Striatal tachykinin and enkephalin mRNAs are normalized by serotonin2 and NMDA manipulation following dopamine depletion

We have examined the effects of serotonin2 (5-HT2) stimulation and NMDA antagonism on preprotachykinin (PPT) and preproenkephalin (PPE) gene regulation in the dopamine (DA) depleted striatum. Following DA lesions, PPT mRNA expression was reduced (dorsomedial (DM) 44 +/- 9%, dorsolateral (DL) 40 +/- 4%), whereas PPE message levels were elevated (DM 207+/-28%, DL 198+/-25%). Within this state of dysregulated gene activity, DOI (5-HT2 agonist) increased PPT message levels (174 +/- 5%, DM; 153 +/- 13%, DL) without affecting PPE gene expression. In addition, MK-801 (NMDA antagonist) decreased PPE message levels (DM 59 +/- 10%, DL 52 +/- 7%) without significantly altering PPT mRNA expression. Combined application of DOI and MK-801 resulted in normalization of both PPTand PPE message. Statistical analysis revealed no drug interactions in this paradigm suggesting independent mechanisms for 5-HT2 and NMDA receptors in controlling neuropeptide production following DA depletion.     

Magnitude and duration of hyperactivity following neonatal 6-hydroxydopamine is related to the extent of brain dopamine depletion

This experiment examined the relationship between the extent of brain dopamine (DA) neuron destruction in the neonatal rat and locomotor hyperactivity during subsequent development. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular injections of 6-hydroxydopamine (6-OHDA) following desmethylimipramine (DMI) pretreatment of both days 3 and 6 of life. Groups of rats received total doses of 50, 70, 100 or 200 microgram of 6HDA or the vehicle solution. Each group of rats given 6-OHDA displayed 3- to 5-fold increases in locomotor activity relative to vehicle control rats on days 16 and 18 of life. Rats given 50 or 70 microgram of 6-OHDA displayed hyperactivity that diminished during days 18-32 of life, approaching the level of activity seen in vehicle-treated rats. It contrast, rats given 100 or 200 microgram of 6-OHDA displayed consistently high levels of locomotion during days 18-32 of life. When tested as adults (days 55-66 of life) only those rats given 200 micrograms of 6-OHDA as neonates continued to display locomotor hyperactivity. The extent of 6-OHDA-induced depletion of DA was proportional to the magnitude of locomotor hyperactivity seen during neonatal life. Brain DA was depleted to the greatest extent in rats which displayed permanent hyperactivity. Regardless of the extent of depletion of brain DA, adult rats given intraventricular injections of 125, 200 or 275 micrograms of 6-OHDA at 48 days of age (following pargyline and DMI pretreatment) displayed no significant change in locomotor activity. These results indicate that the magnitude and duration of locomotor hyperactivity seen following neonatal 6-OHDA injections are correlated with the extent of loss of central DA neurons and suggest that brain DA projections exert important influences on the ontogeny of normal locomotion.     

Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression

Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague-Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 microg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine (PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60-66% across three subregions of the A-STR and 52-59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50-62%) and P-STR (55-82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.     

Changes of amino acid and monoamine levels after neonatal 6-hydroxydopamine denervation in rat basal ganglia,substantia nigra,and raphe nuclei

The effects of a neonatal dopaminergic deafferentation with the neurotoxin 6-hydroxydopamine (6-OHDA) on endogenous tissue levels of catecholamines, indoleamines, and amino acids were investigated in discrete rat brain regions. After producing the lesion at postnatal day 3 by intraventricular injections of 6-OHDA, with a desipramine pretreatment to protect noradrenaline neurons, the animals were kept for 3 months. Their brains were dissected to obtain samples of neostriatum, Globus pallidus, Substantia nigra, and Raphe nuclei, which were then analyzed by high-performance liquid chromatography, coupled either to electrochemical detection for aromatic monoamines, or to post-column ninhydrin derivatization with spectrophotometry for amino acids. The neonatal 6-OHDA treatment depleted dopamine (DA) levels in neostriatum, Globus pallidus, and Substantia nigra, but in Raphe nuclei DA was increased. The main metabolites of DA were also decreased in neostriatum, Globus pallidus, and Substantia nigra but remained unchanged in Raphe nuclei. Serotonin (5-HT) and its metabolite 5-hydroxyindole-3-acetic acid increased in neostriatum and Raphe nuclei; in Substantia nigra there was a slight increase in 5-HT only. The 6-OHDA lesion caused heterogeneous alterations in amino acid contents, which varied according to the region. In the neostriatum there were increases of γ-aminobutyric acid (GABA), aspartic acid, and glycine. In the Globus pallidus taurine, GABA, glutamic acid, glutamine, aspartic acid, serine, and alanine were elevated. In the Substantia nigra only increases in taurine, GABA, glutamic acid, and glutamine could be documented. This study shows important changes in amino acid levels and in some of their ratios, occurring in different anatomical subdivisions of the basal ganglia and related brainstem nuclei following a neonatal treatment with 6-OHDA. The results thus demonstrate major biochemical modifications in amino acids in the aftermath of a DA denervation and/or a 5-HT hyperinnervation during an early developmental period. © 1993 Wiley-Liss, Inc.     

