Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats

Nakamura, Kazuo; Shirane, Masatoshi; Koshikawa, Noriaki

doi:10.1016/s0006-8993(01)02096-0

Cited by 27 publications

(24 citation statements)

References 62 publications

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“…Furthermore, similar to human AD/HD subjects, SHRSPs exerted male preponderant impairment in attentional performance, which was normalized by clinical dosages of methylphenidate (35). Neurochemical and cognitive studies of male SHRSPs revealed dopaminergic hypofunction in the prefrontal cortex, nucleus accumbens shell, striatum, and basolateral amygdala (48) as well as cognitive impairment, accompanied by central cholinergic dysfunction (49). Moreover, the SHRSP displays higher motor activity than the SHR (50), and cerebrospinal fluid serotonin levels are significantly decreased in the SHRSP, but not in the SHR, as compared with genetic control Wistar-Kyoto rats (WKYs) (51).…”

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confidence: 80%

Gonadal Hormones and Frontocortical Expression of Vascular Endothelial Growth Factor in Male Stroke-Prone, Spontaneously Hypertensive Rats, a Model for Attention-Deficit/Hyperactivity Disorder

et al. 2004

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Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated, in part, with male preponderance and reduced regional cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance and reduced rCBF in AD/HD are unclear. The present study profiles the expression of angiogenic and hormonal factors likely to underlie these symptoms using a recently characterized AD/HD animal model, juvenile male stroke-prone spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth factor (VEGF) signaling cascade and gonadal steroids are key regulators of angiogenesis and genderbased behavior, respectively, we profiled their patterns of expression in the frontal cortex of SHRSP to elucidate their roles in the genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt (pAkt), estrogen receptor-␣, aromatase, and capillary density in sham-operated SHRSP were remarkably down-regulated, whereas androgen receptor levels were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats. Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted these effects. Dihydrotestosterone, but not testosterone, reversed the beneficiary effects of castration. Estrogen receptor-␤ levels remained unchanged in all groups examined. We postulate that changes in androgen metabolism that tend to up-regulate local dihydrotestosterone concentration and diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may lower levels and/or activity of VEGF and its signaling cascade and, subsequently, reduce rCBF. These findings could, in part, help explain the pathogenesis of reduced rCBF and male preponderance in AD/HD. (Endocrinology 145: 4330 -4343, 2004)

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confidence: 80%

Gonadal Hormones and Frontocortical Expression of Vascular Endothelial Growth Factor in Male Stroke-Prone, Spontaneously Hypertensive Rats, a Model for Attention-Deficit/Hyperactivity Disorder

et al. 2004

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“…In the absence of VTA stimulation, previous microdialysis studies reveal an in vivo level of extracellular DA in the 0.5-5.0 nM range (Hedou et al, 2001;Nakamura et al, 2001;Marsteller et al, 2002;Phillips et al, 2004). Modulation of the excitability of PFC neurons by this tonic background DA was revealed by recording the basal current-evoked excitability of the cell every 30 s for at least 10 min, followed by systemic administration of either D 1 (SCH 23390) or D 2 (sulpiride) receptor antagonists and subsequent measurement of current-evoked excitability every 30 s for at least another 10 min.…”

Section: Effect Of Da Receptor Antagonists On Cortical Excitabilitymentioning

confidence: 99%

Long-Term Neuroadaptations Produced by Withdrawal from Repeated Cocaine Treatment: Role of Dopaminergic Receptors in Modulating Cortical Excitability

Nogueira¹,

Kalivas²,

Lavín³

2006

J. Neurosci.

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Dopamine (DA) modulates neuronal activity in the prefrontal cortex (PFC) and is necessary for optimal cognitive function. Dopamine transmission in the PFC is also important for the behavioral adaptations produced by repeated exposure to cocaine. Therefore, we investigated the effects of repeated cocaine treatment followed by withdrawal (2-4 weeks) on the responsivity of cortical cells to electrical stimulation of the ventral tegmental area (VTA) and to systemic administration of DA D 1 or D 2 receptor antagonists. Cortical cells in cocaine-and saline-treated animals exhibited a similar decrease in excitability after the administration of D 1 receptor antagonists. In contrast, cortical neurons from cocaine-treated rats exhibited a lack of D 2 -mediated regulation relative to saline rats. Furthermore, in contrast to saline-treated animals, VTA stimulation did not increase cortical excitability in the cocaine group. These data suggest that withdrawal from repeated cocaine administration elicits some long-term neuroadaptations in the PFC, including (1) reduced D 2 -mediated regulation of cortical excitability, (2) reduced responsivity of cortical cells to phasic increases in DA, and (3) a trend toward an overall decrease in excitability of PFC neurons.

