effect in the latter region.     

Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor binding.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [3H]spiperone saturation studies showed, as expected, an up-regulation of striatal D2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density (Bmax) but not affinity (KD). Ascorbate treatment, however, had no effect on D2 receptor density or the distribution of [3H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [3H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.     

Irreversible blockade of D2 dopamine receptors by fluphenazine-N-mustard increases glutamic acid decarboxylase mRNA in rat striatum

The influence of dopaminergic activity on the function of GABAergic neurons in striatum was examined by administrating rats the irreversible D₂ dopamine receptor antagonist, fluphenazine-N-mustard (FNM), and determining the level of glutamic acid decarboxylase (GAD) mRNA in striatum. Rats were given either an acute single injection or chronic daily injections of FNM (20 gmmol/kg, i.p.) for 6 days. The level of GAD mRNA in striatum was determined by in situ hybridization histochemistry. The results showed that acute treatment with FNM failed to significantly change striatal GAD mRNA. However, chronic FNM treatment significantly increased in the level of striatal GAD mRNA. These results demonstrate that irreversible blockade of D₂ dopamine receptors increases the expression of GAD mRNA in rat striatum.     

Exogenous GM1 gangliosides induce partial recovery of the nigrostriatal dopaminergic system in MPTP-treated young mice but not in aging mice

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to young (2-3 months) and aging (12 months) C57BL/6 mice (4 x 20 mg/kg, i.p., given 12 h apart) reduced tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in the striatum, and reduced dopamine (DA) concentration to 28% of controls in young, and 16% of controls in aging mouse brain five weeks after administration. Although GM1 ganglioside treatment (30 mg/kg, i.p., daily for 5 weeks) restored striatal dopamine concentration to 74% of the control concentration in young mice, such an apparent recovery was not seen in aging brain. Immunocytochemical analysis also showed marked recovery of TH-IR fibers in the striatum of MPTP-depleted young mice treated with GM1 ganglioside while TH-IR fibers in the striatum of MPTP-depleted aging mice showed no recovery with such treatment. We conclude that treatment of MPTP-depleted young mice with GM1 ganglioside results in partial recovery in the striatal DA system, but such benefits do not extend to aging mice.     

Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum

Striatal glutamatergic inputs are known to participate in the modulation of dopaminergic transmission. Accordingly, the non-competitive N-methyl-D-aspartate receptor antagonists memantine and amantadine increase striatal dopamine levels, the latter being widely used in Parkinson's disease therapy. Based on our previous work revealing increased function of dopamine receptors and dopamine transporter after amantadine treatment, we studied the effects of repeated memantine administration on dopaminergic neurotransmission. On rat striatal membranes, dopamine-stimulated [(35)S]GTPgammaS binding was significantly reduced (20%) after 2 days injection with memantine (20 mg/kg per day, i.p.) but not after longer treatments (4 or 7 days). Evaluation of [(3)H]SCH 23390 and [(3)H]spiperone specific bindings only revealed a significant increase in D1 receptor density after 4 or 7 days treatment. Finally, none of these treatments were found to change the activity of the neuronal dopamine transporter in striatal synaptosomes. This shows that amantadine and memantine differentially affect striatal dopaminergic transmission, which could indicate that these two related aminoadamantanes display distinct pharmacodynamic properties.     

Clozapine prolongs hypotonic immobility in rats with bilateral 6-hydroxydopamine lesions of the striatum

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.     

Preclinical profile of befloxatone, a new reversible MAO-A inhibitor.

Befloxatone, a novel oxazolidinone derivative, is a potent, selective and reversible monoamine oxidase A (MAO-A) inhibitor in vitro (K1A = 1.9-3.6 nM) and ex vivo (ED50 MAO-A = 0.02 mg/kg, p.o.). It does not interact with a large number of receptors, monoamine transporters or other amine oxidases. Binding studies with [3H]-befloxatone in rat brain sections show that it labels with high affinity (Kd = 1.3 nM) a single population of sites with the pharmacological characteristics and regional distribution of MAO-A. In the rat brain, befloxatone (0.75 mg/kg, i.p.) increases tissue levels of monoamines and decreases levels of their deaminated metabolites. Acute administration of befloxatone (0.75 mg/kg, i.p.) induces an increase in extracellular striatal dopamine and cortical norepinephrine but not cortical serotonin levels in the rat. Befloxatone (1 mg/kg, i.p.) potently inhibits the firing rate of serotonergic neurons, partially decreases the firing of noradrenergic neurons and has no effect on the firing of dopaminergic neurons (a mirror image of its effects on monoamine release in terminal regions), suggesting that the relative effects of befloxatone on monoamine release may be governed by autoreceptor-mediated control of monoaminergic neurons at the cell body level. Befloxatone (0.03-0.3 mg/kg, p.o.) exhibits potent activity in behavioural models predictive of antidepressant activity. Befloxatone (up to 1.5 mg/kg, p.o.) does not potentiate the pressor effects of orally administered tyramine at centrally active doses and duodenal [3H]-befloxatone binding is displaced by increasing doses of orally administered tyramine (0.1-40 mg/kg, i.p.). These results suggest that befloxatone is a potent reversible MAO-A inhibitor with antidepressant potential and a wide safety margin with regard to the potentiation of the pressor effect of tyramine.     

