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R R Holson

Publications and source records attributed to R R Holson.

At least 19 recordsLinked to original sources
PubMed1996

Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion.

To investigate changes in striatal dopamine release over a series of brief methamphetamine (METH) exposures, METH was pulsed three times at 2-h intervals, with the first exposure occurring 2 h after microdialysis probe insertion. Whether METH was administered directly into the striatum via the microdialysate (20 microM of METH for 10 min), or via peripheral intraperitoneal (i.p.) injection (1 mg/kg METH, i.p.), the dopamine (DA) peak elicited by the third METH exposure was only 50% as large as that elicited by the first exposure, 4 h earlier. This decline in the magnitude of METH-induced DA release probably continued over at least 24 h, since the magnitude of a single peak 26 h after probe implantation was only one-seventh of that at 2 h. This reduction in the response to METH was a function of time post-probe insertion, and not of prior METH exposure. Thus, peak size was the same at 6 h post-implantation in animals which received two prior METH pulses or no prior METH pulses, and in both cases this 6-h peak was substantially lower than that at 2 h post-implantation. Circadian influences were also excluded as a factor, because size of the initial METH-induced DA peak did not vary as a function of time of probe implantation. It is concluded that METH-stimulated striatal DA release declines rapidly over time post-probe insertion. When METH exposures occur repeatedly at short intervals, this decline can mimic, but is not caused by, desensitization or depletion in response to prior METH exposure.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Effects of ischemia-hypoxia induced by interruption of uterine blood flow on fetal rat liver and brain enzyme activities and offspring behavior.

The effects of acute perinatal ischemia-hypoxia on fetal liver and brain energy metabolism, fetal brain total free fatty acid concentration and subsequent offspring behavior were investigated in rats. Ischemia-hypoxia was induced at term either by ligation of the uterine blood vessels or submersion of the entire uterine horn in warmed saline. Fetuses of the adjacent horn served as within-dam controls for all assessments and fetuses of dams which had not undergone the surgical stress served as independent controls for enzyme assays. Ischemia-hypoxia was associated with reduced activity of fatty acid synthase in the liver and brain. Total free fatty acid concentration significantly increased in the fetal hypoxic brain. Pups not used for enzyme analyses were cross-fostered for behavioral assessments. Relative to the enzymatic alterations, there were few behavioral alterations associated with ischemia-hypoxia. At postnatal day 30, rats made hypoxic by ligation of the uterine blood vessels had decreased caudate nucleus and brain stem weights relative to within-dam controls. At postnatal day 85, rats made hypoxic by submersion of the uterine horn had decreased olfactory bulb weight. The results of this study indicate an initial acute response to a brief period of ischemia-hypoxia at term pregnancy in the fetal rat brain and liver.

Age Factors↗
PubMed1996

Individual differences in dopamine release but not rotational behavior correlate with extracellular amphetamine levels in caudate putamen in unlesioned rats.

It has been postulated that differences in pharmacokinetics do not contribute to the well-known individual variability in response to amphetamine (AMPH), but this is yet to be investigated thoroughly. Therefore, rotational behavior of outbred rats (Sprague-Dawley, 4 months old) was recorded during microdialysis sessions and striatal microdialysate was analyzed concomitantly for AMPH and dopamine concentrations after a single injection of 2.5 mg/kg AMPH SC. Three hours later these rats received three doses of 5 mg/kg AMPH SC (spaced 2 h apart) and their brain temperature was recorded every 20 min. The most important findings were: 1) the increase in extracellular dopamine was highly correlated with the corresponding peak AMPH levels in the microdialysate; 2) the peak dopamine level in response to 2.5 mg/kg AMPH was predictive of the hyperthermic response observed during 3 x 5 mg/kg AMPH and 3) high versus low rotators differed neither in their AMPH nor in their dopamine extracellular striatal concentrations.

Amphetamine↗
PubMed1995

Nitric oxide regulation of methamphetamine-induced dopamine release in caudate/putamen.

