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PubMed1994

Methamphetamine potentiation of carbon tetrachloride hepatotoxicity in mice.

Previous studies have indicated that adrenergic agents may potentiate the hepatotoxicity of compounds such as CCl4. Methamphetamine is a powerful central nervous system stimulating drug which also possesses significant adrenergic activity, and its effects on CCl4 hepatotoxicity were examined in male ICR mice. Cotreatment of mice with methamphetamine (15 mg/kg i.p.) resulted in a significant increase in the hepatocellular necrosis produced by minimally toxic to moderately toxic doses of CCl4 (0.005-0.02 ml/kg i.p.), as indicated by changes in serum alanine aminotransferase activity and by histopathologic examination. Methamphetamine alone at this dosage was not hepatotoxic. The ability of methamphetamine to potentiate CCl4 hepatotoxicity was dose-related and became statistically significant at methamphetamine doses of 10 mg/kg or greater. Pretreatment of animals with either the selective alpha-1 adrenoreceptor antagonist prazosin (5 mg/kg i.p.) or the selective alpha-2 adrenoreceptor antagonist yohimbine (5 mg/kg i.p.) blocked the methamphetamine potentiation. The increase in CCl4 toxicity produced by methamphetamine was not associated with an increase in hepatic concentrations of either CCl4 or one of its major metabolites, chloroform. The increase in toxicity was associated, however, with increases in the in vivo covalent binding of radiolabeled CCl4 to both hepatic proteins and lipids. The cause of the increased covalent binding was not identified, but did not appear to be related to methamphetamine-induced hepatic glutathione suppression. The results of this study suggest that methamphetamine potentiates CCl4 through an adrenoreceptor-related mechanism that may involve either the increased production or diminished conjugation of the reactive metabolites normally formed during the metabolism of CCl4.

Alanine Transaminase↗

PubMed1993

[Changes of the dopamine uptake sites in the rat striatum induced by repeated methamphetamine administration: a neurochemical approach to a mechanism of relapse in amphetamine psychosis].

We investigated the effects of repeated administrations of methamphetamine on the dopamine uptake sites in the rat striatum, by using an increasing dose paradigm of methamphetamine (2.5, 5, 7.5, 10 mg/kg sc x 2, every other day for a week) which has been established to produce behavioral sensitization in methamphetamine-induced behavior. A significant decrease in the Bmax value of [3H] GBR12935 binding and in the Vmax value of [3H] dopamine uptake was demonstrated in rats sacrificed 7 days after the final methamphetamine administration, and it was also shown that the Bmax value of [3H] GBR12935 binding was reduced in the dose dependent manner. Moreover, repeated administrations of methamphetamine significantly reduced the [3H] GBR12935 binding sites in the rat striatum even 30 days after the drug discontinuation. These data suggest that repeated administrations of methamphetamine induces a long lasting decrease of the dopamine uptake sites in the rat striatum. For an understanding of neurochemical basis of these findings, we investigated the effects of pharmacological manipulations in the presynaptic dopaminergic system by the pretreatment of alpha-methyl-p-tyrosine, reserpine or amfonelic acid and the blockade of postsynaptic dopamine receptor by a pretreatment of SCH23390 or YM-09151-2, on decrease in the dopamine uptake sites following the repeated administration of methamphetamine in the rat striatum. While pretreatment of alpha-methyl-p-tyrosine or amfonelic acid prevented a reduction in the dopamine uptake sites, pretreatment of reserpine accelerated this reduction. These data suggest that presynaptic newly synthesised dopamine plays an important role in the methamphetamine-induced decrease in the dopamine uptake sites. Pretreatment of SCH23390 or YM-09151-2 protected the dopamine uptake sites from reductive effect of repeated methamphetamine administration. Because there was no presynaptic dopaminergic mechanism understanding this result, some other neronal networks, which communicate with dopaminergic system, might make a reasonable explanation of this result.

Amphetamine↗

PubMed1995

Methamphetamine and amphetamine derived from the metabolism of selegiline.

