Biomedical subjects

G R Hanson

Publications and source records attributed to G R Hanson.

At least 73 records · Page 4Linked to original sources

PubMed1996

Cloning and sequence analysis of the dimethylsulfoxide reductase structural gene from Rhodobacter capsulatus.

The dimethylsulfoxide reductase structural gene (dorA) of Rhodobacter capsulatus was cloned from a lambda expression library. The nucleotide sequence of the dorA gene was determined and it was found to encode a protein of 825 amino acids. Comparison of the deduced amino-acid sequence of DorA with N-terminal sequence of purified dimethylsulfoxide reductase from Rhodobacter capsulatus showed that the pre-protein possesses a 41-amino-acid N-terminal signal polypeptide. All of the conserved segments which have been described in bacterial enzymes which bind molybdopterin guanine dinucleotide (Berks, B.C., Ferguson, S.J., Moir, J.W.B. and Richardson, D.J. (1995) Biochim, Biophys. Acta 1232, 97-173) were identified in Rhodobacter capsulatus dimethylsulfoxide reductase.

Amino Acid Sequence↗

PubMed1996

Dopamine D2-receptors regulate neurotensin release from nucleus accumbens and striatum as measured by in vivo microdialysis.

The present study was undertaken to examine the role of dopamine D2-receptors in the regulation of neurotensin release. Through a modification of the methods described by Maidment et al. (Neuroscience, 45 (1991) 81-93), we have developed a highly reproducible method of measuring changes in extracellular NT in the striatum and nucleus accumbens by in vivo microdialysis in awake animals. It was observed that calcium-dependent release of NT was evoked in both structures by infusing a high concentration of potassium. In addition, systemic administration of the D2 agonist quinpirole (5 mg/kg) induced a rapid increase of approximately 200% in extracellular NT levels in the lateral caudate and 30-40% in the nucleus accumbens. Conversely, treatment with the D2 antagonist eticlopride (0.5 mg/kg) reduced extracellular NT in the medial anterior caudate and nucleus accumbens 20-30%, but had no effect in the lateral anterior caudate. These data demonstrate for the first time that D2-receptors are important in the dopaminergic regulation of extrapyramidal and limbic NT release in conscious animals.

Animals↗

PubMed1996

Mechanisms for tolerance to methamphetamine effects.

Pretreatment with incremental increases in methamphetamine causes tolerance to serotonergic effects caused by challenging with multiple high doses of methamphetamine (11.5 mg/kg/dose). The brain concentration of methamphetamine following this challenge was reduced in tolerant rats, yet the plasma concentration was elevated. The tolerance was selective for methamphetamine and did not occur when cocaine was used in the pretreatment. The possibility that tolerance affects the distribution of methamphetamine in or out of the brain through an active transport system was examined by combining the transport-blocking drug, probenecid, with a low dose of methamphetamine. The presence of probenecid enhanced methamphetamine-induced serotonergic changes in the hippocampus. The brain concentration of methamphetamine increased in the presence of probenecid; however, a similar increase in the plasma methamphetamine concentration suggests that the effects of probenecid on methamphetamine distribution are not related to the redistribution of methamphetamine that occurs in tolerant animals.

Animals↗

PubMed1996

Detection of hydroxyl and carbon-centred radicals by EPR spectroscopy after ischaemia and reperfusion of the rat kidney.

Recent studies suggest that oxygen-derived free radicals are involved in mediating renal reperfusion injury. EPR spectroscopy and spin trapping with the spin traps DMPO and PBN, were used to detect and quantitate the formation of hydroxyl radicals in rat kidney after ischaemia-reperfusion in vivo and in vitro in the isolated rat kidney perfused in the absence of leucocytes. EPR analysis of homogenised kidneys and of venous samples did not detect radical adducts with either spin trap. With PBN, radical adducts were not detected in vitro. When DMPO was used as the spin trap in kidneys perfused without albumin in the perfusate, EPR signals characteristic of hydroxyl and carbon-centred radical adducts were detected during early reperfusion following ischaemia. These studies confirm the generation of hydroxyl radicals during ischaemia-reperfusion in kidney. During reperfusion the total DMPO adduct concentration reached 4.35 +/- 1.05 nmol/g kidney/3 min, p < 0.05. In control kidneys total adduct were present at lower concentration (2.55 +/- 1.1 nmol/g kidney/3 min). Addition of 15 mM dimethylthiourea abolished formation of these adducts following ischaemia-reperfusion but did not prevent a reduction in glomerular filtration rate. These results indicate that significant levels of hydroxyl and carbon-centred radicals are formed in the absence of circulating neutrophils during early renal reperfusion following ischaemia.