Limbic system, basal ganglia, and dopaminergic neurons. Executive and regulatory neurons and their role in the organization of behavior

Mesencephalic dopaminergic neurons appear to be involved in the organization of the behavioral response. They seem to facilitate the functioning of the integrative structures they innervate and to have a coordinated functioning, thus regulating the information transfer between these structures. In the present paper these two aspects have been investigated by behavioral and neurochemical approaches. Experimental studies were focused on the dopaminergic innervation of the nucleus accumbens.     

Bilateral, symmetrical hemorrhagic infarction of the basal ganglia and thalamus following neonatal asphyxia

With the advancement of perinatal intensive care, the occurrence of subependymal germinal matrix hemorrhage (= GMH) in low-birth-weight (premature) infants has became a major concern in perinatal medicine. The pathophysiology of the GMH has long been controversial. The introduction of computed tomographic (= CT) scanning to perinatal medicine has revealed various pathological events heretofore unknown in newborn infants having respiratory and circulatory distress. At our serving the entire Osaka Prefecture, infants suffering from birth asphyxia with severe perinatal brain damage were found to have CT findings distinguishable from those of GMH. We report three asphyxiated newborn infant who had hemorrhagic infarction in bilateral caudate nucleus, striatum and thalamus on the CT scan. Reports of similar findings are rare, and ours is the first serial observation of such CT scan image in newborn infants. The mechanism of development and pathology of this pathological condition have been variously argued as pathophysiology of GMH. The present study lacks postmortem examination, however, the findings in serial CT scans in three infants and review of the literatures related to the pathology of neonatal asphyxia indicate the following course. The thrombosis in the internal cerebral veins led to severe swelling of the brain, and hemorrhage occurred with the reduction in the swelling, eventually resulting in diffuse leukomalacia. Etat marbré (status marmoratus), mentioned earlier, is considered to represent a milder stage of this pathologic course.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of MPTP-induced denervation on basal ganglia GABA(B) receptors: correlation with dopamine concentrations and dopamine transporter

We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA(B(1a+b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA(B) receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of (3)H-CGP54626 binding (-10%) and of the expression of GABA(B(1a+b)) mRNA (-13%). The decrease of the expression of GABA(B(1a+b)) mRNA was correlated with dopamine content, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-CGP64213 binding (-40%), GABA(B(1a+b)) mRNA (-69%) and GABA(B(2)) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease.     

Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons

Numerous studies suggest that the dopamine transporter (DAT), responsible for dopamine reuptake, may act as a vulnerability factor in the pathogenesis of Parkinson's disease (PD) and the vesicular monoamine transporter (VMAT2), responsible for its vesicular storage, as a neuroprotective factor. However, the relevance of each on the differential vulnerability of midbrain DA cells remains unknown. Here we studied the relationship between the expression pattern (mRNA and protein) of both transporters and the differential vulnerability of midbrain DA cells in a model of PD (intracerebroventricular injection of 6-OHDA in rats) and in monkey and human midbrain. Our results revealed that the expression patterns for VMAT2 mRNA and protein and DAT mRNA are similar, with the highest levels in the rostromedial region of substantia nigra (SNrm), followed by the caudoventral region of SN (SNcv), the ventral tegmental area and pigmented parabrabraquial nucleus (VTA/PBP), and finally the linear and interfascicular nuclei (Li/IF). In contrast, the expression of DAT protein in rats, monkeys, and humans followed a caudoventrolateral-to-rostrodorsomedial decreasing gradient (SNcv > SNrm > VTA/PBP > Li/IF), matching the degeneration profile observed after intracerebroventricular injection of 6-OHDA and in PD. In addition, DAT blockade made all midbrain DA cells equally resistant to 6-OHDA. These data indicate that DAT protein levels, but not DAT mRNA levels, are closely related to the differential vulnerability of midbrain DA cells and that this relationship is unaffected by the relative levels of VMAT2. Furthermore, the difference between DAT mRNA and protein profiles suggests internuclear differences in its posttransductional regulation.     

