Biomedical subjects

S P Sivam

Publications and source records attributed to S P Sivam.

At least 19 recordsLinked to original sources

PubMed1996

Dopamine, serotonin and tachykinin in self-injurious behavior.

The neurobiologic basis of self-injurious behavior (SIB) in Lesch-Nyhan syndrome and in other neuropsychiatric conditions remains unclear. The purpose of this review is to summarize recent data concerning SIB induced by the dopamine (DA) uptake inhibitor, GBR-12909 (GBR) and to compare the neurochemical data that have accumulated over the years on SIB in neonatal 6-hydroxydopamine (6OHDA) lesioned rats. The DA uptake inhibitor, GBR, upon repeated administration to adult rats elicits SIB that is temporally associated with a reduction of striatal DA (approximately 30%), increased turnover of serotonin and a robust induction of tachykinin transcription resulting in enhanced biosynthesis and presumably release of tachykinins (substance P and neurokinin A). GBR-induced SIB could be blocked by dopaminergic lesions or by D1 or D2 antagonists. Neonatal dopaminergic lesions result in a high degree of DA loss (> 90%) and elevated levels of serotonin. In this model, SIB is precipitated by DA agonists via activation of D1 DA receptors which are in turn linked to an induction of tachykinin biosynthesis and release. The data taken together suggest that (a) a substantial reduction of DA accompanied by an increase in serotonin turnover may be essential conditions that are conducive to the occurrence of SIB, and (b) this phase is either superimposed with, or followed by a D1 and/or D2 DA receptor-linked activation of striatonigral tachykinin neurons resulting in enhanced tachykinin biosynthesis and release that may sustain the SIB. Thus, a dynamic interplay between DA, serotonin and tachykinin neuronal systems of the basal ganglia appear to influence the genesis and/or expression of SIB.

Animals↗

PubMed1996

Dopaminergic regulation of striatonigral tachykinin and dynorphin gene expression: a study with the dopamine uptake inhibitor GBR-12909.

The present study examined the modulatory role of dopamine (DA) on striatonigral preprotachykinin (PPT) and prodynorphin (PD) gene expression, employing the DA uptake inhibitor, GBR-12909 (GBR), as a tool. The striatal and nigral levels of tachykinin (substance P (SP), neurokinin A (NKA)) and dynorphin (dynorphin A(1-8) (DYN)) peptides were determined by radioimmunoassays. The abundance of mRNAs in the striatum was quantified by Northern blot analysis. The rate of transcription of PPT and PD genes in the striatum was measured by transcription run-on assays. A regimen of repeated administration of GBR (20 mg/kg/day, i.p., for 1-4 days) to female Sprague-Dawley rats increased striatal and nigral SP, NKA, and DYN peptide levels. The increased peptide levels were associated with increases in the abundance of PD mRNA and PPT mRNA and increases in the rate of transcription of PD and PPT genes in the striatum, suggesting a GBR-induced activation of the striatonigral tachykinin and dynorphin neurons. Dopaminergic denervation with 6-hydroxydopamine (6OHDA) blocked the GBR-induced increases in SP and DYN and PPT and PD mRNAs. The concurrent administration of the D1 DA antagonist, SCH-23390, blocked the GBR-induced increases in SP, NKA and PPT mRNA but failed to affect DYN or PD mRNA levels; the concurrent administration of the D2 DA antagonist, spiperone, blocked the GBR-induced increases in SP, NKA and PPT mRNA and also DYN and PD mRNA. The study reveals that repeated administration of GBR enhances the levels of tachykinin and dynorphin peptides in striatonigral neurons by a stimulus-transcription-biosynthesis coupling mechanism. The GBR-induced effects are dependent on the integrity of nigrostriatal dopaminergic neurons and the presence of D1 and/or D2 DA receptors.

Animals↗

PubMed1996

Dopaminergic regulation of postnatal development of dynorphin neurons in rat striatum.

