Application of gene therapy to treat age-related loss of dopamine D2 receptor

Ingram, Donald K.; Ikari, Hiroyuki; Umegaki, Hiroyuki; Chernak, Jeffrey M.; Roth, George S.

doi:10.1016/s0531-5565(98)00043-6

Cited by 17 publications

(9 citation statements)

References 28 publications

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“…At the mechanism level, increased PPI can be observed with a reduction in functional dopamine D2 receptors (Geyer, Krebs-Thomson, Braff, & Swerdlow, 2001). Thus the increased PPI with age demonstrated here could have been due to the reduction in dopamine D2 receptors observed with aging (Ingram, Ikari, Umegaki, Chernak, & Roth, 1998; Morgan et al , 1987). Alternatively, it is possible that with age comes a shift in the activation of cortical-striatal loop circuitry that favors stronger inhibition of startle by prepulses (Swerdlow, Geyer et al , 2001).…”

Section: Discussionmentioning

confidence: 71%

Age-associated improvements in cross-modal prepulse inhibition in mice.

Young¹,

Wallace²,

Geyer³

et al. 2010

Behavioral Neuroscience

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Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe pre-attentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented.

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Section: Discussionmentioning

confidence: 71%

Age-associated improvements in cross-modal prepulse inhibition in mice.

Young¹,

Wallace²,

Geyer³

et al. 2010

Behavioral Neuroscience

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“…(Thanos et al, 2001(Thanos et al, , 2004 and 20 days for the inbred alcohol preferring P rats (Thanos et al, 2001(Thanos et al, , 2004. It has been previously shown that this D2R vector produced significant D2R upregulation for eight days before returning to baseline by day 10 (Ingram et al, 1998;Ogawa et al, 2000;Thanos et al, 2001Thanos et al, , 2004. Several factors may be involved in explaining the difference in the duration of this effect of D2R upregulation in cocaine versus alcohol administration.…”

Section: Discussionmentioning

confidence: 96%

“…Null), as previously described (Thanos et al, 2001(Thanos et al, , 2004, and then returned to the daily CSA sessions for 1-week. Subsequently, all animals were similarly microinfused once into the NAc with the D2R vector (AdCMV.DRD2), [see previous studies for details (Ikari et al, 1995;Ingram et al, 1998;Thanos et al, 2001Thanos et al, , 2004Umegaki et al, 1997)] and then returned to the CSA for 14 days.…”

Section: Methodsmentioning

confidence: 99%

D2R DNA transfer into the nucleus accumbens attenuates cocaine self‐administration in rats

Thanos

Michaelides

Umegaki

et al. 2008

Synapse

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Dopamine (DA) D2 receptor (D2R) agonists and antagonists can modulate self-administration behavior, conditioned place preference, and locomotor responses to cocaine. Low levels of D2R have also been observed in cocaine addicted subjects and in non human primates after chronic cocaine exposures. Prior studies had shown that D2R upregulation in the nucleus accumbens (NAc) in rodents trained to self-administer alcohol markedly attenuated alcohol preference and intake. Here we assess the effects of D2R upregulation in the NAc on cocaine intake in rats trained to self-administer cocaine. Following 2 weeks of i.v. cocaine self-administration (CSA), rats were stereotaxically treated with an adenovirus that carried the D2R gene to upregulate D2R in the NAc. D2R vector treatment resulted in a significant decrease (75%) in cocaine infusions and lever presses (70%) for cocaine. This effect lasted 6 days before cocaine consumption returned to baseline levels, which corresponds roughly to the time it takes D2R to return to baseline levels. These findings show that CSA and D2R in the NAc are negatively correlated and suggest that cocaine intake is modulated in part by D2R levels in NAc. Thus strategies aimed at increasing D2R expression in NAc may be beneficial in treating cocaine abuse and addiction.

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“…DNA transfer via adenoviral vector has been an effective strategy to introduce particular genes into tissue and has provided a high specificity targeting and delivery (Crystal, 1992;Suhr and Gage, 1993). The effectiveness of the present vector for intracerebral transfer of D2R as well as the expression of functional D2R effects has been previously well established (Ikari et al, 1995(Ikari et al, , 1999Ingram et al, 1998;Ogawa et al, 2000;Thanos et al, 2001;Umegaki et al, 1997). Rats infected with this adenoviral vector produced significant increases in D2R expression with significant decreases in alcohol preference and intake (Thanos et al, 2001(Thanos et al, , 2004.…”

Section: Introductionmentioning

confidence: 93%