Dopamine dependent decrease in enkephalin and substance P levels in basal ganglia regions of postmortem Parkinsonian brains

This study examined whether a relationship exists between the degree of dopamine (DA) loss and the changes in opioid (Met5-enkephalin, ME; dynorphin A (1-8) (DYN)) or tachykinin (substance P, SP) peptidergic systems in basal ganglia (caudate and putamen) and limbic (frontal cortex) regions of postmortem tissue samples derived from patients who died of Parkinson's disease (PD). The levels of ME, SP and DYN were determined by radioimmunoassays. The levels of DA and 5-hydroxytryptamine (5-HT) and their metabolites were determined by HPLC with electrochemical detection. The degree of loss of DA in PD tissues was classified into two major categories, those with less than 80% and those with more than 80% loss as compared to control. The results reveals that only the category with greater than 80% DA loss exhibited lower levels of ME in caudate and SP in putamen whereas no differences were observed in the levels of DYN in these regions. The frontal cortical region exhibited no changes in the levels of peptides. In other studies, experimental DA deficiency in rodents induced by neurotoxin such as 6-hydroxydopamine (6-OHDA) produced an increase in ME and a decrease in SP in basal ganglia. However, the levels of both peptides were lower in postmortem Parkinsonian basal ganglia in the present study. It appears that there is a DA-dependent, secondary loss of enkephalin and tachykinin peptides in PD. In view of the involvement of these peptidergic systems in the regulation of behaviour, movement, memory and other functions, derangements in these systems should be considered as additional factors in the progression of symptoms of PD.     

Alpha frequency modulation in the human basal ganglia is dependent on motor task

Depth recordings from the basal ganglia of patients suffering from Parkinson's disease (PD) or dystonia have revealed local field potential (LFP) activity in specific frequency bands. Depth recordings also allow us to study LFP power spectra during different types of limb movements, thus helping to elucidate the role of the basal ganglia in specific motor tasks. Accordingly, we recorded bilateral LFP activity from the subthalamic nucleus (STN) of patients with PD (n=9) and from the globus pallidus internum (GPi) of patients with dystonia (n=8). Recordings were taken during the performance of repetitive passive, active and ballistic fast extensions and flexions of the elbow joint and during rest. The first result was that the frequency spectra varied task-specifically in a similar fashion in GPi and STN. The amplitude of the alpha frequency on the contralateral side was significantly higher in ballistic fast movements compared with rest, passive and active performance in both STN and GPi. In conclusion, ballistic fast movements cause synchronized basal ganglia activity in the alpha range. Because this was seen in both patient groups (PD and dystonia) we consider this activity as task-specific rather than disease-related.     

The effect of neurointermediate lobe denervation on hypothalamic neuroendocrine dopaminergic neurons

The contribution of tuberohypophyseal and periventricular-hypophyseal dopaminergic neurons to the regulation of the secretion of prolactin (PRL) has yet to be clarified. In this study, we used pituitary stalk compression to disrupt hypothalamic neural input to the neurointermediate lobe (NIL). Neurointermediate lobe denervation (NIL-D) selectively disrupts the axons of tuberohypophyseal and periventricular-hypophyseal dopaminergic neurons, while leaving tuberoinfundibular dopaminergic neurons and the vascular supply of the pituitary gland intact. NIL-D was performed in ovariectomized (OVX) rats. The concentration of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence (ME) and various regions of the pituitary gland of OVX and OVX+NIL-D rats were measured by HPLC-EC. The concentration of PRL, α-melanocyte stimulating hormone (α-MSH), and luteinizing hormone (LH) in serum were determined by radioimmunoassay. Successful NIL-D was confirmed by increased water intake. One week after NIL-D, serum PRL and α-MSH were elevated, but there was no change in the concentration of LH in serum. The concentration of DA was increased in the median eminence (ME), decreased in the outer zone of the anterior lobe (AL-OZ), as well as the intermediate (IL) and neural lobes (NL), and remained unchanged in the inner zone of the anterior lobe (AL-IZ). The concentration of DOPAC was increased in the ME and NL, decreased in the IL, and remained unchanged in both the AL-IZ and AL-OZ. These data confirm that pituitary stalk compression denervates the NIL. Moreover, decreases in the concentration of DA in the IL and AL-OZ, coupled with elevation of serum PRL and α-MSH indicate that DA from the NIL contributes to the increased inhibition of the secretion of PRL and α-MSH in OVX rats.     

Catecholaminergic neurons in the diencephalon and basal ganglia of SIDS.