This study examined whether the postnatal development of the biosynthesis of an opioid peptide, dynorphin A (1-8) (DYN) is influenced by dopamine (DA) deficiency. The neurotoxin 6-hydroxydopamine (6-OHDA) was used as a tool to induce DA deficiency on the third day of the postnatal period in Sprague-Dawley rat pups. During the postnatal period, the levels of striatal DYN steadily increased in an age-dependent fashion and appeared to peak between 35 and 45 days. In neonatal 6-OHDA-lesioned animals, the category with 95% or more DA loss exhibited a reduction in the levels of DYN in the postnatal period whereas the category with less than 95% DA loss did not show significant changes in DYN levels. The results indicate that the normal development of striatal DYN is negatively affected only when there is a near-total loss of DA during early postnatal period.

Animals↗

PubMed1995

GBR-12909-induced self-injurious behavior: role of dopamine.

A regimen of repeated administration of GBR (10 or 20 mg/kg/day, i.p., for 4 days) to female Sprague-Dawley rats induced a dose-and time-related increase in the incidence of self-injurious behavior (SIB) that consisted of injury to body areas, paws and tail. The treatment regimen decreased striatal DA and DOPAC levels. Dopaminergic denervation with 6-hydroxydopamine (6-OHDA) or D1 DA antagonist, SCH-23390 or D2 DA antagonist, spiperone, blocked the GBR-induced SIB. Male rats were less sensitive than female rats to exhibit a comparable incidence of SIB. Taken together, the study reveals that repeated administration of GBR induces SIB that is dependent on the integrity of nigrostriatal dopaminergic system and the presence of D1 and/or D2 DA receptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Dopaminergic modulation of serotonin metabolism in rat striatum: a study with dopamine uptake inhibitor GBR-12909.

The dopamine (DA) uptake inhibitor, GBR 12909 (GBR) and a neonatal dopaminergic denervated rat model were used as tools to study the influence of DA on the serotonin (5HT) system in the striatum. The striatal levels of the amines and their acid metabolites (dihydroxyphenylacetic acid, DOPAC; 5-hydroxyindoleacetic acid, 5HIAA) were determined by HPLC. The administration of a single dose (20 mg/kg) of GBR failed to affect the steady-state levels of the amines or metabolites. Repeated administration of GBR (20 mg/kg/day) for 2 or 4 days decreased DA and DOPAC; only the 4-day regimen decreased 5HT and increased 5HIAA levels. The neonatal dopaminergic lesion with 6-hydroxydopamine (6OHDA) depleted (> 95%) DA and DOPAC and increased 5HT and 5HIAA levels in the striatum. Administration of GBR (20 mg/kg/day for 4 days) to lesioned animals failed to influence the lesion-induced increases in 5HT and 5HIAA levels. The results suggest GBR decreases the steady-state levels of DA, resulting in a compensatory increase in the turnover of 5HT that is dependent on the presence of intact dopaminergic terminals. Thus, the effect of GBR on 5HT turnover is indirect. The studies provide further support for a prominent dopaminergic influence on striatal 5HT metabolism.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Integration of pharmacology into a problem-based learning curriculum for medical students.

The purpose of this study is threefold: (1) to describe a method of integration of pharmacology subject matter with other disciplines, in a problem-based learning (PBL) curriculum employed at the Northwest Center for Medical Education (NWCME), Indiana University School of Medicine; (2) to present various evaluation methods employed to assess students' learning of pharmacology knowledge; and (3) to compare the academic performance of students who underwent a traditional curriculum versus the PBL curriculum in terms of class evaluations and the standard national board medical licensure examinations. The PBL curriculum is designed for the first 2 years of medical education and consists of six sequential steps: steps 1 and 2 deal with biochemistry and anatomy respectively; steps 3, 4 and 5 deal with physiology, neuroscience and general pathology/microbiology respectively; and step 6 is a multidisciplinary step, which integrates basic science subjects with clinical medicine, emphasizing the mechanism of disease in an organ-system approach. In the PBL curriculum students start learning pharmacology within 6 months of admission. The content and process of pharmacology are spread across the first and in the second year. The pharmacology content is divided into three segments, each of which is integrated with other basic science subjects that have maximum mutual relevance. The three segments are as follows: the general and systemic pharmacology (50%) was included in step 3; the neuropharmacology and toxicology (35%) part was included in step 4; the third segment consisted of antimicrobial agents, anticancer and antiinflammatory agents (15%) and was included in step 5. The class evaluation of student performance in the PBL curriculum consisted of two elements, the content examinations and the process evaluations, which include the tutorial and the triple-jump evaluations of problem-solving skills. In order to assess the overall academic performance of the PBL curriculum and traditional curriculum groups, three classes of students who took the PBLC were compared with three classes of students who underwent a TC for performance in terms of class grades and scores of National Board examinations (NBMEI and/or USMLE I). The PBL curriculum students performed as well as or better than the TC students as measured by the NMBEI and/or USMLE I. The gain in pharmacology knowledge of PBL students is accompanied by the presence of a positive experience that learning pharmacology is enjoyable. Our experience suggests that the segmental integration approach of instruction coupled with a system of content (internal and external examinations) and process (tutorial and triple-jump) evaluations, as outlined in this paper is a contextualized learning method that offers an effective way of imparting pharmacology knowledge to medical students.