Animals↗

PubMed1996

Microdialysis assessment of methamphetamine-induced changes in extracellular neurotensin in the striatum and nucleus accumbens.

Stimulants of abuse such as cocaine and methamphetamine (METH) have dramatic effects on tissue neurotensin (NT) levels in the striatum and nucleus accumbens. Presumably these effects are due to the ability of such drugs to increase dopamine transmission. Because changes in dopamine activity appear to influence NT systems, we examined the effects of increasing doses of METH on extracellular NT levels in the medial striatum and nucleus accumbens using in vivo microdialysis in conscious rats. At the lowest dose tested (0.5 mg/kg), METH almost doubled the extracellular concentration of NT in both regions. When the dose of METH was increased to 5.0 mg/kg, extracellular NT concentration was elevated, but only to approximately 150% of control. At the highest dose examined (15.0 mg/kg), extracellular NT was not altered compared to pretreatment control levels. The role of DA D-1 and D-2 receptors in mediating these effects was determined by combining specific antagonists with the low dose of METH. The D-1 antagonist SCH 23390 blocked the METH-induced increase in extracellular NT levels in the striatum, but not in the nucleus accumbens. Pretreatment with the D-2 antagonist, eticlopride, blocked the increase in extracellular NT in both regions. Changes in striatal NT extracellular levels after a single METH injection were compared to the alterations in tissue NT levels following multiple administrations of the same doses of METH. Tissue levels were significantly elevated with 5 or 15 mg/kg METH in the medial, but not the lateral, striatum. There was not a clear correlation observed between the METH effects on striatal NT tissue levels and extracellular NT concentration.

Animals↗

PubMed1996

Methcathinone: an initial study of its effects on monoaminergic systems.

Methcathinone is a stimulant recently designated a Schedule I drug. Its use and popularity are growing; however, little data are available concerning its neurochemical properties. We investigated the effects of single and multiple doses of methcathinone on dopaminergic and serotonergic systems in the rat. Multiple doses of 30 mg/kg methcathinone caused dramatic decreases in neurochemical parameters associated with both dopaminergic and serotonergic systems in the striatum; corresponding decreases also occurred in serotonergic parameters in hippocampus and frontal cortex. These reductions in enzyme activity and concentrations of transmitters and their metabolites were apparent of 18 and 72 hr after drug administration. In addition, a single dose of methcathinone caused a significant decrease in the serotonergic enzyme activity in the striatum that was evident at 30 min and 2 hr after drug administration. We found that doses of 10 and 20 mg/kg causes no effect on striatal monoaminergic systems; however, doses higher that the 30 mg/kg dose caused significant lethality. In comparison with other stimulants of abuse, methcathinone appears to be most similar to methamphetamine with regard to its effects on monamine systems.

Amines↗

PubMed1995

Body temperature effect on methylenedioxymethamphetamine-induced acute decrease in tryptophan hydroxylase activity.

Brain tryptophan hydroxylase activity decreases within 15 min after a single administration of 3,4-methylenedioxymethamphetamine. In the present study, the effect of body temperature on this acute decrease of tryptophan hydroxylase activity was examined. 2 h after a single dose of 3,4-methylenedioxymethamphetamine (20 mg/kg, s.c.), rats exhibited hyperthermia (38.7 degrees C) or hypothermia (35.8 degrees C) when maintained at 25 degrees C or 6 degrees C, respectively. The rectal temperature of control animals maintained at 6 degrees C was not altered. Tryptophan hydroxylase activity measured in the hippocampus, striatum and frontal cortex of hyperthermic rats treated with 3,4-methylenedioxymethamphetamine was decreased to 61%, 65%, and 71% of control levels, respectively, 2 h after drug treatment. However, in hypothermic rats, 3,4-methylenedioxymethamphetamine had no effect on tryptophan hydroxylase activity in the hippocampus, striatum or frontal cortex. Non-drug-induced hyperthermia or hypothermia did not affect tryptophan hydroxylase activity. Since hypothermia may prevent the 3,4-methylenedioxymethamphetamine-induced decrease in tryptophan hydroxylase activity by reducing the formation of free radicals, the effect of a free radical scavenging agent, N-tert-butyl-alpha-phenylnitrone, was examined. N-tert-butyl-alpha-phenylnitrone (200 mg/kg, i.p.) alone caused hypothermia but had no direct effect on tryptophan hydroxylase activity. Preadministration of N-tert-butyl-alpha-phenylnitrone prevented 3,4-methylenedioxymethamphetamine from raising the temperature above normal and attenuated the drug-induced decrease in tryptophan hydroxylase activity in hippocampus, striatum and frontal cortex. However, when the rats treated with a combination of N-tert-butyl-alpha-phenylnitrone and 3,4-methylenedioxymethamphetamine were maintained at hyperthermic conditions, N-tert-butyl-alpha-phenylnitrone had no protective effect. These results suggest that body temperature plays a prominent role in the 3,4-methylenedioxymethamphetamine-induced acute decrease in tryptophan hydroxylase activity.