A possible role for NO modulation of dopamine (DA) release in the caudate/putamen (CPU) during methamphetamine (METH) exposure was investigated using in vivo microdialysis in rats. Inclusion of the nitric oxide synthase (NOS) inhibitors NG-nitro-L-arginine (NOARG), NG-nitro-L-arginine methyl ester (L-NAME) or D-NAME (less potent inhibitor) in the microdialysis buffer prior to METH minimally affected basal levels of DA, DOPAC or HVA in CPU microdialysate. However, L-NAME and NOARG produced concentration-dependent decreases of up to 64% (100 microM) in CPU DA levels in microdialysate during exposure to four doses of METH (5 mg/kg i.p./2 h), with lesser effects on DOPAC or HVA. Reversal of the NOARG inhibition was produced by inclusion of 500 microM of either L-arginine or L-citrulline in the microdialysate. D-NAME (100 microM) minimally affected levels of DA or metabolites. Paradoxically, inclusion of from 20 to 2 microM of the NOx generators isosorbide dinitrate (ISON) or sodium nitroprusside (SNP) in the microdialysis buffer decreased DA and DOPAC levels in microdialysate during METH exposure. This paradox might result from the concentrations of NOx produced by SNP or ISON being great and not regionally specific resulting in inhibition of DA release and/or synthesis while the NO generated endogenously during METH exposure may have localized and site-specific actions. Alternatively, NOx may inhibit NOS or other enzymes in the NO synthesis pathway, thereby reducing levels of an intermediate (other than NO) which potentiates DA release. In their entirety, our results indicate that NO generation in the CPU may augment the release of DA during METH exposure.

Animals↗
PubMed1995

Decreased dominance in a limited access test but normal maternal behavior in micrencephalic rats.

Micrencephalic offspring produced by gestational treatment with the antimitotic compound/methylazoxymethanol acetate (MAM) are remarkable for substantial preservation of function concurrent with severe neural stunting. Altered behaviors in these micrencephalics, including light shyness and response perseveration, are similar to those produced by frontal cortex lesions. Consistent with this, the frontal cortex is one of several regions severely stunted by gestational MAM treatment. Because the frontal cortex has been implicated in rodent social behavior, maternal behavior in females and dominance in both sexes were assessed. Dominance was measured via water competition in 24-h water-deprived dyads (1 control and 1 MAM) matched for sex and body weight. Micrencephalic rats exhibited shorter drinking time than controls (males: 101 vs. 219 s, p < 0.001; females: 114 vs. 176 s, p < 0.03), indicating that micrencephalics were more submissive. For maternal behavior tests, micrencephalic and control females were bred to control males and pup retrieval was measured on postnatal days 3-13. Micrencephalic dams were unimpaired in any aspect of pup retrieval. Of 8 standard behavior measures used here and previously, access time in water competition tests produced the clearest differentiation between control and micrencephalic rats. These studies indicate that at least one aspect of social dominance in both sexes is severely reduced by MAM treatment while maternal behavior remains intact.

Animals↗
PubMed1995

Amphetamine levels in brain microdialysate, caudate/putamen, substantia nigra and plasma after dosage that produces either behavioral or neurotoxic effects.