Education, Medical, Undergraduate↗

PubMed1993

Influence of monoamine oxidase inhibitors on striatonigral dynorphin system: a study with deprenyl and clorgyline.

This study examined the influence of selected monoamine oxidase (MAO) inhibitors on basal ganglia neurotransmitters (dopamine and 5-hydroxytryptamine) and neuropeptide (dynorphin) systems of Sprague-Dawley rats. The striatum or substantia nigra or both were used for biochemical determinations. The striatal concentrations of DA, 5-hydroxytryptamine (5-HT) and their metabolites were determined by HPLC. The levels of striatal and nigral dynorphin A (1-8) (DYN) were determined by radioimmunoassay. The abundance of striatal prodynorphin (PD) mRNA was determined by Northern blot analysis using a cRNA probe. Deprenyl, a MAO-B selective inhibitor (0.25, 0.5, 5, 10 or 20 mg/kg/day, subcutaneously (s.c.) for 4 d) and clorgyline, a MAO-A inhibitor (0.5, 5, 10 or 20 mg/kg/day, s.c. for 4 d) produced a dose-related increase in DA and 5-HT and a decrease in their metabolites in the striatum. Only high doses (20 mg/kg) of deprenyl or clorgyline induced an increase in DYN levels in the striatum and substantia nigra (DYN terminal region); the increased level of DYN was accompanied by an increase in PD-mRNA levels in striatum (DYN cell-body region). Co-administration of low doses (2.5 mg/kg/day, s.c. for 4 d) of deprenyl and clorgyline, that would selectively inhibit MAO-B and MAO-A respectively, produced a marked increase in DA and 5-HT, a decrease in DOPAC and 5-HIAA, an increase in DYN levels in the striatum and substantia nigra and an increase in PD-mRNA levels in the striatum. The results indicate that concurrent inhibition of MAO-B and MAO-A, that results in markedly elevated levels of DA and 5-HT in the striatum, is associated with an increase in dynorphin biosynthesis in the striatonigral neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Tachykinin systems in the spinal cord and basal ganglia: influence of neonatal capsaicin treatment or dopaminergic intervention on levels of peptides, substance P-encoding mRNAs, and substance P receptor mRNA.

The aim of the study was to test whether the synthesis of substance P (SP) and that of its receptor (also known as NK1 receptor) are coordinately regulated after chronic pharmacologic intervention in two neural systems, the spinal cord and basal ganglia. In one set of experiments, capsaicin was administered subcutaneously during the early postnatal period (day 3 after birth) to induce degeneration of afferent sensory neurons in the spinal cord. In the other set of experiments, interruption of dopaminergic transmission was achieved by two methods: (a) The neurotoxin 6-hydroxydopamine was used to denervate dopaminergic neurons during the early postnatal period, and (b) haloperidol was used in adult animals to block dopaminergic transmission by receptor blockade. The spinal cord, striatum, or both were used for the quantification of tachykinin [SP and neurokinin A (NKA)] and opioid peptides [[Met5]-enkephalin (ME) and dynorphin A (1-8) (DYN)] by radioimmunoassays. The abundance of total SP-encoding preprotachykinin (PPT) mRNA and SP receptor (SPR) mRNA in spinal cord (C5 to T1 segments), striatum, or microdissected substantia nigra was determined by northern blot or solution hybridization analysis. Amines and their acid metabolites were quantified by HPLC. Capsaicin administration (subcutaneously) during the early postnatal period increased latency in a hot-plate test, decreased SP and NKA levels, increased levels of PPT mRNAs, and did not affect SPR mRNA levels in the spinal cord. Intraspinal SP systems may attempt to compensate for the loss of afferent SP input, whereas spinal cord receptor mRNA levels do not appear to be altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Neonatal administration of L-cysteine does not produce long-term effects on neurotransmitter or neuropeptide systems in the rat striatum.

