Long-lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: effects on zif 268 and homer 1a

Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers ( zif 268 and homer 1a ) that offer a high anatomical resolution to map cocaine-induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21-day, but not 1-day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a , changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long-lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction.     

Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum

Methylphenidate is a psychostimulant which inhibits the dopamine transporter and produces dopamine overflow in the striatum, similar to the effects of cocaine. Excessive dopamine action is often associated with changes in gene expression in dopamine-receptive neurons. Little is known about methylphenidate's effects on gene regulation. We investigated whether a methylphenidate treatment regimen known to produce behavioural changes would alter gene expression in the striatum. Using in situ hybridization histochemistry, we assessed the effects of acute and repeated methylphenidate treatment on the expression of immediate-early genes (c-fos, zif 268) and neuropeptides (dynorphin, substance P, enkephalin) in adolescent rats. Acute methylphenidate treatment (0-10 mg/kg, i.p.) produced a dose-dependent increase in the expression of c-fos and zif 268. These effects were most pronounced in the dorsal striatum at middle to caudal striatal levels, and were found for doses as low as 2 mg/kg. Repeated treatment with methylphenidate (10 mg/kg/day, 7 days) increased the expression of dynorphin, which was highly correlated with the acute immediate-early gene response across different striatal regions. Moreover, after repeated methylphenidate treatment, cocaine-induced expression of c-fos and zif 268, as well as of substance P, was significantly attenuated throughout the striatum. These effects of repeated methylphenidate treatment mirror those produced by repeated treatment with cocaine or other psychostimulants and are considered to reflect drug-induced neuroadaptations. Thus, our findings demonstrate that acute and repeated methylphenidate treatment can produce molecular alterations similar to other psychostimulants.     

Unilateral striatal dopamine depletion: time-dependent effects on cortical function and behavioural correlates

Previously, we showed that unilateral blockade of D1 dopamine receptors in the striatum inhibits immediate-early gene expression bilaterally throughout large parts of the cortex, including sensory-evoked expression in the barrel cortex. To further investigate this dopamine regulation of cortical function, we examined the effects of dopamine depletion on cortical gene regulation and behavioural correlates. Two days after unilateral infusion of 6-hydroxydopamine into the midbrain, rats displayed a (to some degree) bilateral reduction in cortical zif 268 expression that was more pronounced on the lesioned side. This decrease was found across motor, somatosensory, insular and piriform, but not cingulate, cortex, similar to the effects of blockade of striatal D1 receptors. Furthermore, whisker stimulation-evoked c-fos and zif 268 expression in the barrel cortex ipsilateral to the lesion was also attenuated by acute dopamine depletion. These cortical deficits were accompanied by a breakdown of spontaneous behaviours in an open-field test. In contrast, 21 days after dopamine depletion, both basal and sensory-evoked gene expression in the cortex were near-normal. This cortical recovery was paralleled by recovery in locomotion and in sensory-guided behaviour (scanning) related to the hemisphere contralateral to the lesion, but not in scanning by the dopamine-depleted hemisphere. Our results suggest that striatal dopamine exerts a widespread facilitatory influence on cortical function that is necessary, but not sufficient, for normal behaviour. Moreover, the mechanisms mediating this cortical facilitation appear to be subject to substantial neuroplasticity after dopamine perturbation.     

Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: Relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction

Dynorphin, an endogenous kappa opioid receptor ligand, acts in the striatum to regulate the response of striatonigral neurons to D1 dopamine receptor stimulation. We investigated the relative contributions of both presynaptic kappa receptors on dopamine terminals and postsynaptic kappa receptors on striatal neurons by analyzing opioid regulation of D1 effects in the absence of presynaptic kappa receptors, after 6-hydroxydopamine depletion of striatal dopamine. D1-receptor-mediated immediate-early gene induction was measured by using in situ hybridization histochemistry. First, repeated treatment with the D1-receptor agonist SKF-38393 (2 mg/kg/day, 3–14 days) was used to increase dynorphin levels in rats with dopamine depletions. In the nucleus accumbens, increased dynorphin expression was accompanied by reduced induction of the immediate-early genes c-fos and zif 268 by SKF-38393. In contrast, in dorsal/lateral aspects of the dopamine-depleted striatum, this D1 response was sustained despite a large increase in dynorphin expression. These results are consistent with a requirement of dopamine terminals (presynaptic kappa receptors) for the inhibitory action of dynorphin in the dorsal/lateral striatum, but not in the ventral striatum. Second, the kappa receptor agonist spiradoline (1–10 mg/kg) reduced c-fos and zif 268 induction by SKF-38393 (2.5 mg/kg) preferentially in ventral parts of the dopamine-depleted striatum, which contain higher levels of kappa receptor mRNA and binding. These results also indicate that postsynaptic kappa receptors contribute to the inhibition of the D1 response at least in the ventral striatum. Together, these results indicate that dynorphin in the striatum functions to regulate dopamine input to striatonigral neurons, acting at both pre- and postsynaptic sites, and that the relative contributions of these mechanisms differ between dorsal and ventral striatal regions. © 1996 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, in the public domain in the United States of America.