Effect of chronic calcium antagonist treatment on dopamine recognition sites in rat striatum

The effects of nimodipine and flunarizine administration (18 days 15 mg/kg/day p.o.) on striatal dopamine recognition sites in rats were investigated in vivo. In vitro flunarizine but not nimodipine displaces [3H]spiroperidol binding. After in vivo treatment both drugs induce a significant increase in the number of sulpiride displaceable spiroperidol binding sites (flunarizine, +114%, nimodipine +61%) concomitant with an increase in the dissociation constant. Binding parameters return toward control values after 1 week of suspension of the treatment. The results suggest that the repeated in vivo treatment with nimodipine and flunarizine may significantly interact with dopaminergic transmission leading to adaptive changes of the dopamine recognition sites.     

Effects of neurotoxic and mechanical lesions of the mesostriatal dopamine pathway on striatal polyamine levels in the rat: modulation by chronic ganglioside GM1 treatment

In male rats, partial hemitransections but not 6-hydroxydopamine (6-OHDA)-induced lesions of the mesostriatal dopamine (DA) pathway produce after 7 days a marked and a modest increase of striatal putrescine and spermidine levels, respectively, on the lesioned side. Following chronic ganglioside GM1 treatment of partially hemitransected rats, an increase of striatal polyamine levels was observed also on the intact side. It is suggested that retrograde cell body changes produced by hemitransection may induce striatal ornithine decarboxylase activity and in this way increase striatal putrescine levels, favoring regenerative mechanisms. The increase of striatal polyamine levels by GM1 treatment on the intact side of both 6-OHDA and mechanically lesioned rats compared with intact unoperated rats may also reflect an increased synthesis of striatal polyamines.     

Excitotoxic lesions of the pedunculopontine differentially mediate morphine- and d-amphetamine-evoked striatal dopamine efflux and behaviors

Cholinergic and glutamatergic cells in the pedunculopontine tegmental nucleus are a principal source of excitatory input to midbrain dopamine neurons projecting to the striatum. Disruption of these brainstem inputs has been shown to respectively enhance and reduce psychostimulant and opiate self-administration in rats. In the present study, d-amphetamine- and morphine-induced behaviors and dorsal striatal dopamine efflux, measured using in vivo chronoamperometry, were investigated 21 days after bilateral excitotoxic (ibotenate) lesions of the pedunculopontine in rats. Compared to sham-operated controls, pedunculopontine lesions enhanced stereotyped behaviors induced by a challenge injection of d-amphetamine (1.5 mg/kg, i.p.) to an extent that markedly interfered with the expression of locomotor behavior. A significant augmentation in striatal dopamine efflux was also observed in these lesioned animals under urethane anesthesia in response to a similar challenge injection of d-amphetamine (1.5 mg/kg, i.v.) 2 days following these behavioral observations. In direct contrast, pedunculopontine lesions in a separate group of rats significantly attenuated morphine-induced (2 mg/kg, i.p.) stereotyped activity, although no significant differences were observed in locomotion compared to sham-operated animals. Under urethane anesthesia, these lesions attenuated striatal dopamine efflux evoked by a similar challenge injection of morphine (2 mg/kg, i.v.).These findings indicate that the pedunculopontine differentially mediates the pharmacological actions of two diverse drugs of abuse on striatal dopamine neurotransmission and resultant behaviors. These results also imply that the pedunculopontine tegmental nucleus may serve as a major striatal-motor interface in the processing of salient environmental stimuli, and their incentive rewarding impact on dopamine-mediated behavioral responses.     

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of dexamphetamine

Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally administered dexamphetamine produces similar effects. Using a brain microdialysis technique that is combined with a microinjection needle, the contribution of the vesicular and cytosolic pools to the dopamine efflux induced by striatal injection of dexamphetamine was analyzed in rats. The transient striatal dopamine efflux induced by intrastriatal injection of dexamphetamine (1.0 microg/0.5 microl) was significantly reduced by systemic administration of reserpine (5mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of dexamphetamine on the striatal dopamine were nearly nullified by combined treatment with reserpine and alpha-methyl-para-tyrosine. The sum of the amounts of extracellular dopamine that was sensitive to either reserpine or alpha-methyl-para-tyrosine, was far greater than 100%, namely 146.1% of the basal dopamine level and 144.0% of the dexamphetamine-induced dopamine level. The present study indicates that both the vesicular dopamine pool and the cytosolic dopamine pool contribute to the transient increase of striatal dopamine efflux induced by intrastriatal injection of dexamphetamine. This study also suggests that striatally applied dexamphetamine can promote the redistribution of rat striatal dopamine from vesicles to the cytosol in vivo.     