Routine methamphetamine testing identified a urine specimen with inconsistent screening and confirmation results. The methamphetamine RIA screening test (Diagnostic Products Corporation) indicated a borderline positive specimen, while the achiral confirmatory GC/MS result showed 4690 ng/mL of methamphetamine and 1895 ng/mL of amphetamine. Analysis of the specimen after derivatization with S(-)-N-trifluoroacetylprolyl chloride showed only the presence of 1-amphetamine and 1-methamphetamine. It was later learned that the individual providing the specimen had been taking Selegiline. Selegiline, (-) propynylmethamphetamine, is a monoamine oxidase inhibitor used for the treatment of Parkinson's disease. It is sold under the trade name Eldepryl. Its major metabolites are 1-methamphetamine, 1-amphetamine and N-desmethylselegiline. Urine specimens from other Selegiline users were obtained and analyzed. A characteristic metabolic pattern was noted, exemplified by a ratio of 1-methamphetamine to 1-amphetamine of about 2.8. This is in contrast to what is observed in the urine of individuals who ingest pure 1-methamphetamine, such as with Vicks Inhaler, where the 1-methamphetamine to 1-amphetamine ratio in the urine is usually greater than 8. Caution is advised when interpreting methamphetamine results without using a chiral identification technique.

Amphetamine↗

PubMed1996

The incidence of acute cocaine or methamphetamine intoxication in deaths due to ruptured cerebral (berry) aneurysms.

Acute intoxication with either cocaine or methamphetamine may contribute to formation and rupture of a berry aneurysm by causing transient hypertension and tachycardia. We report the results of a retrospective study to determine the incidence of acute cocaine or methamphetamine intoxication in deaths due to ruptured berry aneurysm in our jurisdictions. We reviewed all deaths from ruptured cerebral aneurysms that fell within our jurisdictions during the seven years from 1 January 1987 to 31 December 1993 and found 83 cases. The mechanism of death invariably involved subarachnoid hemorrhage, although some cases also had intracerebral hemorrhage. A history of drug abuse was found in 13 cases. Toxicological analysis was performed in 39 cases. Of these methamphetamine was detected in six cases and cocaine in three cases--an incidence of 21%. (In one case both methamphetamine and cocaine were detected). The incidence of acute cocaine intoxication in all autopsies in Jefferson County was 13.6%. The incidence of methamphetamine intoxication in all autopsies in San Diego County was 4.9%. Although the exact mechanism by which berry aneurysms form remains undetermined, research indicates that propagation and rupture of the aneurysm are aggravated by hypertension and tachycardia, both of which are pharmacologic side effects of cocaine and methamphetamine. Based on the preponderance of methamphetamine associated with deaths due to ruptured berry aneurysms it appears that methamphetamine is more toxic than cocaine, perhaps owing to the longer half-life of methamphetamine.

Adolescent↗

PubMed1998

Cause and manner of death in fatalities involving methamphetamine.

We reviewed a series of deaths in which methamphetamine was detected in the decedent's blood. Analysis of postmortem whole blood was performed by gas chromatography/mass spectrometry with a limit of quantitation of 0.05 mg/L. Methamphetamine was detected in 146 cases; 52 were drug caused, i.e., a death in which the direct toxic effects of the drug caused or contributed to the death, 92 were classified as drug related, i.e., a death in which the drug was demonstrated in the blood, but did not directly cause death. A large proportion of the deaths resulted from homicidal (27%) or suicidal (15%) violence. An examination of methamphetamine concentrations in drug related deaths (n = 92), suggests that the range of concentrations in the recreational abusing population is substantial (0.05-9.30 mg/L) but with a median concentration of 0.42 mg/L, and with 90% of that population having concentrations less than 2.20 mg/L. There was substantial overlap in methamphetamine concentration between drug related deaths and drug caused deaths, although the highest concentrations were seen in the unintentional (accidental or undetermined) drug caused deaths. Methamphetamine related traffic deaths (n = 17) showed patterns of driving behavior consistent with reports elsewhere, and showed blood methamphetamine concentrations ranging from 0.05-2.60 mg/L (median 0.35 mg/L). The data show that most methamphetamine deaths occur with blood concentrations greater than 0.5 mg/L, but can occur with levels as low as 0.05 mg/L, though usually in conjunction with other drugs or significant natural disease. Neither apparently toxic nor therapeutic concentrations should be used in isolation to establish conclusively whether a death was caused by methamphetamine; proper classification of deaths involving methamphetamine requires complete death investigation, including investigation of the scene and circumstances of death, and a complete autopsy.