Extracellular levels of d-amphetamine (AMPH) in caudate/putamen were determined using microdialysis and HPLC quantitation after s.c. doses that produced increased motor activity (1 mg/kg), stereotypic behavior (2.5 mg/kg) or dopamine depletion in the caudate/putamen (4 x 5 mg/kg). In 6-mo-old rats exposed to neurotoxic doses of AMPH sulfate (4 x 5 mg/kg in a 23 degrees C environment), extracellular caudate/putamen AMPH rose to levels of 7.9 +/- 0.9 microM after the first dose and peaked at 15.1 +/- 2.5 microM after the third dose with no further increases after the fourth dose. After one or three doses of 5 mg/kg, peak plasma and tissue levels of AMPH were 1.7 +/- 0.2 and 2.9 +/- 0.3 microM in plasma, 36 +/- 6 and 73 +/- 10 in substantia nigra and 25 +/- 4 and 50 +/- 8 in caudate/putamen, respectively. Caudate/putamen extracellular AMPH levels were about three times higher (in either 6- or 12-mo-old rats) after 4 x 15 mg/kg in a 10 degrees C environment and tissue levels in caudate/putamen and substantia nigra were three to five times higher after three doses of AMPH. However, these higher levels did not produce dopamine depletion in the caudate/putamen, while the lower doses (4 x 5 mg/kg) given at 23 degrees C did. Estimated caudate/putamen extracellular AMPH levels of 2.5 to 5 microM after single doses (1 and 2.5 mg/kg) that caused hyperactivity and stereotypic behavior are compatible with the 2 to 10 microM AMPH concentrations reported to be necessary to produce pronounced dopamine release in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice.

Recently we have reported that methamphetamine (METH) neurotoxicity in rats depends on the environmental temperature. Here, we evaluate whether a cold environment (4 degrees C) or drugs which chloride and glutamate ion channel function block METH neurotoxicity in mice. Adult male CD mice received METH i.p. (4 x 10 mg/kg METH at 23 degrees C along with saline. 2.5 mg/kg (+)-MK-801, 40 mg/kg phenobarbital or 2.5 mg/kg diazepam and either 4 x 10 or 4 x 20 mg/kg METH at 4 degrees C). Multiple injections of METH (4 x 10 mg/kg i.p.) at room temperature (23 degrees C) produced a significant depletion of dopamine (DA) in striatum at 24, 72 h, 1 and 2 weeks. Three days post 4 x 10 mg/kg METH at 23 degrees C, an 80% decrease in striatal dopamine (DA) occurred while the same dose at 4 degrees C produced only a 20% DA decrease, and 4 x 20 mg/kg METH at 4 degrees C produced a 54% DA decrease. At 23 degrees C (+)MK-801 completely blocked while phenobarbital (40% decrease) and diazepam (65% decrease) partially blocked decreases in striatal DA produced by 4 x 10 mg/kg METH. Decreases in DOPAC and HVA were similar to the decreases in DA after METH and antagonists. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature also produced a significant depletion of serotonin (5-HT) in striatum at 24, 72 h, 1 and 2 weeks. This depletion of 5-HT at room temperature was blocked either by changing the environmental temperature to 4 degrees C, or by pretreatment with MK-801, diazepam and phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Prenatal neuroleptic exposure and growth stunting in the rat: an in vivo and in vitro examination of sensitive periods and possible mechanisms.

There is increasing evidence that a number of neurotransmitters can play a trophic role in the development of the central nervous system. Dopamine is one candidate for this role. In a series of papers, Lewis, Patel, and colleagues have demonstrated that exposure to compounds which interfere with dopaminergic neurotransmission ("neuroleptics") can block cell proliferation in the brains of 11-day-old rat pups for at least 24 hr. More recently our laboratory has reported that prenatal exposure to haloperidol (HAL), a neuroleptic which binds to and blocks dopamine receptor sites in the adult brain, permanently stunts body and brain growth when that exposure extends throughout postimplantation pregnancy. Reported here are the results of two experiments conducted to further examine this phenomenon. The first experiment attempted to identify sensitive gestational periods for the HAL effect on growth in vivo. This experiment also assessed the effect of exposure to reserpine (RES), a compound which in the adult blocks dopaminergic neurotransmission by rupturing monoamine storage vesicles, an effect which is quite distinct from the HAL mechanism of action. In a second experiment, gestational day (GD) 9 embryos were exposed in vitro for 48 hr to either HAL, RES, or one of two specific blockers of dopamine receptor subtypes. Schering 23390 (SCH) was used as the D1 blocker, and sulpiride (SULP) as the D2 blocker. The in vivo experiment showed that twice-daily exposure to subcutaneous injections of HAL (5 mg/kg for each of the 2 injections) or RES (0.1 mg/kg for each injection) permanently stunted brain growth when injections were given in midpregnancy (GD 12-16), but not in late pregnancy (GD 16-20). RES was substantially more fetotoxic than HAL, especially late in pregnancy. The growth stunting produced by either compound with GD 12-16 exposure was not restricted to dopamine-rich areas of the brain, or indeed to the brain itself, in that body weight was also depressed. Pair-fed controls did not show the same magnitude or duration of stunting, indicating that this effect was not due to drug-induced maternal hypophagia. The in vitro experiment revealed that exposure to micromolar concentrations of any of the 4 neuroleptics reduced embryonic GD 11 DNA and protein content and delayed development. HAL and SCH had the most pronounced effects at concentrations close to blood levels reportedly produced by exposure to doses used in the in vivo experiments. RES was less potent, and SULP still less potent than RES.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1994