     

Acute methamphetamine-induced zif/268, preprodynorphin, and preproenkephalin mRNA expression in rat striatum depends on activation of NMDA and kainate/AMPA receptors

This study tested the role of N-methyl-d-aspartate and kainate/AMPA receptors in mediating mRNA expression of the immediate early gene zif/268 and the opioid peptide genes preprodynorphin and preproenkephalin in rat forebrain following a single injection of methamphetamin. At 3 h after acute methamphetamine [4 mg/kg, intraperitoneally (IP)], quantitative in situ hybridization histochemistry revealed that zif/268 mRNA expression was increased in the dorsal striatum (caudoputamen) and in the sensory cortex. Preprodynorphin was increased in both dorsal and ventral striatum (nucleus accumbens) and preproenkephalin was increased in the dorsal striatum. Pretreatment with (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (10 mg/kg, IP), an N-methyl-d-aspartate receptor antagonist, blocked the methamphetamine-induced zif/268 mRNA expression in the striatum and in the region of sensory cortex representing the upper limb and nose. 6,7-Dinitro-quinoxaline-2,3-dione (DNQX) (100 mg/kg, IP), a kainate/AMPA receptor antagonist, did not reduce the ability of methamphetamine to induce zif/268 mRNA in striatal and cortical neurons. Furthermore, both antagonists caused a parallel blockade of methamphetamine-stimulated preproenkephalin mRNA expression in the dorsal and ventral striatum but did not significantly affect methamphetamine-stimulated preproenkephalin mRNA expression. CPP and DNQX reduced basal levels of zif/268 mRNA in cortical and striatal neurons but did not affect the constitutive expression of the two opioid mRNAs in the striatum. Neither antagonist had a significant effect on methamphetamine-induced demonstrate that both N-methyl-d-aspartate and kainate/AMPA receptor-mediated glutamatergic transmission is linked to modulation of the methamphetamine-stimulated opioid peptide gene expression in rat forebrain. Furthermore, N-methyl-d-aspartate receptors participate in methamphetamine-stimulated zif/268 expression.     

Blockade of neurotensin receptors suppresses the dopamine D1/D2 synergism on immediate early gene expression in the rat brain

A remarkable feature of dopamine functioning is that the concomitant activation of D1-like and D2-like receptors acts to intensify the expression of various dopamine-dependent effects, in particular the expression of the immediate-early genes, c-fos and zif268. Using non-peptide neurotensin receptor antagonists, including SR48692, we have determined that blockade of neurotensin receptors reduced the cooperative responses of direct acting D2-like (quinpirole) and partial D1-like (SKF38393) dopamine agonists on the expression of Fos-like antigens and zif268 mRNA. Pretreatment with SR48692 (3 and 10 mg/kg) reduced the number of Fos-like immunoreactive cells produced by the combined administration of SKF38393 (20 mg/kg) and quinpirole (1 mg/kg) in the caudate-putamen, nucleus accumbens, globus pallidus and ventral pallidum. High-affinity neurotensin receptors are likely to be involved in these D1-like/D2-like cooperative responses, as compounds structurally related to SR48692, SR48527 (3 mg/kg) and its (-)antipode, SR49711 (3 mg/kg), exerted a stereospecific antagonism in all selected brain regions. Pretreatment with SR48692 (10 mg/kg) also diminished Fos induction by the indirect dopamine agonist, cocaine (25 mg/kg), particularly at the rostral level of the caudate-putamen. In situ hybridization experiments in the caudate-putamen indicated that SR48692 (10 mg/kg) markedly reduced zif268 mRNA labelling produced by SKF38393 plus quinpirole in cells not expressing enkephalin mRNA, but was unable to affect the concomitant decrease of zif268 mRNA labelling in enkephalin-positive cells. Taken together, the results of the present study indicate that neurotensin is a key element for the occurrence of cooperative responses of D2-like and partial D1-like agonists on immediate-early gene expression.     

Regulation of rat cortex function by D1 dopamine receptors in the striatum.

