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Biomedical subjects

L G Bush

Publications and source records attributed to L G Bush.

At least 19 recordsLinked to original sources
PubMed1997

Comparison of neurotensin responses to MDL 100,907, a selective 5HT2A antagonist, with clozapine and haloperidol.

The unique pharmacological profile of atypical antipsychotics, such as clozapine, suggests that action on non-dopaminergic transmitter systems might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, the response of neurotensin systems to drugs with antipsychotic potential was examined because of this peptide's putative association with psychiatric disorders. The effects of treatments by haloperidol, clozapine, and MDL 100,907 (a selective 5HT2A antagonist thought to have antipsychotic activity) on NT pathways were determined in various extrapyramidal and limbic regions and compared. The response of neurotensin systems was determined by measuring neurotensin-like immunoreactivity after 1, 2, 4, and 5 drug administrations. It was observed that tissue content of this peptide in caudate and nucleus accumbens regions tended to be elevated after 1 or 2 drug administrations, but had either returned or was returning to control levels after 4 or 5 drug administrations. In general, the extrapyramidal and limbic neurotensin levels responded in a similar manner to clozapine and the 5HT2A antagonist, but differently for haloperidol in most regions examined. An important exception was in the nucleus accumbens, where all three drugs had similar effects on neurotensin tissue levels. These results suggest that 5HT2A receptors exert basal control over some extrapyramidal and limbic neurotensin systems and this interaction might contribute to the antipsychotic effects of these drugs.

Animals↗
PubMed1995

Response of extrapyramidal and limbic neurotensin systems to phencyclidine treatment.

Although phencyclidine (PCP) has several neurochemical effects, the most pharmacologically relevant are thought to be its ability to antagonize the activity of N-methyl-D-aspartate (NMDA)-type glutamate receptors and to increase extracellular dopamine concentrations. In order to elucidate the nature and consequence of PCP actions on glutamatergic and dopaminergic pathways, this study examined the response of extrapyramidal and limbic neurotensin systems to this drug. Multiple, but not single, doses of PCP caused increases in striatal neurotensin-like immunoreactivity content of 150-200% of control. These effects were blocked by the dopamine D1 receptor antagonist, SCH 23390, suggesting they were caused by PCP-mediated enhanced dopamine activity at dopamine D1 receptors. In contrast, MK-801 (dizocilpine), a selective NMDA receptor antagonist that acts at the same site as PCP, had no effect on neurotensin-like immunoreactivity content when given alone. In addition, coadministration of MK-801 with PCP did not alter the effect of PCP on striatal neurotensin-like immunoreactivity content. This lack of effect suggests that the actions of PCP on NMDA receptors was not involved in the neurotensin response. The PCP effect on neurotensin striatal pathways also appeared not to be associated with the dopamine D2 or gamma-aminobutyric acid (GABA) systems: a possible role for the sigma receptor in this effect could not be eliminated. Administration of multiple doses of PCP also affected neurotensin-like immunoreactivity content in the nucleus accumbens (160% compared to control) and frontal cortex (40% compared to control), but not the substantia nigra. The neurotensin effects of PCP are compared to those of another psychotomimetic drug of abuse, methamphetamine.

Animals↗
PubMed1994

Endogenous neurotensin antagonizes methamphetamine-enhanced dopaminergic activity.

