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J W Gibb

Publications and source records attributed to J W Gibb.

At least 55 records · Page 3Linked to original sources
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

Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse.

4-Methylaminorex is an amphetamine analog which has recently gained attention due to its potential as a stimulant of abuse and the ease with which it is synthesized. Administration of acute and multiple doses of 4-methylaminorex caused rapid (3-h) and long-term (7-day) declines in striatal tryptophan hydroxylase activity with few changes in other serotonergic parameters. The acute response by tryptophan hydroxylase to this drug was reversed by incubating the tissues in a reducing environment suggesting that 4-methylaminorex alters this enzyme through oxidative mechanisms. The 4-methylaminorex-induced long-term reduction in tryptophan hydroxylase activity might be due to neurotoxic action on serotonergic systems. In contrast, although a decline in striatal tyrosine hydroxylase occurred 3 h following a single dose of 4-methylaminorex, no changes in this enzyme were observed at 7 days after acute or multiple dosing with this drug. This result suggests that 4-methylaminorex is not neurotoxic to the dopaminergic neurons. Even though this amphetamine analog apparently does not have long-term effects on dopaminergic systems, it does appear to enhance substantially dopaminergic activity. Evidence for increased dopamine activity resulting from 4-methylaminorex administration included dramatic but temporary rises in the levels of nigral neurotensin, dynorphin A and substance P following multiple drug administration. Similar peptide changes have been observed with other amphetamine-related stimulants and are mediated by increases in dopaminergic activity. In summary, 4-methylaminorex has significant impact on monoaminergic pathways. In general, its spectrum of effects on these systems is like that of the ring-substituted amphetamines, such as methylenedioxymethamphetamine.

Animals↗
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↗
PubMed1992

Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms.

In summary, we have observed that drugs of abuse, which can cause schizophrenia-like paranoia, alter striatal and accumbens NT systems in a similar, dramatic fashion. The NT responses to these drugs, in particular METH, are mediated by activation of DA D1 receptors. We have observed that NMDA-type glutamate receptors are essential for the D1-NT interaction. NMDA receptors are selective, since they do not contribute to the antagonistic effects of DA D2 receptors on NT activity. This observation suggests that NT responses to D1 and D2 regulation are mediated through separate and distinct mechanisms. Finally, we found that the presence of METH dramatically reduces striatal NT release, which most likely leads to NT accumulation in nerve terminals and the observed increase in NT tissue level. The blockade of NT release by a psychotogenic drug, such as METH, is consistent with the hypothesis that NT has antipsychotic activity and a decrease in its release may contribute to some forms of schizophrenia similar to that caused by intense use of the stimulants of abuse.

Animals↗
PubMed1992

Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems.

The effects of 3,4-dihydroxymethamphetamine (DHM) and 2,4,5-trihydroxymethamphetamine (THM) on central serotonergic and dopaminergic systems were investigated to determine if these metabolites share the neurochemical properties of 3,4-methylenedioxymethamphetamine. THM (50-200 micrograms) or DHM (135 micrograms) was administered i.c.v. to rats; 5 days later, cortical, striatal and hippocampal tryptophan hydroxylase (TPH) activity were decreased by THM in a dose-dependent manner, whereas DHM was without effect in these brain structures. The concentration of serotonin in the brain structures contralateral to the side of THM injection was also decreased, but to a lesser degree. THM (100 and 200 micrograms) increased TPH activity to 155% of control in the dorsal raphe, whereas a dose of 50 micrograms increased TPH activity to 132% of control in the median raphe nucleus. THM also markedly reduced striatal tyrosine hydroxylase activity, but did not alter enzyme activity in the substantia nigra; DHM increased striatal tyrosine hydroxylase activity to 115% of control. These results suggest that THM, but not DHM, is toxic to both dopaminergic and serotonergic nerve terminals. Although THM could not be established as the neurotoxic metabolite explaining 3,4-methylenedioxymethamphetamine (MDMA) toxicity, its properties may prove useful in elucidating amphetamine toxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Effect of flunarizine and nimodipine on the decrease in tryptophan hydroxylase activity induced by methamphetamine and 3,4-methylenedioxymethamphetamine.

The effect of calcium channel blockers on the decrease in central tryptophan hydroxylase (TPH) activity and serotonin (5-HT) concentration induced by repeated large doses of methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received four or five injections of METH (10 or 15 mg/kg) or MDMA (10 mg/kg) at 6-h intervals, and were sacrificed 18 to 20 h or 1 week after the last administration. Flunarizine (30 mg/kg) prevented the decline in cortical and neostriatal TPH activity induced by MDMA, but failed to alter the effect of METH. The effect of flunarizine on the METH- and MDMA-induced changes in cortical 5-HT and 5-hydroxyindoleacetic acid concentrations paralleled the changes in enzyme activity. Nimodipine, diltiazem or TA-3090 failed to prevent the MDMA- and the METH-induced decline in TPH activity or in 5-HT and 5-hydroxyindoleacetic acid content. Because haloperidol failed to mimic the protective action of flunarizine, it is unlikely that flunarizine exerts its action by blocking the dopamine D-2 receptors. This study suggests that calcium influx may participate in the MDMA-induced decline in central TPH activity, and that the mechanism by which MDMA and METH decreases TPH activity differs.

3,4-Methylenedioxyamphetamine↗
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↗
PubMed1991

Norepinephrine does not contribute to methamphetamine-induced changes in hippocampal serotonergic system.

