Biomedical subjects

P D Walker

Publications and source records attributed to P D Walker.

At least 37 records · Page 2Linked to original sources

PubMed1999

Suppression of serotonin hyperinnervation does not alter the dysregulatory influences of dopamine depletion on striatal neuropeptide gene expression in rodent neonates.

Sixty days following neonatal dopamine depletion (>98%) with 6-hydroxydopamine, preprotachykinin and preprodynorphin mRNA levels were significantly reduced (67 and 78% of vehicle controls, respectively) in the anterior striatum as determined by in situ hybridization while preproenkephalin mRNA expression was elevated (133% of vehicle controls). Suppression of the serotonin hyperinnervation phenomenon in the dopamine-depleted rat with 5,7-dihydroxytryptamine yielded no significant alterations in reduced striatal preprotachykinin (66%) or preprodynorphin (64%) mRNA levels, while preproenkephalin mRNA expression remained significantly elevated (140%). These data suggest that striatal serotonin hyperinnervation does not contribute to the development of dysregulated striatal neuropeptide transmission in either direct or indirect striatal output pathways following neonatal dopamine depletion.

5,7-Dihydroxytryptamine↗

PubMed1999

Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Synergistic interaction between serotonin-2 receptor and dopamine D1 receptor stimulation on striatal preprotachykinin mRNA expression in the 6-hydroxydopamine lesioned rat.

The regulation of striatal preprotachykinin (PPT) mRNA expression can be mediated through both dopamine (DA) D1 and serotonin (5-HT) 5-HT2A/2C receptors. In the present study, we used in situ hybridization to examine possible synergistic interactions between 5-HT2A/2C and D1 receptor-mediated regulation of striatal PPT mRNA levels in the rat depleted of DA with 6-hydroxydopamine. Acute administration of the 5-HT2A/2C receptor agonist DOI (2 mg/kg) significantly increased (+75%) PPT mRNA levels in the dorsal striatum. Acute administration of the D1 receptor agonist SKF-38393 (2 mg/kg) did not significantly alter PPT mRNA levels in the dorsal striatum. However, the co-administration of SKF-38393 and DOI produced a significant increase (+300%) in striatal PPT mRNA expression restricted to the periventricular region of the dorsal-medial striatum. This synergistic interaction was not observed in the remaining aspect of the dorsal striatum where DOI alone increased PPT mRNA expression. These data show that 5-HT2A/2C and D1 receptors can act in a synergistic manner to regulate striatal PPT mRNA in a subregion of the DA-depleted striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1999

Acute p-chloroamphetamine increases striatal preprotachykinin mRNA: role of the serotonin 2A/2C receptor.

Acute administration of p-chloroamphetamine (pCA) significantly increased (+90%) preprotachykinin (PPT) mRNA levels in the rat striatum. Administration of the serotonin2A/2C receptor antagonist, ritanserin, blocked the pCA-induced increase in PPT mRNA levels. alpha-Methyl-p-tyrosine pretreatment (alpha-MT, to reduce dopamine transmission) inhibited the pCA-induced increase in PPT mRNA levels. These results indicate that the pCA-induced increase in striatal PPT mRNA expression is mediated by serotonin2A/2C receptors but also requires dopamine tone.

Animals↗

PubMed1999

Differential sensitivity of tachykinin vs. enkephalin gene expression in the posterior striatum in response to acute p-chloroamphetamine treatment during postnatal development.

The acute effects of the monoamine releaser p-chloroamphetamine (pCA, 10 mg/kg, i.p.) on preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the anterior (A-STR) vs. posterior (P-STR) striatum were studied in rodents at postnatal days (PND) 10, 21 and 35. Northern analysis 4 h post-injection yielded no significant mRNA changes within the A-STR of any pCA group. However, significant increases (80-200% of saline control) in PPT mRNA levels occurred within the P-STR at all three postnatal ages. Interestingly, pCA did not increase PPE mRNA levels within the P-STR until PND 35 (150% of saline control). Such observation suggests that tachykinin neurons of the P-STR achieve an earlier monoamine-responsive signal transduction linkage to gene regulation as compared to enkephalin neurons. Given its predominance in the caudal regions of the striatum, 5-HT neurotransmission at the 5-HT2 receptor is suggested to play a central role in this mechanism.

Aging↗

PubMed1999

Effects of serotonin inhibition on neuronal and astrocyte plasticity in the phrenic nucleus 4 h following C2 spinal cord hemisection.