Effects of methylazoxymethanol-induced micrencephaly on temporal response differentiation and progressive ratio responding in rats.

Micrencephalic Sprague-Dawley rats were produced by an injection of 20 mg/kg methylazoxymethanol acetate on gestational Day 14. Brain weights of the offspring were 70% of controls while weights of frontal cortex and hippocampus were approximately 58% (Ferguson, Racey, Paule, & Holson, 1993). Operant performance was measured with particular emphasis on assessment of time estimation. The temporal response differentiation (TRD) and the progressive ratio (PR) tasks, previously used in the NCTR operant test battery for monkeys, were chosen for evaluation. The TRD schedule is notably different from other temporal tasks in that it requires subjects to initiate and maintain a lever press for 10-14 s. The PR task was included as a measure of motivation to work for food reinforces. Micrencephalics acquired and performed both tasks comparably to controls. During extinction, however, micrencephalics exhibited an increased TRD lever hold duration. This suggests an atypical response perservation, that is, perseverating the previously correct response. Previously, frontal cortical alterations were suggested to contribute heavily to micrencephalic-induced behavioral alterations (Ferguson et al., 1993). This study provides further evidence that response perseveration, a hallmark of frontal cortical lesions, is expressed in micrencephalic rats.

Animals↗
PubMed1994

Further studies of the role of hyperthermia in methamphetamine neurotoxicity.

The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently, rats saved by hypothermic intervention have greater depletion of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hyperthermia in METH neurotoxicity. However, hyperthermia (alone or with haloperidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection. Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH.

Animals↗
PubMed1993

Development of dopamine and N-methyl-D-aspartate systems in rat brain: the effect of prenatal phencyclidine exposure.

Phencyclidine (PCP) inhibits the uptake of the neurotransmitter dopamine (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in rat brain. Prolonged exposure to PCP in adults has been observed to reduce the number of PCP binding sites in brain. We designed these experiments to evaluate whether prolonged prenatal exposure to PCP produces alterations in the development of DA and NMDA systems in brain. To do so, we characterized the normal course of development of basal and stimulated DA release in striatal slices, the ontogeny of striatal DA concentrations, and the development of NMDA receptor channels and associated glutamate binding sites in frontal cortex. We compared these developmental profiles to those in rats exposed to prenatal PCP, in an attempt to characterize the effect of prenatal PCP exposure on the pattern of brain development. Pregnant CD rats were injected s.c. with either 0, 10 or 20 mg/kg PCP daily on gestational days 8 through 20. On postnatal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tissues isolated for in vitro assessment. In vitro [3H]DA release from striatal slices evoked by either 40 microM glutamate or 15 mM K+ increased over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-methamphetamine (D-METH)-evoked [3H]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Effects of a cold environment or age on methamphetamine-induced dopamine release in the caudate putamen of female rats.