The purpose of this study was to determine whether norepinephrine (NE) mediated the reduction in the activity of tryptophan hydroxylase (TPH) in the hippocampus and other serotonergic changes, induced by a single or multiple administrations of methamphetamine. The NE in the hippocampus was depleted by injecting rats with DSP4 intraperitoneally, 10 days prior to administration of methamphetamine. A single administration of methamphetamine (15 mg/kg) reduced the activity of TPH to 40% of control after 3 hr. A 90 to 98% reduction in the concentration of NE in the hippocampus, failed to alter this methamphetamine-induced response. The reduction in serotonin (5-HT) in the hippocampus induced by methamphetamine, was not altered by the treatment with DSP4. These observations were confirmed by a lack of effect on methamphetamine-induced changes in 5-HT and TPH after inhibition of the synthesis of NE with U-14,624. The pretreatment with DSP4 also failed to block the decline in activity of TPH in the hippocampus or concentrations of 5-HT measured 18 hr after the last of 4 doses of methamphetamine (15 mg/kg, s.c.). The results presented in this study indicate that NE is not involved in the response of the serotonergic system to methamphetamine.

Animals↗
PubMed1991

Response of extrapyramidal and limbic neuropeptides to fenfluramine administration: comparison with methamphetamine.

The responses of extrapyramidal and limbic neuropeptide and striatal dopamine and serotonin systems were evaluated after treatment with fenfluramine in rats. After multiple administrations of fenfluramine, its active metabolite, norfenfluramine, and methamphetamine (METH), striatal neurotensin (NT) content was similarly increased to approximately 200% of control. In contrast, nigral NT levels were unaltered by fenfluramine, intermediately increased by norfenfluramine (148% of control) and maximally increased by METH (267% of control). Striatal and nigral substance P (SP) and dynorphin A (Dyn) systems were unaltered by fenfluramine, whereas norfenfluramine caused an intermediate increase in striatal Dyn content but did not significantly alter striatal SP or nigral SP and Dyn levels. However, METH significantly elevated striatal and nigral Dyn and SP concentrations to 280 to 425% (Dyn) and 140% (SP) of control. For the most part, the response of the limbic peptides was similar to that seen in the striatum with a couple of notable differences. Further investigation of the striatal NT system showed that the increases induced by fenfluramine were completely blocked by the D1 antagonist, SCH 23390, and the noncompetitive N-methyl-D-aspartate antagonist, MK801. Depletion of 5-hydroxytryptamine with pretreatment by parachloroamphetamine did not alter the response of the striatal NT system to fenfluramine. The present results demonstrate common and unique features in the response of peptide systems to fenfluramine and methamphetamine, which might explain some of the similarities and differences between these two drugs.

Animals↗
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

Effects of cocaine on extrapyramidal and limbic dynorphin systems.

The principal central nervous system effects of cocaine are a consequence of its ability to inhibit monoaminergic uptake systems. This agent influences dopamine-related behavior in a manner similar to other sympathomimetics, such as methamphetamine; however, the effect of these two agents on neurochemical dopaminergic parameters are distinct. Several peptidergic neurotransmitter systems, such as the dynorphin pathways, have been shown to be distal to and regulated by the postsynaptic activity of dopaminergic pathways; therefore, we evaluated the response of extrapyramidal and limbic dynorphin A1-17 (Dyn) systems to cocaine by measuring Dyn content in associated structures. Extrapyramidal and limbic dynorphin-like immunoreactivity (DLI) content markedly increased after cocaine treatment. This change appeared to be due primarily to the ability of cocaine to block dopamine re-uptake; consequently, the increase in DLI levels was either totally or partially blocked by coadministration of selective D1 (SCH 23390) and D2 (sulpiride) receptor blockers and multiple doses of the selective dopamine uptake blockers, amfonelic acid and GBR 12909, caused cocaine-like enhancement of extrapyramidal DLI content. Serotonin did not appear to play a major role in mediating the cocaine effects on Dyn systems as multiple doses of the selective serotonin uptake blocker, fluoxetine, did not alter extrapyramidal DLI levels, and depletion of serotonin by pretreatment with parachloroamphetamine did not significantly alter the increases in extrapyramidal Dyn content caused by cocaine administration. Because the behavioral effects of cocaine and methamphetamine are similar, the neurochemical response of Dyn systems to both of these agents is compared and discussed.

Animals↗
PubMed1990

Neurochemical basis of neurotoxicity.

The neurotoxic properties of 6-hydroxydopamine and 5,7-dihydroxytryptamine are reviewed. The neurochemical responses of the dopaminergic and serotonergic systems after methamphetamine (METH) are reported. METH decreased activities of tyrosine hydroxylase and tryptophan hydroxylase; concentrations of dopamine (DA) and 5-hydroxytryptamine (5HT) and their respective metabolites were decreased in parallel with the decline in activity of the enzymes. When a variety of pharmacologic or surgical procedures were used to decrease DA content prior to administration of METH, the effects of METH were attenuated. From these data it is inferred that DA is essential for the METH-induced response. 3,4-Methylenedioxymethamphetamine (MDMA) produced similar effects which were also DA-dependent. Evidence for a role of glutamate and oxidative stress in the neurotoxicity of the amphetamines is presented.

3,4-Methylenedioxyamphetamine↗