Accidents↗

PubMed1998

Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs.

The involvement of D1 and D2 subtypes of dopamine receptors in behavioral effects of methamphetamine was studied in squirrel monkeys using a two-lever drug discrimination procedure. In monkeys that discriminated i.m. injections of 0.3 mg/kg methamphetamine from saline, methamphetamine (0.03-0.3 mg/kg), cocaine (0.1-1.0 mg/kg) and the selective dopamine uptake inhibitor, GBR 12909 (3.0-17.8 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and, at the highest doses, full substitution. In contrast, the norepinephrine and serotonin uptake inhibitors, tomoxetine (1.0-17.8 mg/kg) and fluoxetine (0.3-10.0 mg/kg), respectively, did not substitute appreciably for methamphetamine. Substitution for methamphetamine also was observed with the D1 receptor agonists, SKF 81297, SKF 82958 and dihydrexidine, and the D2 receptor agonist, (+)-PHNO in the majority of monkeys. Lower-efficacy D1 or D2 agonists substituted for methamphetamine either partially (SDZ 208-911) or not at all (SKF 77434, SDZ 208-912). Pretreatment with dopamine receptor blockers [D1 (SCH 39166, 0.1 mg/kg) or D2 (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D1 (SKF 77434; 3.0 mg/kg) or D2 (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine. In separate studies, comparable doses of each of these drugs, except SKF 77434, induced significant levels of catalepsy-associated behavior. These results support the view that both dopaminergic D1 and D2 mechanisms mediate the discriminative-stimulus effects of methamphetamine; further, they indicate that selected dopamine D1 partial agonists may have antagonist actions at doses that do not produce undesirable effects associated with dopamine receptor blockade.

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

PubMed1992

Effects of repeated MK-801 on ambulation in mice and in sensitization following methamphetamine.

The noncompetitive NMDA receptor antagonist MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine , increased ambulatory activity in the mouse at doses over 0.1 mg/kg (IP). The effect was enhanced when 0.3 mg/kg MK-801 was repeatedly administered at intervals of 3-4 days. In contrast, a reduction of the effect was induced with repeated doses of 0.1 and 1 mg/kg. The mice that had repeatedly experienced 1 mg/kg MK-801 exhibited a decrease in the sensitivity to methamphetamine (2 mg/kg SC). In addition, the repeated co-administration of 1 mg/kg MK-801 with methamphetamine induced a decrease in the sensitivity to methamphetamine. No modification of methamphetamine sensitivity was elicited by 0.1 and 0.3 mg/kg MK-801 in both the single and co-administration schedules. On the other hand, established sensitization to methamphetamine was hardly affected by repeated treatment with 0.1-1 mg/kg MK-801. These results indicate that the mechanism of the inhibitory action of MK-801 on the development of methamphetamine sensitization is different from that of dopamine D2 antagonists, which may act to decrease the effective unit dose of methamphetamine and reduce ambulation-increasing effect of methamphetamine.

Animals↗

PubMed2006

Effect of methamphetamine self-administration on tyrosine hydroxylase and dopamine transporter levels in mesolimbic and nigrostriatal dopamine pathways of the rat.