Extracellular levels of dopamine (DA) and metabolites as well as serotonin [5-hydroxytryptamine (5-HT)] and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the caudate putamen (CPU) of either 6- or 12-month-old female rats using microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ED) before, during, and after four consecutive injections (given at 2-h intervals) of methamphetamine (METH). In 6-month-old rats administered 4 x 5 mg/kg METH at an environmental temperature (ET) of 23 degrees C, peak extracellular DA levels (between 50 and 150 rho g/10 microliters) were attained 30-45 min after each dose of METH while dihydroxyphenylacetic acid (DOPAC) decreased steadily after the first doses of METH until it reached a plateau at 50% of control (550-700 pg/10 microliters) levels. Increases in 5-HT levels during METH administrations paralleled DA increases while 5-HIAA decreases paralleled DOPAC decreases. The total CPU DA and 5-HT content of these rats was about 65% of control at 3 days post-METH. Reducing the ET to 4 degrees C during dosing decreased the peak and average DA levels attained during the 4 x 5 mg/kg METH administration to about 50% of that observed at a 23 degrees C ET. Increasing the dose to 4 x 10 mg/kg METH (4 degrees C ET) increased peak and average CPU DA levels to 200% that observed during 4 x 5 mg/kg METH at a 23 degrees C ET. However, no significant decreases in total CPU DA content of any rats dosed with METH at a 4 degrees C ET were observed 3 days post-METH. In 12-month-old rats dosed with 4 x 5 mg/kg METH (23 degrees C ET), the peak and average extracellular DA levels were only 30-60% that of 6-month-old rats. However, the CPU DA content of older rats was significantly decreased both 3 (30% control) and 14 (60% control) days post-METH. In summary, METH toxicity may not be predicted solely by the extracellular levels of DA attained during METH administration; age and ET also greatly influence METH neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Behavioral effects of methylazoxymethanol-induced micrencephaly.

This study was prompted by reports of functionally normal humans with micrencephaly or cortical hypoplasia. Methylazoxymethanol acetate (MAM) treatment, which induces micrencephaly in rats, was administered by injection (20 mg/kg) on gestational day 14. Prior to weaning and into adulthood, offspring were assessed on many behavioral tests. There were 3 findings. First, MAM rats (forebrain weight less than 2/3 of controls) were not profoundly hyperactive. Increased activity was seen only on prolonged tests or after amphetamine administration. Second, MAM rats were hypoactive in some conditions. These rats were light shy and less likely to explore lighted areas. MAM rats appeared hyperreactive to environmental stimuli, but not hyperactive. Finally, no MAM effect on behavior was as large as that on brain weight. Thus, as with clinical findings, rat micrencephalics are more remarkable for functional sparing than for behavioral abnormalities.

Alkylating Agents↗
PubMed1993

Haloperidol effects on the developing dopamine system: conflicting results and implications for neurobehavioral teratology research.

In an attempt to further develop basic principles to guide research in neurobehavioral teratology, six experiments were conducted to examine the effects of prenatal haloperidol (a D2 dopamine antagonist) exposure on striatal D1 and D2 binding sites. Another laboratory has repeatedly reported that prenatal exposure to this dopamine antagonist reduces striatal dopamine binding sites in exposed offspring. Our initial studies were successful in replicating and extending these previously reported reductions in D2 dopamine binding sites in caudate of rats exposed prenatally to haloperidol. However, additional experiments in our laboratory, in which pups were exposed to a range of haloperidol doses over gestational periods when the dopamine system has been reported to be most vulnerable to prenatal haloperidol exposure effects, have repeatedly failed to replicate our initial findings. Three other laboratories have also failed to duplicate this effect. The results of these studies suggest that beyond "standard" confounding variables, neurobehavioral teratologists are faced with as yet poorly understood factors that influence replication of findings within and between laboratories. These findings also emphasize the importance of within- and between-laboratory replication of experimental findings.

Animals↗
PubMed1992

Prenatal dexamethasone exposure in rats: effects of dose, age at exposure, and drug-induced hypophagia on malformations and fetal organ weights.

