Abstract
Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR1 gene, with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Although fragile X syndrome is considered a typical Mendelian disorder, we have recently reported that the environment, specifically the fmr1+/- or fmr1-/- [H or knockout (KO)] maternal environment, elicits on its own a partial fragile X-like phenotype and can contribute to the overall phenotype of fmr1-/0 (KO) male offspring. Genetically fmr1+/0 (WT) males born to H females (Hmaternal > WToffspring), similar to KO male offspring born to H and KO mothers (H > KO and KO > KO), exhibit locomotor hyperactivity. These mice also showed reduced D2 autoreceptor function, indicating a possible diminished feedback inhibition of dopamine (DA) release in the nigrostriatal and mesolimbic systems. The GABAergic system also regulates DA release, in part via presynaptic GABAB receptors (Rs) located on midbrain dopaminergic neurons. Here, we show that the locomotor inhibitory effect of the GABABR agonist baclofen [4-amino-3-(4-chlorophenyl)-butanoic acid] is enhanced in all progeny of mutant mothers (H > WT, H > KO, and KO > KO) compared with WT > WT mice, irrespective of their own genotype. However, increased sensitivity to baclofen was selective and limited to the locomotor response because the muscle-relaxant and sedative effects of the drug were not altered by the maternal environment. These data show that GABABR sensitization, traditionally induced pharmacologically, can also be elicited by the fmr1-deficient maternal environment.
Footnotes
-
This study was supported by the FRAXA Foundation.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.143990.
-
ABBREVIATIONS: FXS, fragile X syndrome; KO, knockout; WT, wild type; DA, dopamine; VTA, ventral tegmental area; R, receptor; baclofen, 4-amino-3-(4-chlorophenyl)-butanoic acid; CGP46381, (3-amino-propyl)-cyclohexylmethyl-phosphinic acid; ANOVA, analysis of variance; LSD, least significant difference; ADHD, attention deficit hyperactivity disorder.
- Received July 25, 2008.
- Accepted September 22, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|