RATIONALE AND OBJECTIVES: Many studies have examined the effect of experimenter-delivered methamphetamine on the mesolimbic and nigrostriatal dopamine pathways. In contrast, little is known about the effect of methamphetamine self-administration on these neuronal pathways. We studied the effect of methamphetamine self-administration on two key regulators of dopamine transmission, tyrosine hydroxylase (TH), and dopamine transporter (DAT), in components of the mesolimbic and nigrostriatal dopamine pathways. METHODS: Rats self-administered methamphetamine (0.1 mg/kg per infusion, fixed-ratio-1 reinforcement schedule) or saline (control condition) for 9 h/day over 10 days. The brains of these rats were collected after 1 or 30 days of forced abstinence and the expression levels of TH and DAT were assayed by in situ, hybridization and western blot. RESULTS: TH mRNA and protein levels were increased in the ventral tegmental area (VTA, the cell body region of the mesolimbic dopamine system) and the substantia nigra pars compacta (SNC, the cell body region of the nigrostriatal dopamine system) after 1 day, but not 30 days, of forced abstinence from methamphetamine. In contrast, methamphetamine self-administration had no effect on TH protein levels in dopaminergic terminals located in the nucleus accumbens and caudate-putamen. In addition, methamphetamine self-administration had no effect on DAT mRNA levels in the VTA. CONCLUSIONS: Results suggest that extended daily access to self-administered methamphetamine results in a transient, short-lasting effect on mesolimbic and nigrostriatal dopamine neurons of the rat brain.

Animals↗

PubMed2001

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.

Animals↗

PubMed2006

Association analysis of SOD2 variants with methamphetamine psychosis in Japanese and Taiwanese populations.

SOD2 (superoxide dismutase 2) plays a crucial role in protecting the cells against damage caused by free radicals, by catalyzing their detoxification. On the other hand, cell damage caused by free radical generation following methamphetamine administration has been postulated as one of the possible pathophysiological mechanisms for methamphetamine psychosis. Hence, we investigated the association of SOD2 polymorphisms with the development of methamphetamine psychosis, in two independent populations of Japan and Taiwan. We recruited 116 patients with methamphetamine psychosis and 189 controls in Japan, and 135 patients with methamphetamine psychosis and 204 controls in Taiwan. The methamphetamine group was divided into two clinical subtypes: a transient type of psychosis (i.e., good prognosis) and a prolonged type of psychosis (i.e., poor prognosis), according to the course of the manifestation of psychosis. With reference to the genotypic and allelic frequencies of Ala/Val functional polymorphism in exon 2, we found significant differences between individuals with prolonged methamphetamine psychosis and control samples from Japan and Taiwan in the genotypic (P value 0.014 and 0.016, respectively) and in the allelic (P value 0.004 and 0.047, respectively) frequencies. Our results suggest that Ala/Val polymorphism of the SOD2 gene could be associated with the risk of developing methamphetamine psychosis.

Adolescent↗

PubMed1995

Fetal responses to maternal and fetal methamphetamine administration in sheep.

OBJECTIVES: The current study was designed to test the hypothesis that maternally administered methamphetamine decreases fetal PaO2 by reducing uterine blood flow and to determine the cardiovascular and blood gas responses to varying doses of methamphetamine given both to the fetus and the mother. STUDY DESIGN: Nine near-term pregnant sheep were surgically instrumented to measure maternal and fetal blood pressure and heart rate and uterine and umbilical blood flow. Fetal blood gases and pH were determined before and after each dose of methamphetamine. Methamphetamine was administered as intravenous bolus injections (30 to 35 minutes separating administration of each dose) into the maternal femoral vein in increasing doses of 0.03, 0.1, 0.3, and 1.0 mg/kg and on a separate days to the fetus into the hind limb vein as doses of 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg estimated fetal weight. RESULTS: Maternal methamphetamine administration produced a dose-related increase in maternal and fetal blood pressure and uterine vascular resistance, whereas uterine blood flow decreased in a dose-related fashion. Umbilical blood flow tended to increase slightly, but this did not reach significance. Fetal PaO2 decreased significantly, whereas fetal pH decreased only modestly. Direct fetal administration of methamphetamine produced dose-related increases in fetal blood pressure and umbilical blood flow and a significant decrease in fetal pH but no change in fetal PaO2. CONCLUSIONS: The fetal PaO2 decrease observed after maternal administration of methamphetamine appears to be a result of decreased uteroplacental perfusion, whereas the observed changes in fetal blood pressure and fetal pH appear to be a result of the direct action of methamphetamine on the fetus.

Animals↗

PubMed1976

Influence of methamphetamine on nigral and striatal tyrosine hydroxylase activity and on striatal dopamine levels.