Glucocorticoids cause stunting and cleft palate in rodents. The aim of this study is to identify fetal organs and developmental periods sensitive to stunting induced by maternal exposure to dexamethasone (DEX). DEX (0.2 or 0.4 mg/kg) or saline was given sc to pregnant CD albino rats on Gestation Days (GD) 9-14 or 14-19. On GD 20 dams were euthanized. Fetuses were weighed and examined for cleft palate. Eight fetuses/litter were randomly selected, and weights were obtained. Fetal skeletons were examined for abnormalities, and long bone measurements were taken. A dose-related decrease in maternal and fetal body weights occurred at both exposure periods. Developmental stage-specific malformations were noted in the high-dose group on GD 9-14 (cleft palate) and on GD 14-19 (wavy ribs). A dose-response in stunting occurred in all organs except cerebellum in at least one exposure period. Across both exposure periods the brain, heart, testes, and long bones were relatively resistant to DEX. Sensitive organs included thymus, spleen, adrenals, lungs, liver, and kidneys. DEX substantially reduced maternal food intake and increased water intake in some dams. Pair-feeding experiments suggested that the hypophagic effect of DEX was not responsible for the noted malformations and had little impact on growth stunting. The present findings have identified fetal organs, skeletal regions, and developmental periods sensitive to DEX exposure.

Abnormalities, Drug-Induced↗
PubMed1992

Embryotoxicity of phenytoin in adrenalectomized CD-1 mice.

It has been proposed that the anticonvulsant drug phenytoin (PHT) and glucocorticoids induce orofacial clefting by the same mechanism. Previous work had demonstrated that PHT treatment significantly increased endogenous maternal corticosterone concentrations for approximately 48 hr after dosing in A/J mice. The purpose of the present investigation was to determine whether PHT is embryotoxic in the absence of endogenous maternal glucocorticoids. Maternal adrenal glands were removed on Day 7 of gestation, and the incidence of clefting after PHT treatment was determined. There was a high level of maternal toxicity following adrenalectomy (ADX) and PHT treatment at either 60 or 75 mg/kg. This increased toxicity did not appear to be due to altered maternal drug levels in ADX mice. There was a significant increase in the clefting incidence among offspring of ADX dams treated with PHT at 60 mg/kg. This dose of PHT did not elevate maternal corticosterone levels in ADX dams. These data suggest that PHT is capable of producing clefts in the absence of endogenous maternal corticosterone.

Abnormalities, Drug-Induced↗
PubMed1992

The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum.

When male rats were injected four times (once every 2 hr) with 5 mg/kg methamphetamine (METH) at an environmental temperature of 23 degrees C, transient changes occurred in the levels of striatal dopamine (DA) and the regulation of striatal DA release. Striatal DA levels were minimally affected 1 day after METH treatment, but 3 days after METH treatment, striatal DA levels decreased to approximately 40% of control. DA levels returned to 70% of control 2 weeks after METH. Similarly, striatal tyrosine hydroxylase (TH) activity decreased to approximately 50% of control activity 3 days after METH treatment at 23 degrees C, but did not differ from controls at 1 or 14 days after METH treatment. No changes in striatal DA levels were observed in rats treated with four doses of 5 mg/kg METH at an environmental temperature of 4 degrees C. Striatal DA levels decreased modestly to approximately 70% of controls 3 days after treatment with four doses of 10 mg/kg METH at 4 degrees C, but DA levels returned to control levels 14 days after METH treatment. Furthermore, striatal TH activity was not affected by 10 mg/kg METH at 4 degrees C. Thus, a cold environmental temperature (4 degrees C) reduced the effects of METH on striatal DA levels and striatal TH activity. Changes in the presynaptic regulation of DA release after either 5 mg/kg (23 degrees C) or 10 mg/kg (4 degrees C) METH treatment were determined in vitro using striatal slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