C2 spinal cord hemisection results in synaptic and astroglial changes in the phrenic nucleus which have been associated with the recovery of the ipsilateral hemidiaphragm during expression of the crossed phrenic phenomenon. As part of our ongoing analysis of the neurotransmitters involved, the present study investigated the effects of systemic administration of para-chlorophenylalanine (p-CPA), a serotonin (5-HT) synthesis inhibitor, on plasticity in the rat phrenic nucleus 4 h following C2 hemisection. Hemisected control rats demonstrated typical morphological changes in the ipsilateral phrenic nucleus including: (1) an increased number and length of synaptic active zones and (2) an increased number and length of dendrodendritic membrane appositions. p-CPA treatment 3 days prior to hemisection reduced 5-HT levels and resulted in an attenuation of these changes in the ipsilateral phrenic nucleus 4 h following hemisection compared to hemisected controls. In addition, p-CPA treatment attenuated injury-induced alterations in immunohistochemical staining of glial fibrillary acidic protein (GFAP), although Western blot analysis demonstrated that overall levels of GFAP did not differ significantly between groups. The results suggest that inhibition of 5-HT synthesis by p-CPA attenuates hemisection-induced plasticity in the phrenic nucleus 4 h following an ipsilateral C2 hemisection.

Animals↗

PubMed1999

Effects of the serotonin synthesis inhibitor p-CPA on the expression of the crossed phrenic phenomenon 4 h following C2 spinal cord hemisection.

The present study assesses the effects of para-chlorophenylalanine (p-CPA), a serotonin-depleting drug, on the recovery of respiratory-related activity in the phrenic nerve induced by asphyxia 4 h following ipsilateral C2 hemisection in young adult rats. HPLC analysis was used to quantify levels of serotonin (5-HT), dopamine (DA), norepinephrine, and the 5-HT metabolite, 5-hydroxyindoleacetic acid, in the C4 segment of the spinal cord, all of which were significantly lower in p-CPA-treated hemisected rats compared to hemisected controls receiving saline. Hemisection alone was found to significantly increase 5-HT levels and significantly decrease DA levels compared to normal controls. Eight of eight saline-injected rats expressed recovery of respiratory-related activity in the ipsilateral phrenic nerve during asphyxia 4 h following hemisection, while only 4/8 rats in the p-CPA-treated group expressed recovery in the ipsilateral nerve. Quantification of integrated phrenic nerve wave-forms indicated that the mean amplitude of respiratory-related activity in the ipsilateral phrenic nerve was significantly lower in p-CPA-treated rats than in saline controls. In addition, saline controls demonstrated significant increases in mean respiratory frequency and mean amplitude of contralateral phrenic nerve activity during asphyxia, compared to normocapnia. However, p-CPA-treated rats did not express significant differences in either mean respiratory frequency or mean amplitude of integrated respiratory wave-forms during asphyxia, compared to normocapnia. The results suggest that p-CPA treatment attenuates the recovery of respiratory-related activity in the phrenic nerve 4 h following ipsilateral C2 hemisection and attenuates asphyxia-induced increases in respiratory frequency and respiratory burst amplitude recorded from the contralateral phrenic nerve.

Animals↗

PubMed1999

Serotonin-2 receptor stimulation normalizes striatal preprotachykinin messenger RNA in an animal model of Parkinson's disease.

Dopamine and serotonin neurotransmission regulate striatal preprotachykinin messenger RNA levels. In the present study, we investigated serotonin 2A/2C receptor-mediated regulation of preprotachykinin messenger RNA expression in the rat striatum after adult dopamine depletion produced with 6-hydroxydopamine. Significant reductions (46-61% of control values) in preprotachykinin messenger RNA levels were detected by in situ hybridization in rostral, central and caudal regions of the striatum after >85% dopamine depletion. Repeated administration of the specific serotonin2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide, to dopamine-depleted rats completely reversed the reduction in preprotachykinin messenger RNA levels in rostral, central and dorsal-caudal striatal regions. In unlesioned (vehicle-injected) control animals, repeated administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide did not affect preprotachykinin messenger RNA expression in rostral, central and ventral-caudal striatal regions, but decreased preprotachykinin messenger RNA levels in the dorsal-caudal striatal subregion. In addition, serotonin turnover in the dopamine-depleted rostral striatum was significantly increased by 35-45% which is consistent with serotonin hyperinnervation after 6-hydroxydopamine lesions. These data show that the decrease in striatal preprotachykinin messenger RNA after dopamine depletion can be normalized with repeated serotonin2A/2C receptor stimulation. We hypothesize that this serotonin2A/2C receptor regulation of preprotachykinin messenger RNA expression after 6-hydroxydopamine is a consequence of serotonin hyperinnervation, which may include increased striatal serotonin2A/2C receptors, induced by dopamine depletion. We also propose that the serotonin system could be pharmacologically targeted to restore the direct striatal tachykinin pathway in Parkinson's disease.

