Journal
BIOLOGICAL PSYCHIATRY
Volume 75, Issue 2, Pages 115-123Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2013.07.013
Keywords
Attention-deficit/hyperactivity disorder; GABA; impulsivity; magnetic resonance imaging; nucleus accumbens; psychostimulants
Categories
Funding
- Medical Research Council
- Medical Research Council [G1000183, G1002231, G0001354B, G1000183B, G0001354, G0701500] Funding Source: researchfish
- MRC [G0701500, G1000183, G1002231] Funding Source: UKRI
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Background: Pathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attention-deficit/hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial reaction time task. Methods: We used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger RNA interference targeting glutamate decarboxylase 65/67 (GAD(65/67)) gene expression in the nucleus accumbens core (NAcbC) is sufficient to increase impulsivity in LI rats. Results: We identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats. Conclusions: These results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related disorders.
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