Local infusion of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione does not block D1 dopamine receptor-mediated increases in immediate early gene expression in the dopamine-depleted striatum

Administration of selective agonists of D1 dopamine receptors increases immediate early gene expression in striatal neurons, a response which is particularly robust in the dopamine-depleted striatum. Although interactions between dopamine and glutamate receptor-mediated responses in striatal neurons have been demonstrated in a number of experimental paradigms, our previous findings indicate that N-methyl-D-aspartate antagonists do not block D1 receptor-mediated induction of immediate early genes in the dopamine-depleted striatum. In the present study, we therefore examined interactions between D1 dopamine receptors and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate subtypes of glutamate receptor by determining whether striatal infusion of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione would block D1 receptor-mediated induction of the immediate early genes c-fos and zif268 in the dopamine-depleted striatum. Striatal infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (1 mM) completely blocked (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate-induced c-fos and zif268 expression. However, 6-cyano-7-nitroquinoxaline-2,3-dione (1 microM-1 mM) did not significantly affect induction of c-fos and zif268 by D1 receptor stimulation (SKF 38393, 2 mg/kg, i.p.) in the dopamine-depleted striatum. To more generally block excitatory input, tetrodotoxin (10 microM) was infused into the striatum of rats receiving a D1 agonist. Local infusion of tetrodotoxin had minimal effect on induction of c-fos and zif268 in the dopamine-depleted striatum. In contrast, tetrodotoxin abolished induction of c-fos and zif268 messenger RNAs by the D2 antagonist eticlopride (0.5 mg/kg, i.p.) in both intact rats and dopamine-depleted rats receiving continuous D2 agonist treatment (quinpirole, 0.5 mg/kg/day). The results indicate that D1 receptor-mediated induction of immediate early genes in the dopamine-depleted striatum occurs by mechanisms that are independent of excitatory input through (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors.     

GM1 ganglioside treatment promotes recovery of electrically-stimulated [3H]dopamine release in striatal slices from rats lesioned with kainic acid.

The electrically-evoked release of [3H]dopamine ([3H]DA) from rat striatal slices was studied after a monolateral intrastriatal injection of kainic acid (KA). The release in the KA-lesioned striatum measured 4 days after the lesion was largely reduced (by 80%) with respect to the contralateral striatum. Administration of GM1 ganglioside (GM1) beginning on the day of the lesion resulted in restoration of the catecholamine release. Significant recovery was observed when GM1 was administered i.p. daily at the dose of 3 mg/kg for 6 days. The ganglioside given for 6 days at 30 mg/kg restored to near normal the electrically-evoked [3H]DA release. Similar recovery from the KA-induced injury occurred spontaneously but required 50 days.     

Regulation of dopamine release by impulse flow and by autoreceptors as studied by in vivo voltammetry in the rat striatum

Extracellular dopamine concentration has been monitored in the striatum of pargyline treated, anaesthetized rats using differential normal pulse voltammetry. The catechol oxidation current recorded with electrochemically treated carbon fiber electrodes disappeared when the dopaminergic terminals were selectively destroyed by 6-hydroxydopamine. Calibration of the basal oxidation current revealed that the extracellular dopamine concentration was 26 nM. Brief and moderate electrical stimulation of the nigrostriatal pathway at the level of the medial forebrain bundle induced a large increase in the dopamine current. The observed elevation in the dopamine signal lasted as long as the stimulation. It varied with the frequency (0-25 Hz) of the pulses in an exponential manner. Stimulation pulses distributed in a bursted pattern were twice as potent as an equivalent number of pulses regularly spaced. High frequency stimulations (50 Hz) were also investigated in anaesthetized rats (without pargyline) with untreated carbon fiber electrodes; they induced a very large increase in the dopamine extracellular concentration (up to 8-15 microM). Interruption of the dopaminergic impulse flow either by an electrolytic lesion or by a low dose of apomorphine (0.05 mg/kg) caused an immediate decrease of the dopamine current. The time courses and amplitudes (-70%) of these effects were identical. Subsequent injection of haloperidol (0.5 mg/kg) reversed the apomorphine effect up to +360% of the control basal value. Administration of dopaminergic antagonists such as haloperidol (0.05 and 0.5 mg/kg) or metoclopramide (2 mg/kg) significantly increased the dopamine current up to 317, 340 and 215% of the respective control values. Nomifensine (4 mg/kg) produced a big increase (+417%) of the extracellular dopamine levels. The effect of electrical stimulation of the dopaminergic pathway was potentiated by drugs such as amphetamine (2 mg/kg), nomifensine (4 mg/kg) or haloperidol (0.05 and 0.5 mg/kg) but was not altered by apomorphine (0.05 mg/kg). The study by in vivo voltammetry of the variations in the striatal extracellular dopamine concentrations shows that the release of dopamine is under the influence of both the frequency of impulse flow and of dopaminergic striatal autoreceptors.     