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“…In addition, the selective ␣4␤2 nAChR agonist RJR-2403 increases not only extracellular levels of ACh but also those of biogenic amines such as DA, norepinephrine, and serotonin in the hippocampus and frontal cortex of the rat (Summers et al, 1996). In SHRSP, central dopaminergic hypofunctions, such as lowered extracellular DA levels, have been found in the prefrontal cortex, nucleus accumbens, striatum, and amygdala (Nakamura et al, 2001). Moreover, SHRSP exhibit central cholinergic dysfunctions, such as lowered extracellular ACh levels, in the cerebrospinal fluid (Togashi et al, 1994) and prefrontal cortex (Shirane and Nakamura, 2000), decreased choline acetyltransferase activity in the brain (Nakamura and Shirane, 1999), impaired choline transport through the blood-brain barrier (Kang et al, 1990), and reduced numbers of cerebral high-affinity (i.e., ␣4␤2) nAChR binding sites (Yamada et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

α4β2 Nicotinic Acetylcholine Receptor Activation Ameliorates Impairment of Spontaneous Alternation Behavior in Stroke-Prone Spontaneously Hypertensive Rats, an Animal Model of Attention Deficit Hyperactivity Disorder

Ueno

Togashi²,

Matsumoto³

et al. 2002

J Pharmacol Exp Ther

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The objective of the present study was to elucidate the role of nicotine in impairment of spontaneous alternation behavior of juvenile stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of attention deficit hyperactivity disorder (ADHD). Spontaneous alternation behavior assessed by a Y-maze task was significantly lower, and total arm entries were significantly higher in SHRSP than in genetic control Wistar-Kyoto rats. Nicotine (0.1-1 mg/kg, s.c.) dose dependently improved the spontaneous alternation deficit without affecting total arm entries in SHRSP. Nicotine-induced (1 mg/kg, s.c.) improvement was significantly abolished by the centrally acting nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (1 mg/kg, i.p.), but not by peripherally acting hexamethonium (5 mg/kg, i.p.), suggesting that nicotine-induced improvement is mediated via central nAChR. The ␣4␤2 nAChR antagonist dihydro-␤-erythroidine (3-10 mg/kg, i.p.) dose dependently counteracted nicotine-induced improvement of spontaneous alternation in SHRSP, whereas the ␣7 nAChR antagonist methyllycaconitine (3-10 mg/kg, i.p.) did not. In addition, the ␣4␤2 nAChR agonist RJR-2403 (N-methyl-4-(3-pyridinyl)-3-butene-1-amine; 1-10 mg/kg, s.c.) dose dependently and significantly improved the spontaneous alternation deficit. These findings revealed that nicotine improved spontaneous alternation behavior in SHRSP via the activation of ␣4␤2, but not ␣7, nAChR. Thus, the ␣4␤2 nAChR mechanism might be responsible for the spontaneous alternation deficit in juvenile SHRSP, an animal model of ADHD. This evidence indicates the possibility that selective ␣4␤2 nAChR agonists might be useful for treating attentional dysfunction in ADHD.

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Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats

Cited by 27 publications

References 62 publications

Gonadal Hormones and Frontocortical Expression of Vascular Endothelial Growth Factor in Male Stroke-Prone, Spontaneously Hypertensive Rats, a Model for Attention-Deficit/Hyperactivity Disorder

Gonadal Hormones and Frontocortical Expression of Vascular Endothelial Growth Factor in Male Stroke-Prone, Spontaneously Hypertensive Rats, a Model for Attention-Deficit/Hyperactivity Disorder

Long-Term Neuroadaptations Produced by Withdrawal from Repeated Cocaine Treatment: Role of Dopaminergic Receptors in Modulating Cortical Excitability

α4β2 Nicotinic Acetylcholine Receptor Activation Ameliorates Impairment of Spontaneous Alternation Behavior in Stroke-Prone Spontaneously Hypertensive Rats, an Animal Model of Attention Deficit Hyperactivity Disorder

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