Previous studies by other investigators have shown that neonatal administration of high doses of L-cysteine produces within 6 hrs morphological damage to neurons in many areas of the brain including the striatum; the damage could be blocked by NMDA antagonist MK-801. These studies implicated a potential involvement of this amino acid in neurodegenerative processes including Parkinsonism. The present study attempted to elucidate whether L-cysteine produces long-term changes in neurotransmitter (dopamine; 5-hydroxytryptamine) or neuropeptide (Met5-enkephalin; dynorphin A (1-8); substance P) systems as a corollary to neonatal treatment with L-cysteine. L-cysteine (0.5 or 1 g/kg, s.c.) was administered to 4-day old rat pups and sacrificed 35 days later. The striatal levels of amines and neuropeptides were determined by HPLC and radioimmunoassay respectively. L-Cysteine treatment alone or after a pretreatment with MK-801 (1 mg/kg, s.c.) failed to produce any significant changes in the parameters studied. The results indicate that neonatal administration of L-cysteine does not appear to produce long-term effects on major neuroregulator systems of the striatum.

Animals↗

PubMed1991

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.

Aged↗

PubMed1991

Dopamine-dependent postnatal development of enkephalin and tachykinin neurons of rat basal ganglia.

The influence of deprivation of the neurotransmitter dopamine (DA) on the development of [Met5]-enkephalin (ME) and substance P (SP) neuropeptide systems of the striatum was investigated in Sprague-Dawley rats. The neurotoxin 6-hydroxydopamine (6-OHDA) was used to induce DA deficiency on postnatal day 3 in rats, and the animals were killed at different postnatal time points until 35 days of age. The levels of ME and SP were determined by radioimmunoassay, and the abundance of preproenkephalin (PPE) and preprotachykinin (PPT) mRNA in the striatum was assessed by Northern blot hybridization analysis. The concentrations of DA, 5-hydroxytryptamine (5-HT), and their acid metabolites were determined by HPLC with electrochemical detection. The postnatal development of the PPE-derived peptide ME and the PPT-derived peptide SP closely paralleled the appearance of the respective mRNAs coding for these peptides. The dopaminergic lesion with 6-OHDA led to a marked depletion of DA and its metabolites but produced an increase in content of 5-HT and its metabolite in the striatum. The lesion did not affect the ME and PPE mRNA levels in the striatum up to 25 days but increased the levels at 35 days. In contrast, a decreased developmental expression in SP and PPT mRNA was observed throughout the observation period. The lesion failed to influence the development of the mRNA coding for the structural protein beta-actin. The results indicate that the normal development of enkephalin, tachykinin, and 5-HT systems of the striatum is dependent on the availability of DA, the integrity of dopaminergic neurons, or both. The studies provide evidence for an interrelationship and interdependence between the development of neurotransmitter and neuropeptide systems. It is suggested that an early developmental abnormality in the DA system could permanently alter the neuropeptide systems, which in turn could influence the progression and expression of the DA-deficiency state parkinsonism, Lesch-Nyhan disease, or both.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

The adaptation of enkephalin, tachykinin and monoamine neurons of the basal ganglia following neonatal dopaminergic denervation is dependent on the extent of dopamine depletion.

