Sexual differences in sensitivity to methamphetamine toxicity

Wagner, George C.; Tekirian, Tina L.; Cheo, C. T.

doi:10.1007/bf01244939

Cited by 94 publications

(62 citation statements)

References 11 publications

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“…While remaining cognizant of these limitations, data derived from these animal experiments have served as relatively valid and reliable models for indices of effects in humans. Women show less toxicity [17] and diminished dopamine responses [18] to MA/amphetamine as compared with men, which is similar to that of results obtained with mice [19,20]. Of particular relevance to the present report, are the findings indicating that weight loss is a pervasive characteristic of MA, as seen in mice and humans [1][2][3][4][5][6].…”

supporting

confidence: 77%

Is Body Weight Loss a Harbinger of Methamphetamine-induced Neurotoxicity?

Dluzen¹

2013

J Addict Res Ther

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Methamphetamine (MA) is a drug of abuse of societal concern. Euphoria, increased energy/alertness and enhanced libido all contribute to the appeal, and therefore, abuse of this psychostimulant. Weight loss represents still another attribute of MA as indicated in both human [1][2][3][4] and animal [5,6] studies. In fact, weight loss has been reported as a reason for MA use [7][8][9] and MA under the trademark name Desoxyn, has been approved for use clinically in the treatment of exogenous obesity, as well as for ADHD and narcolepsy [10].In animal studies, MA has served as an agent to induce neurotoxicity within the Nigrostriatal Dopaminergic (NSDA) system, and thus a means to study conditions that modulate this neurotoxicity. For example, sex, hormonal factors and adrenergic blockers all affect the degree of MAinduced neurotoxicity [11][12][13][14][15][16]. A summary of the pair wise differences in MA-induced neurotoxicity (dorsal striatal dopamine depletion) for these three different factors, along with the corresponding changes in body weight to MA is illustrated in panels A-C of the figure 1. In all three situations, conditions showing greater amounts of dopamine depletion (A-males versus females, B-testosterone (TP) versus sesame oil vehicle treated controls, C-Propranolol (PROP) versus Prazosin (PRAZ)) are associated with the greater amounts of body weight reductions.A cursory and seemingly obvious conclusion would be that the greater extent of neurotoxicity produces a corresponding greater degree of generalized malaise, as indicated by body weights. The data presented in panel D of the figure 1 suggest that this may not necessarily be the case. Here are presented results obtained using a similar sex-differences protocol as that presented in panel A, however, with NSDA neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). While nearly identical dorsal striatal dopamine reductions are obtained with MA and MPTP (A versus D), the corresponding sex differences in body weight present to MA, are completely absent with MPTP (A versus D). Such results suggest that sex differences in response to neurotoxins targeting the NSDA system do not inescapably generate identical changes in body weights. Rather, body weight reductions following MA treatment appear to be closely associated with the degree of NSDA loss and are specific for MA-induced NSDA neurotoxicity.Confirmation or refutation of this intriguing relationship awaits further investigation involving formal experiments on dose-response, time-course, cross-species analyses and food restriction/palatability. Moreover, differences in MA regimes between the mouse models as described above and the clinical/street use of this drug also warrant consideration in evaluating this relationship. While remaining cognizant of these limitations, data derived from these animal experiments have served as relatively valid and reliable models for indices of effects in humans. Women show less toxicity [17] and diminished dopamine responses [18] to MA/amphetami...

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supporting

confidence: 77%

Is Body Weight Loss a Harbinger of Methamphetamine-induced Neurotoxicity?

Dluzen¹

2013

J Addict Res Ther

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“…Since Wagner et al [3]reported the sexual differences in the sensitivity to MA-induced striatal DA toxicity, the developmental time window of sex hormone influences in establishing these differences has remained elusive. We now demonstrate that the sexual differences could be determined between 4 and 6 weeks postpartum through two lines of evidence.…”

Section: Discussionmentioning

confidence: 99%

“…The magnitude of this MA-induced striatal DA depletion was reduced in adult female as compared to adult male mice [3, 4]. However, no such sexual difference in the sensitivity to MA-induced striatal DA depletion in Swiss Webster mice gonadectomized on day 20 of life was observed in a preliminary study.…”

Section: Introductionmentioning

confidence: 97%

Ovarian Hormones Do Not Attenuate Methamphetamine-Induced Dopaminergic Neurotoxicity in Mice Gonadectomized at 4 Weeks Postpartum

Yu¹,

Kuo

Cherng

et al. 2002

Neuroendocrinology

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The present study was undertaken to assess the ability of ovarian hormones to alter methamphetamine (MA)-induced dopaminergic toxicity in male and female mice gonadectomized at 4 and 6 weeks of age. None of the following three treatments, estradiol benzoate (EB, 3 × 0.47 µg), progesterone (Prog, 3 × 0.47 µg), or EB (2 × 0.47 µg) followed by Prog (0.47 µg), affected the dopamine (DA)-depleting effects of MA in male and female mice gonadectomized when they were 4 weeks old. However, in contrast to the findings that male mice are more sensitive to MA-induced DA depletion than female mice, no sexual differences in the sensitivity to MA treatment were observed in mice gonadectomized at this age. Moreover, three daily doses of EB (0.47 µg) and EB (0.47 µg) combined with 4-hydroxytamoxifen (4OHT, 6 µg) effectively attenuated striatal DA depletion produced by MA in female mice ovariectomized at 6 weeks of age. Three daily doses of Prog (0.47 µg) and EB (0.47 µg) combined with 4OHT (6 µg) significantly attenuated MA-induced striatal DA depletion in male mice gonadectomized at 6 weeks of age. Taken together, the modulating effects of ovarian hormones on MA-induced DA depletion in mouse striatum could be sex- and age-dependent. 4OHT did not block the protecting effects of EB on MA-induced DA depletion in female and male mice, suggesting that the estrogen receptor may not be involved in the protective effects of EB on attenuating MA-induced DA toxicity.

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“…Males have been reported to be more susceptible to neurotoxic effects of MA in animal studies (Hirata et al, 1996;Wagner et al, 1993). Recently, Chang et al (2002) have reported that male MA users had decreased rCBF and female MA users had increased rCBF in occipital and midline structures, relative to gender-matched comparison subjects (Chang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users

Kim

Lyoo

Hwang

et al. 2005

Neuropsychopharmacol

111

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Changes in relative regional cerebral glucose metabolism (rCMRglc) and their potential gender differences in abstinent methamphetamine (MA) users were explored. Relative rCMRglc, as measured by 18 F-fluorodeoxyglucose positron emission tomography, and frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent MA users and 21 healthy comparison subjects. In addition, male and female MA users and their gender-matched comparison subjects were compared to investigate potential gender differences. MA users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in MA users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male MA users, not in female MA users, relative to their gender-matched comparison subjects. The current findings suggest that MA use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. Our findings also suggest that the neurotoxic effect of MA on frontal lobes of the brain might be more prominent in men than in women.

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Sexual differences in sensitivity to methamphetamine toxicity

Cited by 94 publications

References 11 publications

Is Body Weight Loss a Harbinger of Methamphetamine-induced Neurotoxicity?

Is Body Weight Loss a Harbinger of Methamphetamine-induced Neurotoxicity?

Ovarian Hormones Do Not Attenuate Methamphetamine-Induced Dopaminergic Neurotoxicity in Mice Gonadectomized at 4 Weeks Postpartum

Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users

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