In previous reports, methamphetamine was shown to depress tyrosine hydroxylase (TH) activity in the rat corpus striatum. To evaluate further the mechanism of this decrease in TH activity, enzyme activity was measured in the rat corpus striatum and substantia nigra after repetitive and single-dose methamphetamine administration. Following repeated doses of methamphetamine, nigral TH activity decreased and reached 45% of controls at 12 hr and returned to normal at 60 hr. Striatal TH activity decreased to 40% of control at 36 hr and returned toward normal at 60 hr. When methamphetamine was administered every 6 hr for 30 hr and then discontinued, nigral TH activity returned toward control levels 4 days prior to recovery of striatal TH activity. Methamphetamine initially increased striatal dopamine levels at 6 hr (170% of control). Dopamine levels then decreased in parallel with striatal TH activity but failed to increase as the enzyme recovered. Concurrent administration of chlorpromazine with methamphetamine prevented the methamphetamine-induced decrease in nigral and striatal TH activity and striatal dopamine levels. The results indicate that the methamphetamine-induced depression of striatal and nigral TH activity may be related to increased stimulation of dopamine receptors in the striatum.

Animals↗

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↗

PubMed1992

The neurotoxic effects of methamphetamine on 5-hydroxytryptamine and dopamine in brain: evidence for the protective effect of chlormethiazole.

Studies were undertaken in mice and rats on the neurotoxic effects of methamphetamine on dopaminergic and 5-hydroxytryptaminergic neurones in the brain and the neuroprotective action of chlormethiazole. In initial studies, mice were injected with methamphetamine (5 mg/kg, i.p.) at 2 hr intervals, to a total of 4 times. This procedure produced a 66% loss of striatal dopamine and a 50% loss of tyrosine hydroxylase activity 3 days later. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each dose of methamphetamine, totally prevented the methamphetamine-induced loss of tyrosine hydroxylase activity and partly prevented the loss of dopamine. Phencyclidine (20 mg/kg, i.p.), given in place of chlormethiazole, also prevented the loss of tyrosine hydroxylase. Administration to rats of 4 doses of methamphetamine (15 mg/kg, i.p.) at 3 hr intervals resulted in a 75% loss of striatal dopamine 3 days later and a similar loss of 5-HT and 5-HIAA in cortex and hippocampus. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each injection of methamphetamine, protected against the loss of dopamine and indoleamine content, in the respective regions. Pentobarbital (25 mg/kg, i.p.) also provided substantial protection but diazepam (2.5 mg/kg, i.p.) was without effect. Confirming earlier studies, dizocilpine (1 mg/kg) also provided substantial protection against the methamphetamine-induced neurotoxicity. Preliminary data indicated that chlormethiazole was not neuroprotective because of a hypothermic action. These data therefore demonstrate that chlormethiazole is an effective neuroprotective agent against methamphetamine-induced neurotoxicity and extend the evidence for the possible value of this drug in preventing neurodegeneration.

Animals↗

PubMed1993

Effect of 4-phenyl-1,2,3,4-tetrahydroisoquinoline on ambulation induced by injection of methamphetamine into the nucleus accumbens in rats.

4-Phenyl-1,2,3,4-tetrahydroisoquinoline (4-PTIQ) has previously been shown to have antagonistic properties to methamphetamine in the spinal cord. Administration of 4-PTIQ (5 mg/kg, s.c.) reduced the ambulation induced by methamphetamine (0.5 mg/kg, s.c.) in rats. Methamphetamine (3 micrograms), injected unilaterally into the nucleus accumbens, increased ambulation. Alone, 4-PTIQ (10 micrograms) failed to elicit ambulation; however, it inhibited the methamphetamine-induced increase in ambulation. The alpha 1-antagonist prazosin (0.5 micrograms) or the beta-antagonist propranolol (3 micrograms) showed no effect on ambulation induced by methamphetamine. Haloperidol (5 ng), which possesses strong dopamine-blocking activity, abolished the ambulation induced by methamphetamine. The drug 4-PTIQ had weak affinity for dopamine D1 and D2 receptors. These results support the possibility that the inhibitory effects of 4-PTIQ on the ambulation-stimulating effects of methamphetamine, are due to blocking of the dopamine-releasing effect of methamphetamine but not due to dopamine blocking effects.