The catecholaminergic systems of sudden infant death syndrome victims were examined in the diencephalon and basal ganglia, in addition to the midbrain, pons, and medulla oblongata, using the immuno-histochemical method involving tyrosine hydroxylase. A significant decrease in tyrosine hydroxylase immunoreactivity was demonstrated in the basal ganglia of sudden infant death syndrome victims between 2 to 12 months of age compared with age-matched control subjects. This change in the basal ganglia may be a secondary finding induced by chronic hypoxia or repeated ischemia in sudden infant death syndrome but suggests impairment of the development of the neuronal connection from the brainstem to the upper cardiorespiratory control in sudden infant death syndrome.     

The direction of apomorphine-induced rotation behavior is dependent on the location of excitotoxin in the rat basal ganglia

Adult rats received unilateral kainic acid (KA) lesions of the striatum with the anterior/posterior coordinates of the lesion at either 1.5 mm or 0.3 mm anterior to bregma. Four to six weeks after the lesion rats were placed in an open field environment and injected with apomorphine (1 mg/kg, s.c). Rats receiving the more posterior lesion (0.3 mm) rotated ipsilateral to the lesioned side of the brain. In contrast, the majority of rats receiving the more anterior (1.5 mm) placement of the lesion rotated contralateral to the lesioned side of the brain. Histological analysis of several animals receiving posterior lesions revealed damage to the hippocampus and thalamus that was not seen in the animals receiving anterior lesions. Our results are consistent with the hypothesis that the direction of apomorphine-induced rotation after excitotoxin injection into the rat basal ganglia is dependent on the location of the lesion.     

GABA and dopamine interaction in the basal ganglia: dopaminergic supersensitivity following chronic elevation of brain γ-aminobutyric acid levels

The influence of chronic activation of the gamma-aminobutyric acid (GABA) system on dopaminergic function was evaluated in male rats. Activation of the GABA system was achieved by raising the brain concentration of GABA with aminooxyacetic acid (AOAA), a GABA-transaminase (GABA-T) inhibitor. Repeated i.p. injection (40 or 80 mg/kg/day for 8 days) of AOAA produced a sustained elevation of GABA concentration in the striatum. Beginning 26 h following the last dose of a regimen of AOAA treatment (80 mg/kg/day for 8 days), the animals exhibited a characteristic spontaneous 'sham-fighting' behavioral stereotypy which peaked at 34 h after the last dose of AOAA; this spontaneous behavior dissipated by 38 h postdose. When challenged with apomorphine, the sham-fighting behavior was interspersed with intense fighting episodes; these precipitated behaviors were evident for up to 2 weeks posttreatment observation period. Animals given a lower dose of AOAA (40 mg/kg/day X 8) did not show signs of spontaneous sham-fighting, but responded with fighting upon apomorphine challenge. Qualitatively similar behavioral effects were obtained when gamma-acetylenic GABA (30 mg/kg/day, i.p. for 8 days) was used as the inhibitor of GABA-T. Measurement of dopamine and its acid metabolites in the striatum showed an enhanced turnover of dopamine during the spontaneous behavioral response, suggesting a rebound phenomenon. The levels of 5-hydroxytryptamine or its acid metabolite or neuroactive amino acids such as glutamate, aspartate, taurine, glycine, glutamine in the striatum were not altered by any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

NMDA receptor antagonism modifies the synergistic regulation of striatal tachykinin gene expression induced by dopamine D(1) and serotonin(2) receptor stimulation following neonatal dopamine depletion

Co-application of SKF-38393 (dopamine D(1) agonist; 1 mg/kg) and DOI (serotonin(2) agonist; 1 mg/kg) induced a synergistic increase in striatal preprotachykinin (PPT) mRNA levels in adult rats 60 days after neonatal intracerebroventricular injection of 6-hydroxydopamine. This magnitude of response was not observed in intact (vehicle-injected) rats and was restricted to the dorsomedial (DM, 333+/-25% of lesion) subregion of the anterior striatum, with smaller increases observed in the dorsolateral striatum (DL, 206+/-26% of lesion). A single i.p. injection of MK-801 (NMDA antagonist; 0.1 mg/kg) administered prior to dopamine D(1) (D(1)) and serotonin(2) (5-HT(2)) receptor co-stimulation suppressed the synergistic regulation of PPT mRNA expression in the DM striatum, but also produced a large increase in PPT message levels within the DL striatum (321+/-17% of lesion). These data suggest that the synergistic regulation of PPT mRNA within the DM striatum induced by D(1)/5-HT(2) receptor co-stimulation in the dopamine lesioned rat is dependent on NMDA receptor activity. However, MK-801 may simultaneously potentiate striatal PPT mRNA expression by a separate mechanism due to the changed environment of the dopamine-depleted basal ganglia.     