Neurotensin (NT) has been proposed to be an endogenous neuroleptic based on observations that i.c.v. administration of this peptide antagonizes dopamine-mediated behavior. Because NT influences dopamine activity, this peptide may contribute to the pathogenesis of psychotic disorders such as schizophrenia; however, the precise physiological effects of NT remain speculative. In order to elucidate the function of endogenous NT, a selective NT antiserum (NTAS) was administered i.c.v. through a push-pull cannula in unanesthetized, freely moving rats in combination with dopamine activation caused by methamphetamine (METH). Locomotor and rearing activities induced by a low dose of METH (0.5 mg/kg) were substantially enhanced (4-5-fold) in rats receiving NTAS compared to control animals receiving METH alone. Similarly raised antiserum to vasoactive intestinal polypeptide (VIP) did not alter METH-induced effects. To determine a possible mechanism for these observations, perfusate delivered into the cerebral ventricular space was collected by push-pull cannulae and assayed for dopamine release. METH-induced dopamine release was enhanced 4-5-fold by co-administration of NTAS but not VIP antiserum. To verify these observations, and to identify the site of dopamine release, this experiment was repeated utilizing microdialysis and the recently described NT antagonist, SR-48692. Results from this experiment were similar to those found using NTAS. Like NTAS, co-administration of the NT antagonist enhanced the behavioral responses to a low dose of METH. These studies with SR-48692 also revealed that blockade of NT receptors increased METH-induced release of dopamine from the nucleus accumbens. These findings are the first to demonstrate directly that endogenous NT antagonizes stimulated dopamine pathways and its inactivation substantially enhances METH-induced DA release and related behaviors.

Animals↗
PubMed1994

Dynamic dopaminergic regulation of neuropeptide Y systems in discrete striatal and accumbens regions.

In this study we evaluated the effects of multiple administrations of selective dopamine D1 and D2 receptor agonists and antagonists on striatal, nigral, accumbens, pallidal and cortical neuropeptide Y systems. Treatment with the D1 receptor agonist, SKF 38393, decreased, while that with the D1 receptor antagonist, SCH 23390, increased neuropeptide Y-like immunoreactivity in the globus pallidus and several regions within the caudate-putamen. SCH 23390 did not change accumbens neuropeptide Y-like immunoreactivity levels but SKF 38393 increased neuropeptide Y-like immunoreactivity levels in anterior and decreased neuropeptide Y-like immunoreactivity levels in the posterior nucleus accumbens. Interestingly, reductions in neuropeptide Y-like immunoreactivity content occurred in response to administrations of both D2 receptor agonist, quinpirole, or antagonist, sulpiride, in all identified regions of each structure at some time point. These data suggest that the neuropeptide Y systems studied may be regulated by selective activity at postsynaptic or presynaptic dopamine receptors. They further suggest that within structures such as the caudate-putamen and nucleus accumbens are multiple distinct neuropeptide Y systems which are uniquely influenced by dopamine receptors.

Animals↗
PubMed1993

Effects of ritanserin on the 3,4-methylenedioxymethamphetamine-induced decrease in striatal serotonin concentration and on the increase in striatal neurotensin and dynorphin A concentrations.

The concentration of serotonin (5-HT) measured in rat striatum was reduced to 75% of control 1 week after a single subcutaneous administration of dl-3,4-methylenedioxymethamphetamine (MDMA, 20 mg/kg). This decrease was prevented by pretreating the animals with ritanserin. Eighteen hours after MDMA (20 mg/kg), striatal concentrations of neurotensin-like immunoreactivity (NTLI) and of dynorphin A-like immunoreactivity (DLI) were increased to 250 and 487% of control, respectively, but ritanserin failed to prevent these changes. This study supports a role for 5-HT2 receptors in the mechanism by which a single high dose of MDMA induces neuronal damage to the serotonergic system, but not the MDMA-induced increase in central NTLI and DLI concentrations.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Differential regulation of neuropeptide Y systems in limbic structures of the rat.

Neuropeptide Y-like immunoreactivity (NPYLI) in the frontal cortex and nucleus accumbens was significantly decreased after acute and multiple administrations of phencyclidine-HCl (PCP). The role of dopamine, serotonin and sigma receptors in these PCP-induced effects was evaluated. Neither the dopamine D1 antagonist SCH 23390 nor the D2 antagonist sulpiride by itself altered cortical neuropeptide systems, but in combination they totally blocked the PCP-induced changes. In contrast, sulpiride alone significantly decreased accumbens NPYLI content and enhanced the PCP-induced decreases, whereas SCH 23390 alone had no effect on accumbens NPYLI levels but did attenuate PCP-induced effects. Neither depletion of serotonin nor blockage of the sigma "receptor" had any effect on PCP-induced changes in either structure. The effects of the selective, noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 on cortical and accumbens NPYLI content were similar to those of PCP, suggesting an N-methyl-D-aspartate receptor mechanism in these effects. Administration of gamma-aminobutyric acid-transaminase (GABA-T) inhibitors, gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) or aminooxyacetic acid alone had no effect on cortical NPYLI content; however, administration of aminooxyacetic acid alone decreased accumbens NPYLI levels. Co-administration of these GABA-T inhibitors with PCP completely blocked PCP-induced cortical NPYLI decreases and attenuated NPYLI changes in the accumbens. These data suggest that limbic neuropeptide systems are differentially modulated by N-methyl-D-aspartate and dopaminergic activity and that glutamatergic influences on cortical and accumbens NPY systems are mediated, at least in part, by GABAergic mechanisms.

