The effects of dentate granule cell destruction on behavioral activity and Fos protein expression induced by systemic methamphetamine in rats

British Journal of Pharmacology (Impact Factor: 4.84). 01/2009; 134(7):1411 - 1418. DOI: 10.1038/sj.bjp.0704370


We destroyed dentate granule cells unilaterally or bilaterally by means of intrahippocampal injection of colchicine in rats. Subsequently, we observed behavioural changes following the intraperitoneal injection of 2 mg kg−1 methamphetamine or saline, in addition to quantitatively assessing Fos protein expression in several brain regions, including the medial prefrontal cortex, cingulate cortex, piriform cortex, dorsal striatum, and nucleus accumbens.
Bilaterally lesioned animals, when administered saline, showed a marked increase in locomotor activity compared with those of non-lesioned animals. With respect to the methamphetamine response, bilateral destruction resulted in a marked enhancement of locomotor activity, while the unilateral destruction led to a marked increase in rotation predominantly contralateral to the lesioned side, with no identifiable change in locomotor activity.
Bilaterally lesioned animals, when administered saline and having undergone an immunohistological examination, showed a marked increase in Fos expression in both sides of the nucleus accumbens. Bilaterally lesioned animals administered methamphetamine showed a marked increase in Fos expression in the right and left sides of all regions tested. Unilaterally lesioned animals administered methamphetamine showed a significant and bilateral enhancement in Fos expression in the medial prefrontal and cingulate cortices, and a marked and unilateral (ipsilateral to the lesioned side) enhancement of Fos protein in the piriform cortex, dorsal striatum, and nucleus accumbens.
The present findings suggest that dentate granule cells regulate methamphetamine-associated behavioural changes through the function of widespread areas of the brain, mostly the nucleus accumbens.
British Journal of Pharmacology (2001) 134, 1411–1418; doi:10.1038/sj.bjp.0704370