Interactions between the basal ganglia and the cerebral cortex are critical for normal goal-directed behavior. In the present study, we used immediate-early genes (c-fos, zif 268) as functional markers to investigated how basal ganglia output altered by stimulation/blockade of D1 dopamine receptors in the striatum affects cortical function. Systemic administration of the mixed D1/D2 receptor agonist apomorphine (3 mg/kg) increased immediate-early gene expression in the striatum and throughout most of the cortex. Unilateral intrastriatal infusion of the selective D1 receptor antagonist SCH-23390 (0.5-10 microg) blocked this response bilaterally in striatum and cortex in a dose-dependent manner. Even apparently regionally restricted blockade of striatal D1 receptors attenuated gene expression throughout striatum and cortex in both hemispheres. Intrastriatal administration of the D1 antagonist inhibited apomorphine-induced sniffing/whisking, whereas other motor behaviors were unaffected. To determine whether such changes in cortical gene expression could reflect altered cortical function, we examined the effects of blocking striatal D1 receptors on whisker stimulation-evoked immediate-early gene expression in the sensorimotor cortex. Apomorphine increased sensory stimulation-evoked gene expression in the barrel cortex, and intrastriatal infusion of SCH-23390 attenuated this effect. These results suggest that stimulation of D1 dopamine receptors in the striatum exerts a widespread facilitatory effect on cortical function.     

mGluR5-dependent increases in immediate early gene expression in the rat striatum following acute administration of amphetamine

Metabotropic glutamate receptor 5 (mGluR5) is densely expressed in medium-sized spiny projection neurons of the rat striatum. Activation of mGluR5 increases intracellular Ca2+, resulting in Ca(2+)-dependent cellular responses. Acute administration of the psychostimulant amphetamine (AMPH) induces immediate early gene (IEG) expression in the striatum, which is considered an important molecular event for the development of striatal neuroplasticity related to the addictive properties of drugs of abuse. This study investigated the role of mGluR5 in the mediation of IEG expression in the rat striatum induced by a single dose of AMPH (4 mg/kg, i.p.) in vivo. We found that systemic administration of the mGluR5-selective antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) at a dose of 10 mg/kg, i.p. reduced AMPH-stimulated c-fos mRNA levels in the dorsal (caudoputamen) and ventral (nucleus accumbens) striatum as revealed by quantitative in situ hybridization. Similar results were observed in the three areas of cerebral cortex (cingulate, sensory, and piriform cortex). In contrast to c-fos mRNAs, AMPH-stimulated mRNA expression of another IEG, zif/268, was not significantly altered by the blockade of mGluR5 with MPEP in the entire striatum and the three areas of cortex. Treatment with MPEP alone had no effect on basal levels of c-fos and zif/268 mRNAs in the striatal and cortical areas. These results indicate that an mGluR5-dependent mechanism selectively contributes to c-fos expression in the striatum and cortex in response to acute exposure to AMPH.     

Increased expression of zif268 mRNA in rat retrosplenial cortex following administration of phencyclidine

Phencyclidine (PCP) has been shown to cause neurotoxicity in rat retrosplenial cortex following a single administration, although the precise mechanism underlying PCP-induced neurotoxicity is unclear. Using in situ hybridization and immunohistochemistry, we studied the effects of PCP on expression of immediate early gene zif268 mRNA and zif268 protein in the rat brain. High constitutive levels of zif268 mRNA and zif268 immunoreactivity were observed in the brain of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of zif268 mRNA in the rat retrosplenial cortex, in a dose-dependent manner. However, the basal levels of zif268 mRNA in the other regions of cerebral cortex were decreased by administration of PCP. Emulsion-autoradiographical study suggested that marked expression of zif268 mRNA was observed in the layers III and IV of retrosplenial cortex where the neurotoxicity of PCP was detected. Furthermore, zif268 immunoreactivity in the layer IV of retrosplenial cortex was not changed by administration of PCP (25 mg/kg, i.p., 5 h), but that in the other layers of retrosplenial cortex was reduced by PCP. These results suggest that immediate early gene zif268 may, in part, play a role in the neurotoxicity of NMDA receptor antagonists such as PCP.     

Dynorphin opioid inhibition of cocaine-induced,D1 dopamine receptor-mediated immediatem-early gene expression in the striatum

Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zif 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that (1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5–250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mg/kg); (2) systemic administration of the kappa opioid receptor agonist spiradoline (0.5–10.0 mg/kg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; (3) intrastriatal infusion of spiradoline (1–50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and (4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D1 dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum. © 1995 Wiley-Liss, Inc.     

Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain

The mRNA expression pattern for four different immediate early genes was examined dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6 mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1 and 48 hours. cfos mRNA was induced in cortical areas at early times after either dose of PCP or of MK801; the change was especially prominent in cingulate and auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed (24–48 hour) suppression after PCP and MK801 in neocortical areas. PCP also caused cjun and junB mRNA induction in cortical areas at early times, with a distribution and time course similar to its effects on cfos mRNA. No alterations in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any delayed time (>6 hours) after PCP treatment, whereas suppression of zif268 expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA antagonist, showed a similar pattern of effects on cfos and zif268 mRNA expression. These functional consequences of a PCP- or MK801-induced reduction in NMDA-sensitive glutamate transmission may be relevant to an understanding of animal NMDA pharmacology and/or to clinical psychotomimetic side effects of antiglutamatergic treatments. Synapse 29:14–28, 1998. © 1998 Wiley-Liss, Inc.     

Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment

Early gene induction by L-DOPA in the striatum of dopamine denervated rats represents a useful way to study long-term modifications produced by this drug. The effects of acute and subchronic L-DOPA administration on zif-268 mRNA expression were compared in 6-hydroxydopamine-lesioned rats. Rats received a subchronic intermittent L-DOPA (6 mg/kg) treatment, which produces behavioural sensitization, a correlate of dyskinetic movements. Three days after interruption of subchronic treatment, zif-268 mRNA was evaluated after an L-DOPA challenge. Zif-268 mRNA levels increased in the lesioned dorsolateral striatum after either acute or subchronic L-DOPA administration. Double labelling of striatal cells with zif-268 and enkephalin or dynorphin mRNA probes was performed to assess neuronal activation in the indirect and direct output pathway. Single acute L-DOPA significantly increased zif-268 in all striatal neurons reflecting a hyperresponsiveness of dopamine-depleted striatum. After subchronic L-DOPA, zif-268 mRNA labelling was still increased in the striatonigral pathway, limited to dynorphin(+) neurons, whereas in all other neurons it was similar to the control value. Results suggest that striatal neurons responding to acute L-DOPA differ from those responding to subchronic L-DOPA. L-DOPA-induced behavioural sensitization was associated to a down-regulation in the responsiveness of striatopallidal and striatonigral dynorphin(-) neurons, whereas in striatonigral neurons containing dynorphin a hyperresponsiveness to L-DOPA was observed. High levels of zif-268, together with a persistent hyperresponsiveness of striatonigral dymorphinergic neurons and hyporesponsiveness of striatopallidal neurons, by creating an unbalanced state of striatal efferent neurons, may be implicated in dyskinetic movements observed in Parkinson's disease (PD).     

Topography of cocaine-induced gene regulation in the rat striatum: relationship to cortical inputs and role of behavioural context

Psychostimulants alter gene expression in projection neurons of the striatum, and such neuroplasticity is implicated in drug addiction and dependence. Evidence indicates that excitatory inputs from the cortex and thalamus are critical for these molecular changes. In the present study, we determined the topography of cocaine-induced changes in gene expression in the rat striatum and investigated whether these molecular alterations are associated with particular cortical inputs. Acute induction of c-fos (by 25 mg/kg of cocaine), and the c-fos response and dynorphin expression after repeated cocaine treatment (25 mg/kg, 4 days) were assessed as examples for short-term and longer-term molecular changes, respectively. In addition, we examined whether these molecular effects were influenced by the behaviour performed during cocaine action (running-wheel training vs. open field). Our results demonstrate that the overall topography of cocaine-induced gene regulation in the striatum is remarkably stable. Both acute and longer-term molecular changes were maximal in caudal dorsal striatal sectors that receive convergent inputs from the medial agranular and the sensorimotor cortex. In contrast, relatively minor or no effects were found in rostral and ventral striatal sectors. However, running-wheel training under the influence of cocaine enhanced the c-fos response to a subsequent cocaine challenge selectively in parts of the caudal sensorimotor striatum. These results indicate that cocaine produces molecular adaptations preferentially in cortico-basal ganglia circuits through the sensorimotor striatum, and that some of these neuronal changes are influenced by the behaviour performed during drug exposure.     