Animals↗
PubMed1992

Characterization of phencyclidine-induced effects on neuropeptide Y systems in the rat caudate-putamen.

Multiple administrations of the psychotomimetic drug, phencyclidine-HCI (PCP), decreased striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels in a dose-dependent manner. Single or multiple PCP administrations decreased striatal NPY levels after 10-12 h; levels returned to control 24 h after a single dose or 58 h after multiple doses. In contrast, no significant changes were seen in nigral NPY levels with either acute or multiple-dose PCP treatments. The role of monoamine, sigma or opioid receptors in PCP-induced striatal NPY changes was evaluated. When administered alone, the alpha 1-adrenergic antagonist, prazosin, the sigma antagonist, BMY 14802, and the dopamine D2 antagonist, sulpiride decreased striatal NPY levels; however, only prazosin and the dopamine D1 antagonist, SCH 23390, significantly attenuated PCP-induced changes. Administration of the gamma-aminobutyric acid transaminase (GABA-T) inhibitors, amino-oxyacetic acid (AOAA) or gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) alone had no effect on striatal NPY-LI levels while administration of these indirect GABA agonists prior to or concurrently with PCP treatment completely blocked PCP-induced changes in striatal NPY-LI levels. The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on striatal NPY-LI content resembled that of PCP and was also blocked by the two indirect GABA agonists. These data suggest that NPY systems are modulated by glutamatergic activity (specifically by the NMDA receptor) and that the interaction between these two transmitter systems is mediated by GABAergic mechanisms.

4-Aminobutyrate Transaminase↗
PubMed1992

Role of N-methyl-D-aspartate receptors in dopamine D1-, but not D2-, mediated changes in striatal and accumbens neurotensin systems.

The role of N-methyl-D-aspartate (NMDA) receptors in specific D1 and D2 regulation of striatal and accumbens neurotensin (NT) systems was investigated. As demonstrated previously, stimulation of D1 receptors with multiple administrations of SKF 38393 significantly increased striatal and accumbens NT content to approximately 145% of control. These responses were completely blocked by coadministration of the non-competitive NMDA antagonist, MK 801. Previous studies have documented that D2 receptors tonically regulate striatal NT systems. Thus, multiple doses of sulpiride, a D2 antagonist, increased striatal NT content to 167% of control while quinpirole, a D2 agonist, decreased striatal NT content to 58% of control. MK 801 did not alter either striatal NT response to D2 manipulation. As previously reported, levels of accumbens NT changed only in response to D2 blockade and not to D2 stimulation. Thus, sulpiride increased accumbens NT content to 138% of control; this was not blocked by the coadministration of MK 801. NT content also significantly increased after stimulation of glutamate receptors with NMDA. To determine if D1 receptors participate in this NMDA-mediated change, the D1 antagonist SCH 23390 was coadministered. Blockade of D1 receptors did not significantly alter the response of striatal NT systems to NMDA. However, in both striatum and nucleus accumbens, the NMDA effect on NT systems appeared to be lessened. In summary, expression of D1-, but not D2-mediated changes in striatal and accumbens NT systems are markedly dependent on NMDA receptor activity. In comparison, expression of the NMDA-mediated changes in the same NT systems do not appear to be as dependent on D1 receptor activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

N-Methyl-D-aspartate receptors mediate dopamine-induced changes in extrapyramidal and limbic dynorphin systems.