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Available from: Katsuaki Suzuki, Mar 21, 2014
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    • "This withdrawal-specific effect in LgA rats is worth noting because this maladaptive change could function to return the homeostasis of granule cell neuron turnover, or incubate drug, and drug-context associations relating to drug seeking (Vorel et al, 2001; Hiranita et al, 2006; Rademacher et al, 2006; Shen et al, 2006; Zhou and Zhu, 2006; Lasseter et al, 2010; Noonan et al, 2010; Luo et al, 2011). However, further functional exploration of this putative enhanced survival is warranted, as well as identification of other neuroadaptations during protracted withdrawal that may regulate the hippocampus and hippocampus-dependent relapse behavior (Tani et al, 2001; Hiranita et al, 2006; Zhou and Zhu, 2006; Lasseter et al, 2010; Noonan et al, 2010; Garcia-Fuster et al, 2011). We next determined whether relapse behaviors following noncontingent exposure to methamphetamine produces changes in dentate gyrus neural progenitors and whether these changes are altered compared with protracted withdrawal-induced changes. "
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    ABSTRACT: Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended access) on cognitive performance and relapse to drug seeking and may contribute to the impairments that perpetuate the addiction cycle.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2011; 37(5):1275-87. DOI:10.1038/npp.2011.315 · 7.05 Impact Factor
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    • "Since mesolimbic dopaminergic neurons innervate the SGZ of the dentate gyrus [30], the dopaminergic activities of these neurons may be involved in the regulation of hippocampal neurogenesis. Furthermore, we previously reported that cell destruction of dentate granules by intrahippocampal injection of colchicine enhanced methamphetamine-induced hyperactivity in rats [31], suggesting that dentate granule cells may regulate methamphetamine-induced behavioral changes. Taken together, the evidence suggests that the decrease in hippocampal neurogenesis by irradiation may, in part, be implicated in the hyperdopaminergic activity of irradiated rats although the cumulative numbers of granule cells in the granule layer were not altered in irradiated rats. "
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    ABSTRACT: Epidemiological studies suggest that radiation exposure may be a potential risk factor for schizophrenia in adult humans. Here, we investigated whether adult irradiation in rats caused behavioral abnormalities relevant to schizophrenia. A total dose of 15-Gy irradiation in six fractionations during 3 weeks was exposed to the forebrain including the subventricular zone (SVZ) and subgranular zone (SGZ) with male rats in the prone position. Behavioral, immunohistochemical, and neurochemical studies were performed three months after fractionated ionizing irradiation. Three months after fractionated ionizing irradiation, the total numbers of BrdU-positive cells in both the SVZ and SGZ zones of irradiated rats were significantly lower than those of control (sham-irradiated) rats. Hyperactivity after administration of the dopaminergic agonist methamphetamine, but not the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine, was significantly enhanced in the irradiated rats although spontaneous locomotion in the irradiated rats was significantly lower than that of controls. Behavioral abnormalities including auditory sensory gating deficits, social interaction deficits, and working memory deficits were observed in the irradiated rats. The present study suggests that irradiation in adulthood caused behavioral abnormalities relevant to schizophrenia, and that reduction of adult neurogenesis by irradiation may be associated with schizophrenia-like behaviors in rats.
    PLoS ONE 02/2008; 3(5):e2283. DOI:10.1371/journal.pone.0002283 · 3.23 Impact Factor
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    • "The majority of methods measure locomotor activity in novel environments that are unfamiliar to the rodent. These arenas include the open field (Milesi-Halle et al., 2005; Miller et al., 2005; Gaytan et al., 1998), holeboard (Fernandes et al., 1999), and other pre-constructed laboratory chambers in which the animal is exposed to a new, unfamiliar environment (Quinn et al., 2003; Tani et al., 2001). Animals may need to be placed in these environments for considerable periods of time (e.g. up to 2 h) which can be very time-consuming, but is often necessary as drug-induced responses are sometimes only seen following this extended period (Campbell and Spear, 1999; Tanabe et al., 2004). "
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    ABSTRACT: The advent of automated locomotor activity methodologies has been extremely useful in removing the subjectivity and bias out of measuring this parameter in rodents. However, many of these behavioural studies are still conducted in novel environments, rather than in ones that the animals are familiar with, such as their home cage. The purpose of the present series of experiments was to develop an automated home cage tracking (HCT) profile using EthoVision software and assessing the acute effects of stimulant (amphetamine and methamphetamine, 0-5 mg/kg, sc) and sedative (diazepam, 0-20 mg/kg, sc and chlordiazepoxide, 0-50 mg/kg sc) drugs in this apparatus. Young adult male Sprague-Dawley rats were used, and the home cage locomotor activity was recorded for 11-60 min following administration (n=4 per group). For amphetamine and methamphetamine, a dose-dependent increase in home cage activity was evident for both drugs, with a plateau, followed by reduction at higher doses. Methamphetamine was more potent, whereas amphetamine produced greater maximal responses. Both diazepam and chlordiazepoxide dose-dependently reduced locomotor activity, with diazepam exhibiting a greater potency and having stronger sedative effects than chlordiazepoxide. Three doses of each drug were selected at the 31-40 min time period following administration, and compared to open field responses. Diazepam, chlordiazepoxide and amphetamine did not produce significant changes in the open field, whilst methamphetamine produced a significant increase in the 2.5 mg/kg group. In conclusion, these studies have successfully developed a sensitive HCT methodology that has been validated using drugs with stimulant and sedative properties in the same test conditions, with relatively small numbers of animals required to produce statistically significant results. It has proven superior to the open field investigations in allowing dose-response effects to be observed over a relatively short observation period (i.e. 10 min) for both stimulants and sedatives. In addition, the HCT system can determine differences in potency and efficacy between drugs of a similar chemical class.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2007; 31(7):1456-63. DOI:10.1016/j.pnpbp.2007.06.023 · 3.69 Impact Factor
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