Amphetamines↗

PubMed1999

Patterns of immediate early gene mRNA expression following rodent and human traumatic brain injury.

Cell stimulation which leads to degeneration triggers a prolonged wave of immediate early gene (IEG) transcription that correlates with neuronal demise. In order to determine the relevance of the prolonged IEG response to human traumatic brain injury, we analyzed IEG mRNA levels in brain tissue isolated following a controlled penetrating injury and an injection of the excitotoxin Quinolinic acid (QA), as well as from tissue recovered during routine neurosurgery for trauma. Total RNA was extracted from tissue and subjected to Northern analysis of IEG mRNAs (c-fos and zif/268). Both models produced rapid and prolonged waves of IEG transcription that appeared to correlate with the severity of injury. Increases in zif/268 mRNA were observed within 1 h with levels reaching their peak at 6 h following excitotoxic injury and 3 h following a controlled penetration. In general, human traumatic brain injury resulted in variable increases in IEG mRNA levels following traumatic injury with the largest IEG mRNA increases observed in tissue collected 0-10 h after injury. This post-injury time corresponds to the peak of the prolonged IEG response observed in rodents following excitotoxic injury. Comparisons were made in IEG response between rodent frontal cortex and human cortex, because the majority of the human tissue originated from the cerebral cortex. These results further support the hypothesis that prolonged IEG transcription serves as a marker of traumatic brain injury and may play a role in neurodegeneration and/or glial activation. Moreover, observations of similar IEG patterns of expression reinforces the importance of rodent models of brain injury providing useful information directly applicable to human brain injury.

Animals↗

PubMed1999

Oxidant mechanisms in toxic acute renal failure.

Over the last decade, there is accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, cisplatin, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown both in in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free-radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, recent studies suggest that cytochrome P450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Several recent in vitro and in vivo studies indicate an important role of reactive oxygen metabolites in cisplatin-induced nephrotoxicity. Thus, catalytic iron is increased both in vitro and in vivo by cisplatin, and iron chelators as well as hydroxyl radical scavengers have been shown to be protective. Recent studies indicate that cytochrome P450 may also be an important source of the catalytic iron in cisplatin nephrotoxicity. Cyclosporine A has been shown to enhance generation of hydrogen peroxide in vitro and enhance lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

Acute Kidney Injury↗

PubMed1998

Meprin A, the major matrix degrading enzyme in renal tubules, produces a novel nidogen fragment in vitro and in vivo.

We examined the effect of meprin A, the major matrix degrading metalloproteinase in rat kidney, on the laminin-nidogen complex. N-terminal sequence information from the most abundant 55 kDa fragment revealed that it was a breakdown product of nidogen rather than laminin. In comparison with over 50 nidogen cleavage sites produced by other proteases, the meprin A-induced nidogen cleavage site at amino acid position 899-900, a glutamine-glycine site in the G3 domain, is unique. In addition, these data demonstrate that meprin A degrades the G3 domain of nidogen even in the presence of laminin binding, which usually accords protection from proteolytic degradation. Meprin A also degraded purified nidogen into similar breakdown products. Given that the tubular basement membrane is located on the basilar side of the cell, the location of meprin A on the apical brush border makes it difficult to envision a role for meprin A in injury-induced basement membrane component breakdown. Thus, we examined the possibility that following renal tubular epithelial cell injury, meprin A undergoes a translocation to reach the underlying basement membrane. After renal ischemia-reperfusion there was a marked alteration in meprin A staining with meprin A now distributed throughout the renal tubular cell cytoplasm and directly adherent to the tubular basement membrane. This was in contrast to the usual linear staining of the brush border of tubules in the corticomedullary junction. These data provide unequivocal evidence that following injury, meprin A undergoes redistribution and/or adherence to the tubular basement membrane. Since in our in vitro studies, we identified a distinct meprin-induced 55 kDa nidogen breakdown product, the urine was also examined for the presence of nidogen degradation products after rat renal ischemia-reperfusion injury. Western blots showed a marked increase in the urinary 55 kDa nidogen fragment as early as the first day following ischemia-reperfusion injury and continuing for six days. Taken together, these in vivo data strongly support the notion that the nidogen breakdown products are the result of partial degradation of tubular basement membrane by meprin A following renal tubular ischemia-reperfusion injury.