The N-methyl-D-aspartate (NMDA)-type glutamate receptor was shown to mediate dopamine-induced dynorphin A (Dyn) changes in extrapyramidal and limbic structures. MK801, a potent noncompetitive antagonist of the NMDA receptor, blocked increases in striatal and nigral Dyn content following single and multiple administrations of methamphetamine (METH). Significant attenuation of the METH-induced increases occurred with MK801 doses of 0.1 mg/kg/dose with complete blockade at 2.5 mg/kg/dose. Similar to METH, NMDA itself caused significant increases in striatal and nigral Dyn content. The NMDA-induced increase in striatal Dyn content was blocked by coadministration of an intermediate dose of MK801. The Dyn system associated with the nucleus accumbens responded in a similar manner in that MK801 totally blocked the METH-induced increases; moreover, NMDA elevated the Dyn content in this structure. The inability of MK801 to alter the quinpirole-induced decrease in striatal Dyn content suggests that the NMDA receptor is not involved in the D2 receptor regulation of striatal Dyn systems.

Animals↗
PubMed1991

Blockade of the 3,4-methylenedioxymethamphetamine-induced changes in neurotensin and dynorphin A systems.

The levels of neurotensin-like immunoreactivity (NTLI) and dynorphin-like immunoreactivity (DLI) in the neostriatum, nucleus accumbens and substantia nigra were increased 18 h after a single administration of MDMA (3,4-methylenedioxymethamphetamine, 10 mg/kg). Coadministration of SCH 23390, a dopamine D1 receptor antagonist, or MK-801, a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor complex, prevented the MDMA-induced increase of NTLI and DLI in all three brain structures while the administration of sulpiride, a dopamine D2 receptor antagonist, failed to alter the MDMA effects. These findings suggest that MDMA-induced changes in neurotensin and dynorphin involve both the dopaminergic and the glutamatergic systems.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Dopamine-mediated changes in central nervous system neurotensin systems: a role for NMDA receptors.

A role for N-methyl-D-aspartate (NMDA)-type glutamate receptors in mediating the dopaminergic regulation of neurotensin (NT) systems was observed in extrapyramidal and limbic structures. Blockade of the NMDA receptor with the non-competitive antagonist, MK801, prevented increases in striatal and nigral levels of NT following both single and multiple administrations of methamphetamine. Significant attenuation of the methamphetamine-induced changes in the striatal NT system were observed with MK801 doses as low as 0.01 mg/kg per dose. In contrast, administration of NMDA caused significant increases in both striatal and nigral NT. The NMDA-induced increase in striatal NT content, like that caused by methamphetamine, was blocked by MK801. The NT system associated with the nucleus accumbens responded in a similar manner in that MK801 (0.1 mg/kg per dose) totally blocked the methamphetamine-induced increases and NMDA administration elevated the NT levels in this structure. Since the methamphetamine-related changes in NT content have been previously shown to be due to increased activity at dopamine D1 receptors, these results strongly suggest that NMDA receptors play an important role in mediating the dopamine D1 regulation of neurotensin systems. Interestingly, the presence of MK801 had no impact on sulpiride-mediated changes in striatal NT levels, suggesting that the NMDA receptor is not linked with the dopamine D2 receptor regulation of NT pathways.

Animals↗
PubMed1990

Neurochemical effects of an acute treatment with 4-methylaminorex: a new stimulant of abuse.

4-Methylaminorex (4-MAX) is an amphetamine analog which has recently gained attention due to its potential as a stimulant of abuse. The present study characterized the acute neurochemical changes elicited after a single dose of 4-MAX. Thus, dose-response and time-response studies were conducted in order to assess the effects of this drug on monoaminergic and neuropeptide systems in extrapyramidal and limbic structures. The most dramatic responses in the dose-effect experiments (animals killed 3 h after treatment) were a 2-fold increase in neostriatal homovanillic acid levels and a decrease in neostriatal tryptophan hydroxylase activity to 33% of control in the 20 mg/kg group. Because all animals in the 20 mg/kg group experienced convulsions, 10 mg/kg was used for the time-response studies. The most striking effects in these studies included a reduction in dopamine concentrations to 71% of control, and an increase to 270% of control in the concentrations of dihydroxyphenylacetic acid 30 min after 4-MAX administration. In addition, neostriatal neurotensin and dynorphin A levels increased to approximately 200 and 400% of control, respectively, 18 h after a 10 mg/kg dose. These data suggest that 4-MAX is a potent dopamine releaser, which decreases tryptophan hydroxylase activity in a manner similar to other amphetamine-related drugs. However, in contrast to other amphetamine analogs, 4-MAX has potent convulsant actions.