Animals↗

PubMed1987

Activity rhythms in the circadian domain appear in suprachiasmatic nuclei lesioned rats given methamphetamine.

Female rats were lesioned in the suprachiasmatic nuclei (SCN) electrolytically and treated with methamphetamine. The SCN lesions abolished the circadian locomotor rhythm completely. When methamphetamine was administered in the drinking water, robust rhythmicities in locomotor activity appeared in the SCN lesioned rats, which did not entrain to the 24 hr light cycle. The period of the activity rhythm was dose-dependent; the lower the concentration of methamphetamine was, the shorter the period of the rhythm became. When rats were treated with 0.005% methamphetamine, the mean period was 26.4 hours. In addition, activity time (alpha) became shorter, rest time (rho) longer and alpha/rho ratio lower, when methamphetamine concentration was decreased. After methamphetamine withdrawal, the rhythmicity disappeared and locomotor activity became aperiodic again. When methamphetamine was administered continuously by means of an osmotic minipump, similar rhythmicities appeared in locomotor activity of the SCN lesioned rats. It is concluded that methamphetamine manifests an activity rhythm whose period is in the circadian range. The rhythmicity is independent of the SCN and is not entrained by the light-dark cycle.

Administration, Oral↗

PubMed1991

Methamphetamine effects on rat circadian clock depend on actograph.

Methamphetamine effects on the rest-activity rhythm were examined in 12 blinded rats using two different actographs, an Animex and a running-wheel. D-Methamphetamine was administered chronically by dissolving it in drinking water. During methamphetamine treatment, the rest-activity rhythm measured by an Animex showed a clear sign of relative coordination in addition to the general enhancement of activity level. Analyses of pre- and posttreatment activity rhythms revealed that neither the phase nor the period was affected by methamphetamine treatment. On the other hand, the circadian period was lengthened by methamphetamine treatment when locomotor activity was measured by a running-wheel. These results confirmed our previous findings that the chronic treatment of methamphetamine modified the expression of the circadian rhythms but did not affect the underlying oscillation when measured by an Animex, and further indicated that methamphetamine could affect the underlying oscillation when rats had free access to a running-wheel. It is concluded that the effects of methamphetamine on the circadian clock depend on actograph.

Animals↗

PubMed1982

Circadian variation in methamphetamine- and apomorphine-induced increase in ambulatory activity in mice.

The existence of circadian variation in methamphetamine- and apomorphine-induced change in ambulatory activity in mice was investigated. Adult male mice of dd strain, which had been housed on a 12 hr light-dark schedule (light period; 6:00-18:00) for 4 weeks, received injections of either methamphetamine HCl 1 or 2 mg/kg SC at one of six times of day (3:00, 7:00, 11:00, 15:00, 19:00 and 23:00), or apomorphine HCl 0.5 or 1 mg/kg SC at one of six times of day (3:30, 7:30, 11:30, 15:30, 19:30 and 23:30). The control animals were administered a physiological saline vehicle alone at the corresponding times of day. The ambulatory activity of each mouse was measured by a tilting-type activity cage for 3 hr after methamphetamine, and for 1 hr after apomorphine. A circadian variation in the ambulatory activity was observed after the administration of the saline, methamphetamine and apomorphine. Here, the highest activity counts were found when the saline, methamphetamine and apomorphine were administered during the late dark period (3:00 or 3:30), while the lowest activity counts were found when the saline and apomorphine 1 mg/kg were administered during the mid light period (11:00 or 11:30), and methamphetamine 1 and 2 mg/kg and apomorphine 1 mg/kg were administered during the late light period (15:00 or 15:30). The circadian variation in methamphetamine-induced increase in the activity was abolished by a pretreatment with reserpine 2 mg/kg SC 4 hr before, but that of apomorphine was maintained even by the pretreatment with reserpine. The present results suggest that the methamphetamine- and apomorphine-induced increase in the ambulatory activity in mice is dependent on the time-of-day of the drug administration, and the occurrence is mainly due to a circadian variation in activity of the catecholaminergic systems in the brain.

Animals↗