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The Journal of Neuroscience, September 1, 2000, 20(17):6728 6733 Postural and Anticonvulsant Effects of Inhibition of the Rat Subthalamic Nucleus David Myrdal and Karen Gale Interdisciplinary Program

Although the STN was known previously to be involved in the development, development of synaptic plasticity, and learning, only few studies were conducted with respect to the influence of postulated effects of STN inhibition such as the inhibition of the bilateral amygdala, the hippocampus, or the periaqueductal gray, on behavior. Here, we used an in utero-induced “abnormal” model of anxiety (e.g., cocaine-induced hypo metabolism), and found that maternal STN (MSN) inhibition attenuated cocaine-induced increases in extracellular glutamate concentration in the infant subthalamic nucleus and its associated nucleus incumbent. In addition, maternal STN inhibition led to a significant decrease in the frequency and intensity of cocaine conditioning. In contrast, non-maternal (i.e., cocaine-free) control mice showed no alteration in the frequency or intensity of cocaine conditioning. Moreover, intranet microinjection into Appositive mice in adolescence markedly reduced the frequency of cocaine conditioning with a significant increase found as early as 4 hrs after microinjection. Furthermore, intranet microinjection into young male APOE-negative mice produced a similar phenotype that was attenuated upon the addition of exogenous cocaine. A potential explanation for the observed effects is that in the presence of MSN inhibition, CUFOS expression may be altered and that subsequent MSN stimulation results in reduced CUFOS expression. In agreement with these findings, we found that the frequency of cocaine conditioning was significantly reduced within 2 days after maternal MSN inhibition using microinjection as opposed to controls. Furthermore, we showed that MSN inhibition markedly reduced CUFOS expression in the MSN and that MSN inhibition by the combination of intra-mSTN microinjection and microinjection of the VU0313A G protein resulted in a significant attenuation of CUFOS expression compared to MSN inhibition alone. Taken together, these in uteri findings show that maternal STN inhibition inhibits the basal ganglia outflow, through a G protein-coupled receptor kinase mechanism, and that its attenuation of CUFOS expression attenuates cocaine addiction-like responses.

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