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↗

PubMed1995

The role of NMDA receptor systems in neuropeptide responses to stimulants of abuse.

High doses of stimulants of abuse, such as methamphetamine and cocaine, cause significant increases in the content of neurotension- and dynorphin-like immunoreactivity in the striatum and nucleus accumbens (approximately 200-600% of control) in the rat. These changes in neuropeptide content are caused by stimulation of dopamine D1 receptors and prevented by the glutamate NMDA receptor antagonist, MK 801. Stimulation of the NMDA receptor with N-methyl-D-aspartate results in increases in the neuropeptide levels like that caused by methamphetamine and cocaine. These findings demonstrate that stimulants of abuse profoundly influence neurotensin and dynorphin pathways associated with extrapyramidal and limbic structures by an interaction of activated dopamine D1 and glutamate NMDA receptors.

Animals↗

PubMed1995

Myocardial electrophysiological effects of neuropeptide Y in dogs.

Neuropeptide Y (NPY) exerts coronary vasomotor and inotropic effects on the canine heart. To test whether NPY also exerts regional myocardial electrophysiological effects, dose-response and time course changes resulting from intravenous and regional intracoronary infusions of NPY were obtained in 14 alpha-chloralose-anesthetized dogs. Under constant ventricular pacing, activation (A), recovery (R), and A-R interval (ARI) maps were constructed from multiplexed unipolar surface electrograms recorded simultaneously from 64 sites within a 1.6 x 1.6-cm left ventricular region. Effects were compared with those of vasoactive intestinal peptide (VIP) infusions and supramaximal left ansae subclaviae sympathetic nerve stimulation (SNS). The main finding was a uniform shortening of ARI, which reached a maximum of 8.7 +/- 1.2 ms, or 7% of control (P < 0.001), at about three times the baseline NPY plasma concentration (21.6 +/- 1.9 pg/ml). This effect decayed slowly (> 15 min) along with NPY plasma levels. The effect of similar VIP infusions and of SNS was 11%. Thus, compared with the previously identified maximal effect of adenylate cyclase activation (20%), exogenous NPY exerts a moderate but markedly sustained ventricular myocardial electrophysiological effect, which reaches maximum in relatively low plasma concentrations.

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

Effect of neonatal hypoxia-ischemia on nigro-striatal dopamine receptors and on striatal neuropeptide Y, dynorphin A and substance P concentrations in rats.

Perinatal hypoxic-ischemic brain injury was induced in 7- to 8-day-old rats by ligating the left carotid artery with subsequent exposure to 9% oxygen atmosphere for 2.5 h. The animals were killed 7 days later and grouped according to the degree of brain injury sustained after hypoxia-ischemia. Total protein content measured in striatum ipsilateral to the ligation, and dissected from brains showing extensive damage, was reduced to 64% of contralateral tissue. The protein content was not altered in other groups including control animals exposed to air and in sham-operated animals exposed to hypoxic conditions. The concentration of (pg/mg protein) and total (pg/striatum) striatal dynorphin A-like immunoreactivity (DLI) from brains with extensive damage were increased to 481% and 285% of the contralateral side, respectively. Hypoxia-ischemia increased striatal neuropeptide Y-like immunoreactivity (NPYLI) concentration from brains with extensive damage to 157% of contralateral side, but when the results were expressed as total NPYLI content per striatum, NPYLI content in striatum with extensive damage remained unaltered. Substance P-like immunoreactivity (SPLI) concentration and total content per striatum from brains with extensive damage were reduced to 66% and 43% of the contralateral side, respectively. D1 and D2 receptor density in animals killed 10 days after injury was reduced by 24% and 22% of control, respectively, in striatum from brains with extensive damage. These results indicate complex changes in brain neuropeptides following neonatal hypoxia-ischemia. Damage in the substance P system could have functional effects on dopaminergic transmission while the increase in NPYLI and in DLI concentrations may respectively reflect the relative preservation from neuronal damage and possibly an increase in neuropeptide synthesis or decrease in release. The decrease in SPLI concentration and the increase DLI concentration induced by hypoxia-ischemia suggests that these peptides may be present in separate neurons.