D1 Dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior

The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder. Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, L-dihydroxyphenylalanine (L-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The L-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the L-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation: and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.     

Ultrastructural analysis of the serotonin hyperinnervation in adult rat neostriatum following neonatal dopamine denervation with 6-hydroxydopamine.

Serotonin (5-HT) immunocytochemistry was used at the electron microscopic level to characterize the ultrastructural features of 5-HT axon terminals (varicosities) hyperinnervating the neostriatum of adult rats, 3 months after a neonatal destruction of the nigrostriatal dopamine system by intraventricular 6-hydroxydopamine. 5-HT-immunostained terminals from the anterior half of the hyperinnervated neostriatum were examined in single thin sections, and compared to their counterparts in vehicle-injected controls with respect to shape, size, organelle content, presence of a synaptic membrane differentiation and composition of the microenvironment. The intrinsic and relational features of the 5-HT-immunostained varicosities were essentially the same in 5-HT-hyperinnervated and control tissue. In particular, the frequency with which these varicosities made synaptic contacts was similarly low in both conditions (6-8% for whole varicosities), as already described in normal adult rat neostriatum. The distributional frequency of elements juxtaposed to the 5-HT-immunostained varicosities was also comparable in control and 5-HT-hyperinnervated tissue. However, in both conditions, there were much fewer dendritic spines in the microenvironment of 5-HT varicosities than around unlabeled terminals randomly selected from the same thin sections. This difference seemed entirely due to the numerous axo-spinous synaptic contacts made by the randomly selected, unlabeled varicosities. Together with recent observations on the 5-HT-hyperinnervation of adult rat hippocampus after grafts of fetal neurons, these data lead to the suggestion that mostly non-junctional neostriatal 5-HT terminals are not committed to a specific intratissular microenvironment. This might in part explain why they grow in excess when reinnervating adult tissue after a lesion or a graft.     

Differential dopaminergic regulation of proenkephalin and prodynorphin mRNAs in the basal ganglia of rats.

Proenkephalin and prodynorphin mRNA levels in the caudate-putamen and in the nucleus accumbens of rats were measured by in situ hybridization 2, 4 and 8 weeks following unilateral lesion of the medial forebrain bundle by 6-hydroxydopamine (6-OHDA). After 2 weeks a 60% increase of the levels of proenkephalin mRNA in the ipsilateral caudate-putamen was observed which declined to 20% above control after 8 weeks. A smaller increase in the levels of proenkephalin mRNA of about 20% was observed in the nucleus accumbens after 2 weeks and no significant alteration could be observed 4 and 8 weeks after lesioning. The levels of prodynorphin mRNA in the ipsilateral caudate-putamen decreased 20% below control and returned to control levels 4 and 8 weeks post-lesion. In contrast, in the nucleus accumbens a persistent ipsilateral decrease of prodynorphin (20-30%) was found 2, 4 and 8 weeks post-lesion. These findings indicate, that lesions of the mesostriatal dopamine (DA) system differentially influences opioidergic gene expression in distinct areas of the caudate-putamen. The lesions cause an increase in proenkephalin mRNA levels which was higher in the caudate-putamen than in the nucleus accumbens and tend to be reversible. Conversely, the lesion caused a persistent decrease in the levels of prodynorphin mRNA in the nucleus accumbens and a small and transient decrease in the caudate-putamen.     

The weaver mutation reverses the function of dopamine and GABA in mouse dopaminergic neurons.

In the present study, we characterized the intrinsic electrophysiological properties and the membrane currents activated by dopamine (DA) D(2) and GABA(B) receptors in midbrain dopaminergic neurons, maintained in vitro in a slice preparation, from wild-type and homozygous weaver (wv/wv) mice. By using patch-clamp techniques, we found that membrane potential, apparent input resistance, and spontaneous firing of wv/wv dopaminergic neurons were similar to those of dopamine-containing cells recorded from nonaffected (+/+) animals. More interestingly, the wv/wv neurons were excited rather than inhibited by dopamine and the GABA(B) agonist baclofen. This neurotransmitter-mediated excitation was attributable to the activation of a G-protein-gated inward current that reversed polarity at a membrane potential of approximately -30 mV. We suggest that the altered behavior of the receptor-operated wv G-protein-gated inwardly rectifying K(+) channel 2 (GIRK2) might be related to the selective degeneration of the dopaminergic neurons. In addition, the wv GIRK2 would not only suppress the autoreceptor-mediated feedback inhibition of DA release but could also establish a feedforward mechanism of DA release in the terminal fields.