Amino Acid Sequence↗

PubMed1998

Patterns of heat-shock protein 70 biosynthesis following human traumatic brain injury.

Heat-shock protein 70 (hsp70) is activated upon cellular stress/injury and participates in the folding and intracellular transport of damaged proteins. The expression of hsp70 following CNS trauma has been speculated to be part of a cellular response which is involved in the repair of damaged proteins. In this study, we measured hsp70 mRNA and protein levels within human cerebral cortex subjected to traumatic brain injury. Specimens were obtained during routine neurosurgery for trauma and processed for Northern mRNA and Western protein analysis. The largest increase in hsp70 mRNA levels was detected in trauma tissue obtained 4-6 h following injury. By 24 h, hsp70 mRNA levels were similar to nontrauma comparison tissues. hsp70 protein expression exhibited its greatest increases at 12-20 h post-injury. Immunocytological techniques revealed hsp70 protein expression in cells with neuronal-like morphology at 12 h after injury. These results suggest a role for hsp70 in human cortex following TBI. Moreover, since the temporal induction pattern of hsp70 biosynthesis is similar to that reported in the rodent, our observations validate the importance of rodent brain injury models in providing useful information directly applicable to human brain injury.

Blotting, Northern↗

PubMed1998

Heat-shock protein 72 expression in excitotoxic versus penetrating injuries of the rodent cerebral cortex.

The induction of heat shock protein 72 (hsp72) has been described in various experimental models of brain injury. The present study examined hsp72 expression patterns within the rodent cerebral cortex in experimental paradigms designed to mimic two mechanisms of damage produced by penetration of the cerebral cortex: (1) tissue tearing from the missile track and (2) diffuse excitotoxicity during temporary cavitation and shock wave formation. Adult male Spaque-Dawley rats received controlled penetration (stab) or injection of the NMDA receptor excitotoxin, quinolinic acid (QA), into the frontal cortex and were killed 1-24 h later. Tissue from the lesioned, sham-operated, or contralateral uninjected cortex was processed for Western and immunocytochemical analyses of hsp72 protein expression. By 12 h, both controlled penetration and excitotoxic brain injuries produced significant increases in hsp72 immunoreactivity, which decreased toward control levels at 24 h. However, the severity and regional distribution of hsp72 expression varied between the two models. Specifically, the controlled penetration injury produced many hsp72-expressing cells near the needle track, while immunoreactive cells within the QA-injected cortex were found in the periphery of the lesion site. Morphological assessment of brain sections subjected to dual-labeling procedures demonstrated that cells expressing hsp72 were primarily neuronal in both models of injury. These results suggest that although controlled penetration and diffuse excitotoxicity may induce similar temporal and cellular patterns of hsp72 expression, the spatial location of hsp72-immunoreactive cells may differ between the two models.

Animals↗

PubMed1997

Intracellular distribution of heat-induced stress glycoproteins.

Cellular heat stress results in elevated heat-shock protein (HSP) synthesis and in thermotolerance development. Recently, we demonstrated that protein glycosylation is also an integral part of the stress response with the identification of two major stress glycoproteins, GP50, associated with thermotolerance, and P-SG67, the "prompt" stress glycoprotein induced immediately during acute heat stress. In the present study, we characterized the subcellular location and redistribution of these proteins during the cellular injury and recovery phase. In unheated and heated CHO cells, both stress glycoproteins were present in each subcellular fraction isolated by differential centrifugation. However, the subcellular redistribution in the course of cellular recovery after heat stress was specific for each stress glycoprotein. GP50 was present in all subcellular fractions before heat stress, but showed relatively little redistribution after heat stress. By 24 h of recovery following stress, GP50 showed partial depletion from lysosomes and microsomes, and was mainly present in the mitochondria. Glycosylated P-SG67 was redistributed in a more complex fashion. It was seen predominantly in the lysosomes and microsomes immediately following heat-stress, but after 6 h of recovery following heat stress, it largely disappeared from the microsomes and was present mainly in the cytosol. By 24 h of recovery following heat stress, it was found predominantly in the nucleus-rich fraction and mitochondria. The localization of GP50 and P-SG67 by subcellular fractionation is consistent with immunolocalization studies and contrasts with the translocation of HSP70 after heat stress from cytosol to nuclei and nucleoli. These results reflect a characteristic distribution for each stress glycoprotein; their presence in virtually all subcellular fractions suggests multifunctional roles for the various stress glycoproteins in the cellular heat stress response.