This study examined whether dopamine (DA) is necessary for the normal development of striatal enkephalin and striatonigral tachykinin peptide systems. The neurotoxin, 6-hydroxydopamine (6-OHDA) was used to induce DA deficiency on the third day of the postnatal period in Sprague-Dawley rat pups. The animals were sacrificed at 60 days of age. The levels of Met5-enkephalin (ME) and substance P (SP) were determined by radioimmunoassay and preproenkephalin (PPE) and preprotachykinin (PPT) mRNA abundance in the striatum were assessed by hybridization analysis. The concentrations of DA, 5-hydroxytryptamine (5-HT) and their acid metabolites were determined by high-pressure liquid chromatography with electrochemical detection. The lesioned animals were grouped on the basis of the degree of loss of DA, and changes in ME, SP and 5-HT systems were correlated with respect to the degree of DA loss. The nature and extent of the changes in these systems were dependent on the degree of DA depletion. A loss of more than 90% DA was necessary to result in increased levels of ME and its PPE mRNA and reduced levels of SP and its PPT mRNAs; however, increased levels of 5-HT could be observed at a lower degree of DA loss. The results indicate that the normal development of enkephalin and tachykinin and 5-HT systems of basal ganglia are dependent on the availability of DA and/or the integrity of the nigrostriatal dopaminergic neurons. The results are relevant to our further understanding of the neurobiology of DA deficiency disorders.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Compensatory activation of substance P biosynthesis by L-dihydroxyphenylalanine in striatonigral neurons of neonatal dopaminergic denervated rats.

Previous studies have shown that L-dihydroxyphenylalanine (L-DOPA) administration to adult rats that had been subjected to dopamingergic denervation with 6-hydroxydopamine during early postnatal period, led to a marked decrease in the levels of striatonigral substance P (SP). The present study examined the hypothesis of whether there is a compensatory activation of SP biosynthesis in order to replenish the L-DOPA-induced SP depletion. Three-day old Sprague-Dawley rat pups were lesioned with 6-hydroxydopamine and were challenged with L-DOPA at about 60 days of age. The animals were sacrificed 75 min, 6 hr or 24 hr after the L-DOPA administration. The levels of SP (in the striatum and substantia nigra) were determined by radioimmunoassay. The abundance of SP-encoding preprotachykinin (PPT) messenger RNA (mRNA) in the striatum was determined by Northern blot analysis and the abundance of individual PPT-mRNAs (alpha, beta and gamma) was determined by nuclease protection assays. Concentrations of dopamine and its acid metabolite, dihydroxyphenyl acetic acid were determined by high-pressure liquid chromatography with electrochemical detection. At the 75 min time point, L-DOPA produced a greater decrease in SP levels in the striatum and the substantia nigra, than that observed with lesion alone. The SP levels recovered to lesioned-control levels by 6 hr and remained at this level at the 24-hr time point. This recovery was accompanied by a marked increase in striatal SP-encoding PPT-mRNA abundance at 6 hr; mRNA levels were below lesioned-control value at 24 hr. There were no differential changes in the individual SP-encoding PPT-mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

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.

Animals↗

PubMed1989

Lithium increases rat striatal beta- and gamma-preprotachykinin messenger RNAs.

Previous reports indicate that the antimanic drug, lithium, increases substance P-like immunoreactivity (SP-LI) in the basal ganglia. The aim of this study was to use lithium as a pharmacological tool to further understand the mechanism of this process. We have used solution hybridization-nuclease protection assays to quantitate the specific preprotachykinin (PPT) mRNAs and radioimmunoassays and immunocytochemistry to assess SP-LI levels in the striatum of male Fisher F-344 rats. A regimen of subchronic administration of lithium (4 mEq/kg i.p. for 1, 2, 4 or 6 days) increased SP-LI in a time-dependent fashion. Concurrent administration of a dopamine receptor antagonist, haloperidol (1 mg/kg s.c. for 4 days) with a 4-day lithium regimen partially blocked the lithium-induced increase in SP-LI as well as neurokinin A-like immunoreactivity. An analysis of the abundance of individual PPT mRNAs indicated that lithium increases beta- and gamma-PPT mRNAs in the striatum; coadministration of haloperidol attenuates the lithium-induced increases. These results indicate that lithium affects the tachykinin biosynthetic process by accelerating transcriptional and/or translational processes in striatonigral neurons and that the dopaminergic system appears to be partly involved in this process.

Animals↗

PubMed1989

Cocaine selectively increases striatonigral dynorphin levels by a dopaminergic mechanism.