Time-dependent changes in dopamine agonist-induced striatal fos immunoreactivity are related to sensory neglect and its recovery after unilateral prefkontal cortex injury

This study examined interactions between the corticostriatal glutamatergic system and the nigrostriatal dopaminergic system via immunocytochemical examination of dopamine (DA) agonist induction of the striatal immediate early gene product Fos following cortical injury. After unilateral aspiration of the medial agranular cortex (AGm) region of prefrontal cortex, rats were tested for orientation to visual, tactile, and auditory stimuli. Fos immunoreactivity induced by d-amphetamine (5 mg/kg) or apomorphine (5 mg/kg) was quantified in dorsolateral and ventrolateral regions of caudate-putamen (CPu) in rats still demonstrating sensory neglect (5 days postsurgery) and in rats recovered from sensory neglect produced by AGm ablation (29+ days postsurgery). The pattern of immunoreactivity of rats still demonstrating neglect differed from that of unlesioned rats or recovered AGm-ablated rats. In rats demonstrating sensory neglect, d-amphetamine or apomorphine induction of Fos in the ipsilateral CPu was reduced by about 40% compared to the contralateral CPu or to comparable readings in unlesioned controls. These asymmetries were restricted to dorsolateral CPu, the region receiving the densest input from AGm. In contrast, recovered AGm-ablated rats had DA agonist-induced striatal Fos immunoreactivity that was symmetrical between the two hemispheres and comparable to control values. These findings indicate that adaptations involving the striatal medium spiny neuron, a site of convergence of cortical glutamatergic and nigral dopaminergic afferents, may contribute to recovery from behavioral deficits resulting from neocortical injury. © 1995 Wiley-Liss, Inc.     

Cortical stimulation induces fos expression in intrastriatal striatal grafts

Innervation of intrastriatal grafts of fetal striatal tissue by host corticostriatal projections has been shown in a number of previous studies in rats. In the work reported here, induction of Fos protein in grafted striatal neurons by electrical stimulation of the host frontoparietal cortex has been used as cell-level marker of corticostriatal postsynaptic responses within the striatal grafts. Unilateral cortical stimulation 30 min before sacrifice led to bilateral widespread and intense Fos induction throughout the normal striatum, although the response was somewhat more intense ipsilaterally and in the dorsolateral rostral striatum. In adult rats whose striatum had been lesioned with ibotenic acid 10–12 days prior to implantation of fetal striatal tissue, 3- and 18-month-old striatal grafts showed Fos immunoreactivity in a considerable number of cells after either bilateral, or ipsilateral (30–40% of the density of Fos-immunoreactive cells in the normal striatum) or contralateral cortical stimulation. Double-Fos and -DARPP-32 immunohistochemistry revealed that the Fos-immunoreactive nuclei were concentrated in the DARPP-32-positive (i.e. striatum-like) patches, which contained 60% of the density of Fos-positive nuclei in the normal striatum after either ipsilateral or bilateral stimulation. However, Fos-immunoreactive nuclei were unevenly distributed within the DARPP-32-positive compartment of the graft, with some clusters of Fos-immunoreactive nuclei at 2−3 × the density observed in the normal striatum and other areas with Fos-immunoreactive nuclei present at lower density or absent. Fos induction was also observed in 4-week-old grafts, indicating that functional corticostriatal synaptic contacts develop rapidly. Striatal grafts implanted either in non-lesioned host striatum or in long-term (18 months) lesioned striatum, similarly showed Fos-positive nuclei after cortical stimulation, indicating that host corticostriatal fibers are equally capable of establishing functional synaptic contacts under these conditions. These results indicate that host corticostriatal fibres not only form an axonal network within the graft but also induce postsynaptic responses which may contribute to the observed graft-induced amelioration of lesion-induced behavioural deficits.     

Basal EGR-1 (zif268, NGFI-A,Krox-24) expression in developing striatal patches: role of dopamine and glutamate

Egr-1 (also known as zif268, NGFI-A, or Krox 24) is an immediate-early gene of the zinc finger family that exhibits relatively high constitutive expression in the brain, as well as inducibility by seizure activity, stimulants, and salient physiological stimuli. Immunocytochemical detection of the Egr-1 protein in the developing striatum revealed that in the late prenatal and early postnatal period, Egr-1 protein was expressed selectively in patches of striatal neurons under basal conditions. Egr-1 immunoreactivity was co-expressed with known markers of striatal patch neurons, indicating that expression was greatest in the striatal patch compartment. This patchy expression of Egr-1 transitioned to a nearly homogeneous pattern of Egr-1-immunoreactive cells by postnatal day 10, at which time most striatal neurons appeared to be Egr-1-immunoreactive. The dopamine D1 antagonist SCH23390 (0.5-1.0 mg/kg) reduced Egr-1 expression during the first week postnatal, but it was no longer effective at postnatal day 10. On the other hand, the noncompetitive NMDA antagonist MK-801 (0.5-1.0 mg/kg) became more effective at reducing Egr-1 expression with age. Neonatal destruction of nigrostriatal dopamine afferents reduced the basal pattern of Egr-1 expression for 2-3 days after the lesion, but then Egr-1 expression returned. Thus, Egr-1 expression in the developing striatum appears to be driven first by dopaminergic afferents, and then later in development by excitatory glutamatergic afferents.