Aging↗

PubMed1994

Vanadium in ascidians: changes in vanadium coordination and oxidation state upon cell lysis.

Changes in vanadium coordination during cell lysis have been followed by EPR spectroscopy of the blood cells of the phleborbranch ascidians Ascidia ceratodes and PHallusia julinea. The spectra obtained for A. ceratodes whole blood samples can be mainly ascribed to aquated oxovanadium(IV) in which the signals are broadened in freshly frozen blood relative to when the cells are lysed by thawing. The sources of this broadening are discussed and it is shown that the oxovanadium(IV) signal has its origin in a small percentage of damaged or lysed cells which release vanadium into a low sulfate, low acid environment in fresh samples. When thawed, the cells lyse releasing acid and sulfate into the environment of the oxovanadium(IV), with consequent narrowing of the EPR spectral linewidth. Freshly frozen P. julinea blood cell samples have EPR spectra with parameters intermediate between aquated oxovanadium(IV) and the "type I" parameters observed in a previous investigation of tissue samples of this species (S. G. Brand, C. J. Hawkins, A. T. Marshall, G. W. Nette, and D. L. Parry, Comp. Biochem. Physiol. 93B, 425 (1989)). A. ceratodes tissue samples also have EPR spectra that differ from that of the blood. It is suggested that EPR studies on tissue samples are more indicative of the resting state of vanadium in the cells as there is more physiological material to provide a pH buffering effect to stabilize the cells. Schemes are presented which incorporate all of the EPR observations in ascidian literature, where cellular lysis is proposed to be accompanied by vanadium undergoing oxidation and a series of chelate exchanges from a "type I" complex to aquated oxovanadium(IV). Protons released during these exchanges are suggested to provide the acidity characteristic of blood cell lysates. The biological implications of the concomitant release of vanadium and tunichrome (S. W. Taylor, D. L. Parry, C. J. Hawkins, and J. H. Swinehart, Comp. Biochem. Physiol. 106A, 531 (1993)) from the blood cells, to the process of wound repair are discussed.

Animals↗

PubMed1994

A purified ferredoxin from Giardia duodenalis.

A ferredoxin has been purified to homogeneity from the ancient protozoan parasite Giardia duodenalis. As far as we know, this is the first electron transport protein to be characterised from the organism. The ferredoxin exhibits absorption maxima at 296 and 406 nm with molar absorption coefficients of epsilon 296 = 16,650 +/- 240 M-1 cm-1 and epsilon 406 = 13,100 +/- 370 M-1 cm-1 respectively. The A406/A296 ratio ranged over 0.78-0.82. The molecular mass of the apoprotein calculated by mass spectrometry was 5730 +/- 100Da and the minimum molecular mass by amino acid analysis was 5926Da. There were four cysteine residues/molecule protein but no methionine, arginine, histidine or tyrosine. The absence of these latter residues is consistent with the amino acid content of most ferredoxins. The N-terminal amino acid sequence exhibited greatest similarity to Desulfovibrio gigas ferredoxin II and indicated the potential to coordinate an iron-sulfur cluster. There were 3.21 +/- 0.41 mol sulfide and 2.65 +/- 0.06 mol iron/mol protein. Electron paramagnetic resonance studies of this protein have indicated the presence of an iron-sulfur centre consistent with those of known ferredoxins. Ferredoxin serves as a biological electron acceptor from giardial pyruvate dehydrogenase with metronidazole as a terminal electron acceptor. Such a pathway may serve as a possible mechanism for the reductive activation of metronidazole in this parasite. A second ferredoxin has been purified to homogeneity, but at this stage there is insufficient material to fully characterise this protein. No other low-molecular-mass electron transport proteins have been identified in Giardia under the growth conditions described.

Amino Acid Sequence↗

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↗

PubMed1994

Vagal-induced tachycardia: release of vasoactive intestinal peptide and peptide HI.