The influence of the acute (single dose) or subchronic (one dose daily for 4 days) administration of cocaine to Sprague-Dawley rats on striatal enkephalin (Met5-enkephalin) and striatonigral tachykinin (substance P) and dynorphin [dynorphin A (1-8), DYN] levels was investigated. The peptide levels were determined by radioimmunoassay. The concentrations of the striatal levels of dopamine (DA), 5-hydroxytryptamine and their acid metabolites were determined by high-performance liquid chromatography with electrochemical detection. An acute administration of cocaine (20 or 30 mg/kg i.p.) did not affect the peptide levels in the striatum or in the substantia nigra. A regimen of subchronic administration of cocaine (20 mg/kg/day for 4 days) increased the striatonigral DYN levels, without altering the levels of Met5-enkephalin or substance P. The increase in DYN levels were persistent for at least 4 days after the last dose of the subchronic administration of cocaine. The DYN levels returned to control values by 12 days after the last dose. The DA levels in the striatum were increased 30 min after a single dose of cocaine. None of the other treatments elicited any changes in DA or 5-hydroxytryptamine or their metabolites. The subchronic cocaine administration to dopaminergic denervated rats with 6-hydroxydopamine failed to evoke any increase in DYN levels in the striatum or substantia nigra. The concurrent administration of the D1 DA antagonist, SCH-23390, or the D2 DA antagonist, spiperone, to the subchronic regimen of cocaine also blocked the cocaine-induced increase in DYN levels. These results indicate that cocaine selectively enhances the synthesis or decreases the release of DYN in the striatonigral neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Lithium increases dynorphin A(1-8) and prodynorphin mRNA levels in the basal ganglia of rats.

The aim of this study was to understand the possible influence of the antimanic drug, lithium, and the neuroleptic, haloperidol, alone or in combination, on the regulation of dynorphin biosynthesis in the striatum. The study was done using male Fisher-344 rats subjected to a regimen of subchronic administration of lithium chloride (4 mEq/kg/day for 1,2,4 or 6 days, i.p.) or a regimen of chronic oral administration of a diet containing lithium carbonate (1.5 g/kg of the diet). Subchronic administration of lithium increased striatal dynorphin A(1-8)-like immunoreactivity (DN-LI) in a time-related fashion. Immunocytochemistry revealed an increase in DN-LI in fibers and cells clustered in 'patches' throughout striatum. The increase in DN-LI was reversible on cessation of lithium administration. Concurrent administration of lithium and an opiate antagonist, naltrexone, or a dopamine receptor antagonist, haloperidol, did not influence the changes induced by lithium. Chronic oral administration of lithium for 21 days led to an increase in DN-LI in the striatum. Co-administration of haloperidol with the 21 day regimen of lithium administration failed to affect the increase in DN-LI. The prodynorphin mRNA abundance in the striatum was quantitated by a molecular hybridization procedure using a prodynorphin 32P-cRNA probe generated from the Riboprobe system. Evidence from the Northern blot analysis reveals that lithium increases the prodynorphin mRNA abundance in the striatum. These results indicate that lithium affects the dynamics of prodynorphin biosynthesis in the striatum, presumably increasing transcription and/or translational processes.

Animals↗

PubMed1988

Effects and mechanism of action of lithium chloride on gastric acid secretion in rats.

Lithium chloride reduce the measured parameters of gastric secretion (gastric volume, hydrogen ion concentration, and gastric acid output) 2 h after intracerebroventricular, intravenous, or subcutaneous administration in pylorus-ligated rats, in a dose-dependent manner. Intracerebroventricular administration of lithium was approximately five times and 10 times more potent than intravenous and subcutaneous injection, respectively. Time-course study demonstrated that the action of lithium (400 micrograms) on gastric secretion reached a peak at 1 h after intracerebroventricular administration; however, the effects on volume and output were still significant after 8 h. Prior intracerebroventricular injection of indomethacin (400 micrograms) reversed the action of centrally administered lithium on gastric secretion. However, central administration of the opiate receptor blocker naltrexone (100 micrograms), as well as subcutaneous administration of indomethacin (5 mg/kg), failed to modify the effect of lithium on gastric acid secretion. Our data suggest that lithium appears to act centrally to modulate gastric acid secretion in rats through a mechanism involving the synthesis of prostaglandinlike material(s) in the brain. Furthermore, the effect of centrally administered lithium is independent of stimulation of opiate receptor(s) in the brain.

Animals↗