Central administration of p-hydroxyamphetamine produces a behavioral stimulant effect in rodents: evidence for the involvement of dopaminergic systems

Onogi, Hiroshi; Hozumi, Masato; Nakagawasai, Osamu; Arai, Yasuhiko; Ishigaki, Seiichiro; Sato, Atsushi; Furuta, Seiichi; Niijima, Fukie; Tan-No, Koichi; Tadano, Takeshi

doi:10.1007/s00213-009-1734-x

Cited by 6 publications

(2 citation statements)

References 52 publications

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“…Other studies have reported that direct injection of Amph into the NAc is sufficient to induce a sensitized response in rats previously chronically injected with psychostimulants, suggesting that the NAc is involved in the induction of behavioral sensitization [5,14,53,56]. More recent studies reported increased locomotor activity following microinjections of p-hydroxyamphetamine directly into the NAc [51]. Although several studies purport that behavioral sensitization originates in the VTA while expression occurs in the NAc, the above observations along with our own suggest that the NAc is also involved in the induction of behavioral sensitization.…”

Section: Discussionmentioning

confidence: 99%

Nucleus accumbens lesions modulate the effects of methylphenidate

Podet¹,

Lee²,

Swann³

et al. 2010

Brain Research Bulletin

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The psychostimulant methylphenidate (MPD, Ritalin) is the prescribed drug of choice for treatment of ADHD. In recent years, the diagnosis rate of ADHD has increased dramatically, as have the number of MPD prescriptions. Repeated exposure to psychostimulants produces behavioral sensitization in rats, an experimental indicator of a drug’s potential liability. In studies on cocaine and amphetamine, this effect has been reported to involve the nucleus accumbens (NAc), one of the nuclei belonging to the motive circuit. The aim of this study was to investigate the role of the NAc on the expression of behavioral sensitization as a response to MPD exposure. In the present study, 20 male Sprague-Dawley rats were divided randomly into three groups: an intact control group, a sham operated group, and a NAc bilateral electrical lesion group. Locomotor activity was assessed for the first two hours following 2.5 mg/kg MPD injection, using open field monitoring systems. Recordings were made during six days of continuous MPD administration, and then upon re-challenge with the same dose following three days of washout. Acute MPD exposure elicited an increase in locomotor activity in all three groups. However, the NAc lesion group exhibited significantly increased locomotor activity in comparison to sham and control groups. Chronic MPD did not elicit sensitization in the NAc lesion group, while both sham and control groups did exhibit behavioral sensitization to repetitive MPD administration. These findings suggest that the NAc plays a significant role in eliciting locomotor activity as an acute effect of MPD, and in the expression of sensitization due to chronic MPD exposure.

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Section: Discussionmentioning

confidence: 99%

Nucleus accumbens lesions modulate the effects of methylphenidate

Podet¹,

Lee²,

Swann³

et al. 2010

Brain Research Bulletin

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show abstract

“…There seems to be a misconception by practitioners of the glymphatic theory that molecules injected ICV or CM in awake animals do not circulate, penetrate the parenchyma, and clear. There are numerous studies dating back decades showing psychostimulants, peptides, and neurotransmitters have immediate effects-within minutes-on nociception, gastric motility, heart rate, blood pressure, urine volume, hormone secretion and behavior following ICV injection (for examples see Pedigo et al, 1975;Hall, 1981;Berkowitz and Sherman, 1982;Cowan et al, 1985;Tsukamura et al, 2000;Hanada et al, 2001;Stone et al, 2003;Barcia and Gallego, 2009;Onogi et al, 2010;Toll et al, 2012). Radiolabeled peptides spread across the parenchyma hitting their target receptors and peaking within 2-5 min after ICV injection and almost immediately appear in the systemic blood (Saija et al, 1989).…”

Section: The Confound Of Anesthesiamentioning

confidence: 99%

Rethinking the Conditions and Mechanism for Glymphatic Clearance

Ferris

2021

Front. Neurosci.

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Critical studies that form the foundation of the glymphatic system and the clearance of metabolic by-products of unwanted proteins from the brain are reviewed. Concerns are raised about studying glymphatic flow in anesthetized animals and making assumptions about the whole brain based upon data collected from a cranial window on the cortex. A new model is proposed arguing that the flow of cerebral spinal fluid and parenchymal clearance in the perivascular system of unwanted proteins is regulated by circadian changes in brain temperature and blood flow at the level of the microvasculature.

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The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

et al. 2021

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Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

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Central administration of p-hydroxyamphetamine produces a behavioral stimulant effect in rodents: evidence for the involvement of dopaminergic systems

Abstract: These data suggest that dopaminergic systems in the NAc may play important roles in p-OHA-induced locomotor activity in rodents.

Cited by 6 publications

References 52 publications

Nucleus accumbens lesions modulate the effects of methylphenidate

Nucleus accumbens lesions modulate the effects of methylphenidate

Rethinking the Conditions and Mechanism for Glymphatic Clearance

The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

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