The relationship between vagal-induced tachycardia (VT) and release of vasoactive intestinal peptide (VIP) and peptide HI (PHI) into cardiac lymph and coronary sinus blood was studied in 23 alpha-chloralose-anesthetized open-chest dogs that were autonomically decentralized and pretreated with atropine and propranolol. After simultaneous right and left cervical vagal stimulation at 5 V, 20 Hz for 3 min mean +/- SE, increase in heart rate was 38 +/- 6 beats/min, and increase in lymph VIP output from control was 0.308 +/- 0.093 pg/min (P = 0.004). The decrease in VIP arterial minus coronary sinus concentration was not significant. The increase in heart rate did not significantly correlate with increase in lymph VIP output (R2 = 0.141) or decrease in VIP arterial minus coronary sinus concentration (R2 = 0.059). The increases in heart rate and lymph VIP output were blocked by hexamethonium. Increase in lymph PHI output from control during VT (5 dogs) was 0.797 +/- 0.658 pg/min. Arterial-coronary sinus PHI concentration difference did not change in these dogs. These data indicate that VT is associated but not significantly correlated with VIP and PHI release into cardiac lymph. Cholinoceptive nicotinic receptors may mediate VIP release and VT in anesthetized dogs.

Animals↗

PubMed1994

Differential effects of antipsychotic and psychotomimetic drugs on neurotensin systems of discrete extrapyramidal and limbic regions.

The effects of two antipsychotic (dopamine antagonist) drugs, haloperidol and clozapine, and of two psychotomimetic (dopamine-releasing) drugs, methamphetamine and cocaine, on neurotensin (NT) concentrations in discrete regions of the caudate nucleus, nucleus accumbens and globus pallidus were examined. Multiple administrations of haloperidol (HA, 1 mg/kg), clozapine (20 mg/kg), methamphetamine (METH, 10 mg/kg) or cocaine (30 mg/kg) increased NT-like immunoreactivity (NTLI) in the whole striatum (caudate nucleus plus globus pallidus). The effects of combined HA and METH treatment on striatal NTLI were additive. In contrast, the effects of clozapine plus METH were not different from those caused by either drug alone. The caudate nucleus, nucleus accumbens and globus pallidus were dissected into nine areas based on anterior-posterior and medial-lateral position. Across the caudate areas, some differences in NTLI concentrations occurred when cocaine- and METH-treated groups were compared, even though whole striata in these groups did not differ significantly. The effects of the antipsychotic drugs in discrete caudate regions, alone or in combination with METH, confirmed the observations in the whole striata, although significant regional differences existed. There were also differential regional effects in the nucleus accumbens. Drug-induced changes in the NTLI content of the anterior nucleus accumbens were similar to those observed in the whole striatum, whereas NTLI changes in the posterior region of this structure often were opposite. Finally, NTLI concentrations in the globus pallidus were increased by Ha or METH treatment, but were not affected by clozapine or cocaine treatment. These findings suggest that NT systems throughout the entire striatum and nucleus accumbens do not respond in a homogeneous manner to these drugs which stimulate or block dopamine activity. The regional differences in NT responses may reflect different dopamine neurons which are affected differentially by dopamine-altering drugs.

Animals↗

PubMed1994

Role of the 5-HT2 receptor in the methamphetamine-induced neurochemical alterations.

The possibility that serotonin (5-HT) modulates dopamine (DA) synthesis by acting at 5-HT2 receptor sites during methamphetamine (METH) treatment was investigated. The neostriatal accumulation of 3,4-dihydroxyphenylalanine was not altered by ritanserin (1 mg/kg i.p.), a 5-HT2/1c receptor antagonist, or by METH (15 or 25 mg/kg s.c.), which indicates that METH-induced DA and 5-HT release did not invoke increased DA synthesis. Interestingly, the combined treatment of METH with ritanserin reduced 3,4-dihydroxyphenylalanine formation. We also examined the possibility that 5-HT2 receptors participate in the mechanism by which METH alters central tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities as well as the concentration of neurotensin-like and substance P-like immunoreactivity. Five administrations of METH given at 6-hr intervals reduced neostriatal TH and TPH activity to 27 and 13% of control, respectively, 18 to 20 hr after the last drug administration; ritanserin failed to alter these decreases significantly. Ritanserin also failed to alter the METH-induced increase in neostriatal neurotensin-like immunoreactivity or in nigral neurotensin-like immunoreactivity and substance P-like immunoreactivity. Finally, the administration of ICS 205-930, a 5-HT3/4 receptor antagonist, also failed to prevent the METH-induced decrease in TH and TPH activities at doses below 200 micrograms/kg, whereas a dose of 500 micrograms/kg potentiated the effect of METH. These results suggest that 5-HT2 does not modulate DA synthesis nor does it mediate the changes in central TH and TPH activity, or neurotensin-like immunoreactivity and substance P-like immunoreactivity content induced by METH. Because 3,4-methylenedioxymethamphetamine is reported to stimulate DA synthesis by a 5-HT2 receptor-dependent mechanism, these observations suggest that METH and 3,4-methylenedioxymethamphetamine regulate the central dopaminergic system in a different manner.

Animals↗