Altered neurotensin mrna expression in mice lacking the dopamine transporter

Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT-/- mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT-/- mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT-/- mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT-/- mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse.     

Ganglioside GM1 treatment prevents the effects of subacute exposure to toluene on N-[3H]propylnorapomorphine binding characteristics in rat striatal membranes

The effects of ganglioside GM1 treatment (10 mg/kg, i.p., 3 days, once daily) were analyzed on N-[3H]propylnorapomorphine ([3H]NPA) binding characteristics in striatal membrane preparations from air or toluene (80 ppm, 3 days, 6 h/day) exposed adult male rats. It was found that toluene exposure induced increased Kd and Bmax values for [3H]NPA binding. These changes could be blocked by GM1 treatment, which by itself had no significant effects on the binding characteristics of [3H]NPA. The addition of toluene (9.3 mumol/ml) in vitro had similar effects on [3H]NPA binding characteristics as toluene exposure in vivo. These results indicate that the effects of toluene exposure on dopamine receptors are due to an alteration of membrane fluidity which is prevented by GM1 treatment.     

Striatal neurons express increased level of dopamine D2 receptor mRNA in response to haloperidol treatment: a quantitative in situ hybridization study.

In the present study, quantitative in situ hybridization was used to analyse the effect of haloperidol treatment on D2 dopamine receptor gene expression in the rat caudate-putamen nucleus. Variations of D2 receptor mRNA level were studied and measured at the macroscopic level of densitometric analysis of X-ray film and at the microscopic level by counting of autoradiographic silver grains in striatal cells. Macroscopic analysis demonstrated that haloperidol treatment two times 1 mg/kg per day during seven, 14 and 21 days increased D2 receptor mRNA level in the caudate-putamen. Detailed microscopic analysis demonstrated a significant increase in D2 receptor mRNA in the two neuronal populations known to express the D2 receptor gene: medium-sized neurons previously identified as enkephalinergic neurons, and large-sized neurons previously identified as cholinergic neurons. The increase was more important in cholinergic neurons (+119%) than in enkephalinergic neurons (+54%). Haloperidol treatment did not modify the number of medium-sized enkephalinergic neurons expressing the D2 receptor mRNA. In contrast, it significantly increased the percentage of large-sized neurons containing D2 receptor mRNA (from 80 to 94%). These results demonstrate that haloperidol treatment acts at the gene level to modulate D2 receptor content in striatal dopaminoceptive neurons, and that the D2 receptor mRNA increase in postsynaptic neurons contributes to dopamine supersensitivity induced by neuroleptics in the rat. This suggests that dopamine acts trans-synaptically to control D2 receptor gene expression in target striatal neurons. These results suggest that modifications of D2 receptor gene expression may be part of the biological events that lead to the movement disorders induced by neuroleptic drugs or Parkinson's disease.     

Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function in striatum of rats by collateral sprouting*

The effects of chronic ganglioside treatment GM-1 (10 mg/kg, i. p., once daily for 56 days) have been evaluated on the degenerative and regenerative features of nigrostriatal dopamine (DA) neurons following a partial lesion by tyrosine hydroxylase immunocytochemistry in combination with morphometrical analysis and by quantitative DA receptor autoradiography. Chronic GM-1 treatment resulted in the maintenance in the number of DA cell bodies, terminals and striatal area on the lesioned side and also increased dendrite length of the DA nerve cells in the zona reticulata on that side. The lesion induced DA receptor supersensitivity was counteracted by chronic treatment with GM-1 and the apomorphine induced rotational behaviour was significantly reduced. The hypothesis is introduced that following ganglioside treatment some lesioned DA nerve cells do not degenerate, but elongate their dendrites to give increased trophic support to DA cell bodies with intact DA axons. These increased dendro-dendritic interactions may enable the unlesioned DA cells to increase the density of their striatal nerve terminal networks via collateral sprouting leading to recovery of dopaminergic synaptic function as evidenced in the receptor autoradiographical and behavioural analysis. Gangliosides may therefore possibly represent a new type of drug in the treatment of Parkinson's disease and aging processes in DA systems.