Dopamine Production in the Caudate Putamen Restores Feeding in Dopamine-Deficient Mice

Abstract

Dopamine-deficient (DD) mice cannot synthesize dopamine (DA) in dopaminergic neurons due to selective inactivation of the tyrosine hydroxylase gene in those neurons. These mice become hypoactive and hypophagic and die of starvation by 4 weeks of age. We used gene therapy to ascertain where DA replacement in the brain restores feeding and other behaviors in DD mice. Restoration of DA production within the caudate putamen restores feeding on regular chow and nest-building behavior, whereas restoration of DA production in the nucleus accumbens restores exploratory behavior. Replacement of DA to either region restores preference for sucrose or a palatable diet without fully rescuing coordination or initiation of movement. These data suggest that a fundamental difference exists between feeding for sustenance and the ability to prefer rewarding substances.

Affective neuroscience of pleasure: reward in humans and animals

“…Pleasurable subjective pain relief for chronic pain in a phantom limb in a patient was causally induced by effective deep brain stimulation in the PVG/ PAG part of the brainstem. When using MEG to directly measure the concomitant changes in the rest of the brain, a significant change in power was found in the mid-anterior OFC to enhance several aspects of reward (Cardinal et al 2002;Everitt and Robbins 2005;Kelley et al 2002;Kelley et al 2005;Koob and Le Moal 2006;Kringelbach and Berridge 2008;Peciña et al 2006;Robbins and Everitt 2002;Salamone et al 2007;Shizgal et al 2001;Szczypka et al 2001), yet damage to the nucleus accumbens may only subtly impair the hedonic impact or related components of natural rewards such as food (Balleine and Killcross 1994;Parkinson et al 1999;Setlow et al 2002;Whishaw and Kornelsen 1993). Core 'liking' reactions to pleasure may be relatively difficult to abolish absolutely by a single brain lesion or drug, which may be very good in evolutionary terms.…”

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…Moreover, restoration of tyrosine hydroxylase gene expression using gene therapy was able rescue the deficient feeding behavior in these DA-deficient mice [303]. Using gene therapy to enable DA production within only the caudate putamen restored mouse feeding on regular chow diet, and also normal nest-building behavior, whereas restoration of DA production into the NAc only restored the exploratory behavior [304]. …”

“…However, restoration of DA into the NAc in these studies was not sufficient to rescue normal feeding behavior, but this may have been due to an inability to anatomically restore gene expression throughout the entire NAc [304]. Interestingly, when the DA-deficient mice are crossed with obese leptin (Ob/Ob)-deficient mice, the lack of DA blocked the increased feeding behavior normally present in the leptin (Ob/Ob)-deficient mice [305].…”

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

“…Besides mental retardation, fragile X individuals can have seizures, attention deficit, hyperactivity, anxiety, and symptoms associated with autism (Chen and Toth, 2001;Consortium, 1994 Here we report that in the mouse model of fragile X hyperactivity is maternally transmitted, at least partly, while seizures, reduced startle and increased prepulse inhibition are strictly Mendelian traits. Since hyperactivity has been linked to low tonic stimulation of inhibitory dopamine (DA) D2 autoreceptors and consecutively to high phasic DA activity in the striatum (Grace, 2001;Koob et al, 1981;Koob and Swerdlow, 1988;Szczypka et al, 2001), we tested the function of these receptors by quinpirole, a D2 receptor preferring drug (Cory-Slechta et al, 1996; Two cohorts of animals were tested and since they were not statistically different from each other the data from the two experiments were combined. Main effect ANOVA showed both a maternal and offspring genotype effect (see in the Results and Discussion section).…”