The Effects of Norepinephrine Transporter Inactivation on Locomotor Activity in Mice

Mitchell, Heather A.; Ahern, Todd H.; Liles, L. Cameron; Javors, Martin A.

doi:10.1016/j.biopsych.2006.03.057

Cited by 40 publications

(37 citation statements)

References 34 publications

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“…Acute and chronically administered BUP has repeatedly been demonstrated to dose dependently increase locomotor activity in rodents with similar potency, regardless of species, age, or strain (Soroko et al, 1977;Nielsen et al, 1986;Zarrindast and Hosseini-Nia, 1988;Vassout et al, 1993;Redolat et al, 2005;Mitchell et al, 2006;Billes and Cowley, 2007). The current finding that BUP, DA, and DA + NE reuptake inhibition all transiently increased locomotor activity is consistent with the idea that inhibition of the DA transporter is sufficient to cause a significant short-term increase in locomotion and even reverse the decrease in activity caused by inhibition of NE reuptake.…”

Section: Discussionsupporting

confidence: 83%

“…Because reports on the acute effects of BUP on temperature are inconsistent, further research is needed to determine if increased thermogenesis might also contribute to increased energy expenditure by BUP (Zarrindast and Abolfathi-Araghi, 1992;Liu et al, 2002;Hasegawa et al, 2005). We and others have shown that acute peripheral BUP also dose dependently stimulates locomotor activity in rodents, an effect that is consistent with inhibition of the DA transporter (Soroko et al, 1977;Cooper et al, 1980;Nielsen et al, 1986;Zarrindast and Hosseini-Nia, 1988;Vassout et al, 1993;Redolat et al, 2005;Mitchell et al, 2006).…”

Section: Introductionmentioning

confidence: 74%

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Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

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Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA + NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA + NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA + NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA + NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA + NE reuptake (with GBR + NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 74%

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

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“…When bupropion was administered on training day, deficits in contextual fear conditioning were observed in mice treated with 40 mg/kg bupropion, suggesting that high doses of bupropion can disrupt acquisition of contextual fear conditioning. It is also important to note that 40 mg/kg bupropion at training did not impair cued fear conditioning; and though studies have shown that higher doses of bupropion can alter locomotor activity in mice (Mitchell et al, 2006;Redolat et al, 2005), the lack of effect on cued fear conditioning suggests that the deficits in the acquisition of contextual fear conditioning are not due to other factors, such as changes in sensory or motor processes. Thus, the data from the present study suggest that bupropion can effectively counteract nicotine withdrawal-associated deficits in learning-related processes, but higher doses of bupropion can produce impairment in the acquisition and expression of contextual memories.…”

Section: Discussionmentioning

confidence: 99%

“…For all experiments investigating the effects of acute bupropion on fear conditioning, bupropion was dissolved in saline at 2.5, 5, 10, 20, or 40 mg/ kg (injection volume of 10 mg/mL), and was administered subcutaneously twenty minutes before training and/or testing. The doses of bupropion were based on prior research that used a similar range of doses to investigate the effects of bupropion on locomotor activity (Mitchell et al, 2006;Redolat et al, 2005). Additionally, a control group in each experiment was administered saline subcutaneously 20 minutes before training and testing.…”

Section: Drug Administrationmentioning

confidence: 99%

Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Portugal

Gould

2007

Pharmacology Biochemistry and Behavior

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Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/ kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning.

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“…The present experiments assessed whether the same uncoupling of NE-5-HT activity is produced following the exposure to compounds belonging to main groups of drugs of abuse, that is cocaine, morphine, and ethanol. The effect of exposure to clorimipramine or venlafaxine, two antidepressants that stimulate noradrenergic and serotonergic transmissions but do not induce substance dependence nor behavioral sensitization (Mitchell et al, 2006), was also assessed. Similarly, in an effort to unravel the mechanism of this uncoupling, the effect of exposure to GBR 12783, a specific DA reuptake inhibitor was tested.…”

Section: Introductionmentioning

confidence: 99%

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

Lanteri

Salomon

Torrens

et al. 2007

Neuropsychopharmacol

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A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated damphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by a1b-adrenergic and 5-HT 2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT 2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT 2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated damphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

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The Effects of Norepinephrine Transporter Inactivation on Locomotor Activity in Mice

Cited by 40 publications

References 34 publications

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

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