Animals↗

PubMed1997

NMDA receptor overstimulation triggers a prolonged wave of immediate early gene expression: relationship to excitotoxicity.

Exposure of the rodent striatum to quinolinic acid (QA, N-methyl-D-aspartate receptor agonist) induces immediate early gene (IEG; c-fos, c-jun, jun-B, zif/268) expression that may extend 12-24 h after injection. In order to determine the specificity of the prolonged IEG response to the QA injection, the temporal pattern of c-fos mRNA expression was examined during the first 4 h after administration of saline or QA (40 micrograms). As early as 30 min after intrastriatal injection, both saline and QA increased c-fos mRNA levels. In the saline group, this increase in IEG expression was only transient and returned to baseline by 1 h. In contrast, c-fos mRNA levels within QA-injected animals continued to rise significantly at 1 and 4 h. In a second experiment, rats received 4 ng to 40-micrograms injections of QA followed by sacrifice at 6 h to determine if increasing QA doses caused the appearance of the prolonged IEG response phase. The prolonged IEG response was evident at 6 h only in animal groups that received higher dose ranges (4-40 micrograms) of QA. A final experiment was undertaken to determine if blockage of NMDA receptor stimulation would also inhibit the prolonged IEG response at 6 h in relationship to neuronal sparing evidenced at 24 h post-QA injection. The NMDA receptor antagonist, MK-801, blocked the prolonged IEG response at 6 h following QA (40 micrograms) injection while also preventing striatal neuropeptide mRNA decline by 24 h. Delaying the MK-801 administration for 1-2 h post-QA injection revealed that the intensity of the prolonged IEG mRNA response may be predictive of neuronal demise within the QA lesion site. These results suggest that prolonged IEG expression is associated with QA excitotoxicity of the rodent striatum and subsequent neuronal degeneration.

Animals↗

PubMed1997

Oxidant mechanisms in toxic acute renal failure.

Over the last decade, there has been accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown in both in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, the results of recent studies suggest that cytochrome P-450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Cyclosporine A has been shown to enhance the generation of hydrogen peroxide in vitro and lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

Acute Kidney Injury↗

PubMed1997

Demonstration of autoantibodies to the endolymphatic sac in Meniere's disease.

Recent evidence suggests that immune mechanisms may underlie some cases of Meniere's disease. This study was conducted to determine whether an autoimmune mechanism is involved. Sera from 30 patients with Meniere's disease were reacted with human endolymphatic sacs and examined by indirect immunohistochemistry and fluorescence microscopy. Three of the samples (10%) showed positive staining, indicating immunoglobulin G (IgG) binding against the sac. No positive staining occurred when sera from healthy individuals or phosphate-buffered saline was used as a control. Clinical data showed an association between immunoreactivity and extent of disease (worse hearing over a shorter disease course and bilateral involvement). This study suggests that, in some cases of Meniere's disease, autoantibodies directed against human endolymphatic sac are present in the sera, supporting the theory that a specific autoimmune reaction takes place in a minority of patients with Meniere's disease.

Aged↗

PubMed1997

Alterations in the postnatal development of striatal preprotachykinin but not preproenkephalin mRNA expression in the serotonin-depleted rat.

We examined the effects of diminished serotonin (5-hydroxytryptamine, 5-HT) levels on the postnatal development of striatal tachykinin and enkephalin neuropeptide systems. Neonatal rats received intracisternal injection of vehicle or the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 100 micrograms) on postnatal day 2 followed by sacrifice 1-29 days later. Monoamine analysis by high-performance liquid chromatography with electrochemical detection revealed a drastic reduction of midbrain 5-HT levels, but not norepinephrine or dopamine, as early as 1 day and extending to 29 days following 5,7-DHT injection. Striatal preprotachykinin (PPT) mRNA levels were significantly increased 8 days following injection. However, PPT mRNA amounts failed to remain up-regulated, falling back to or below control levels during the second and third weeks following injection. By day 29, striatal PPT mRNA had normalized to control levels even though 5-HT amounts were still markedly reduced. Throughout the entire time course, striatal preproenkephalin mRNA levels did not significantly differ from control levels. These results suggest that striatal tachykinin, but not enkephalin, neurons may be transiently sensitive to lowered 5-HT neurotransmission during postnatal development.

5,7-Dihydroxytryptamine↗