Animals↗
PubMed1990

Neurotensin-dopamine interactions in the substantia nigra of the rat brain.

Single or multiple doses of the potent dopamine releaser, methamphetamine (METH), increases the content of neurotensin (NT)-like immunoreactivity (NTLI) in the substantia nigra of the rat brain by 2- to 3-fold. Concurrent blockade of D-1 receptors with METH treatment completely antagonized the increase in nigral NTLI content induced by this drug. These results suggest that activation of D-1 receptors by endogenous dopamine results in an increase in the level of NTLI in the substantia nigra. The present study was performed to characterize further the mechanisms underlying dopaminergic regulation of nigral NT systems. Prior selective destruction of the nigrostriatal dopamine pathway completely prevented the increase in nigral NTLI content induced by treatment with METH, which suggests that the effects of METH on nigral NT systems are mediated by the nigrostriatal dopamine projections. However, unlike METH, treatment of rats with the direct-acting, D-1-selective agonist, SKF 38393, did not alter nigral NTLI content but when combined with stimulation of D-2 receptors, a significant increase in the level of NTLI occurred. Surprisingly, activation of only D-2 receptors caused a significant decrease in nigral NTLI content. These data suggest that although activation of D-2 receptors alone has an effect opposite to that of the D-1 subtype, in combination with D-1 stimulation they facilitate the effect of D-1 receptors on nigral NT systems. In addition to the effects of direct or indirect stimulation of dopamine activity on nigral NT levels, basally released dopamine also appeared to regulate the level of NTLI in the substantia nigra. Thus, interruption of tonic dopamine activity by reserpine-induced depletion of dopamine significantly reduced the level of NTLI in the substantia nigra. The role of D-1 receptors in this tonic dopaminergic regulation of nigral NT systems was evident when concurrent activation of D-1, but not D-2, receptors with reserpine treatment prevented or reversed the decrease in NTLI content caused by dopamine depletion. Additional evidence for the D-1-mediated tonic regulation of NT systems in the substantia nigra was that blockade of D-1 receptors with SCH 23390 decreased the nigral NTLI content but blockade of D-2 receptors with sulpiride had no effect.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain.

Blockade of dopamine D2 receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus alpha-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus alpha-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert their effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D2 receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D2 receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.

Animals↗
PubMed1989

Glucocorticoids and 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity.

The present study was carried out in order to explore the role of glucocorticoids in 3,4-methylenedio-xymethamphetamine (MDMA)-induced neurotoxicity of the central serotonergic system. The activity of tryptophan hydroxylase (TPH) was used as an index of this drug-induced neuronal degeneration. One week after a single high dose of MDMA (20 mg/kg), a significant decrease in the enzyme activity was measured in both the frontal cortex and hippocampus. Adrenalectomy (ADX) attenuated or blocked this decrease in TPH activity in the hippocampus but not in the frontal cortex. This protective effect of ADX on hippocampal serotonergic neurons disappeared with concurrent administration of corticosterone (CORT) and MDMA administration. The long-term MDMA-induced decreases in hippocampal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were similarly affected by CORT replacement. However, ADX did not alter the short-term decline in hippocampal TPH activity and 5-HT concentrations measured 3 h after a single dose of MDMA (10 mg/kg s.c.). This study suggests that CORT play a role in the development of neurotoxicity induced by MDMA in the hippocampal serotonergic system, but may be less important in other brain structures.

3,4-Methylenedioxyamphetamine↗