Interhemispheric Regulation of the Medial Prefrontal Cortical Glutamate Stress Response in Rats

Abstract

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu 2/3 receptor activation. Local dopamine (DA) D 1 receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following ␣ 1 -adrenoreceptor blockade and GABA B receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.

Disruptions in the Regulation of Extracellular Glutamate by Neurons and Glia in the Rat Striatum Two Days after Diffuse Brain Injury

“…In our study, local application of CPG failed to significantly reduce extracellular glutamate compared with saline in both sham-injured and TBI animals. Similar to our data, multiple reports have detected no significant change in extracellular glutamate with application of CPG in both anesthetized and awake animals (Hascup et al, 2010;Lupinsky et al, 2010;Melendez et al, 2005). In general, the data reported here and from prior reports suggest a limited role for the x c -as a source of extracellular glutamate.…”

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

“…Thus, corticosterone and NE may likewise act synergistically during chronic stress to compromise the functional integrity of the mPFC. In other studies, neither a 1 -adrenergic receptor antagonist administration nor removal of the adrenal glands alone completely blocked acute stress-evoked glutamate release in the mPFC (Moghaddam et al, 1994;Lupinsky et al, 2010). This suggests that individually inhibiting the modulatory actions of either NE or corticosterone during chronic stress may reduce stressevoked glutamate release to a level that maintains function, but is no longer so excessive as to compromise the integrity of the mPFC.…”

“…In other studies, repeated stressinduced cognitive impairments have been attributed to glutamate-mediated pyramidal cell dendritic atrophy in the mPFC and hippocampus (Woolley et al, 1990;Liston et al, 2006;Martin and Wellman, 2011). The a 1 -adrenergic receptor is expressed on mPFC pyramidal cells, in which stress-induced dendritic remodeling has been noted (Marek and Aghajanian, 1999;Wellman, 2001;Radley et al, 2004;Lupinsky et al, 2010). Thus, CUS-induced deficits in cognitive flexibility may be the result of repeated induction of noradrenergic facilitation in mPFC, leading to excessive glutamate transmission and pyramidal cell dysfunction.…”

“…In addition, we found that a 1 -adrenergic receptor activation enhances cognitive flexibility in the mPFC (Lapiz and Morilak, 2006;Bondi et al, 2010). The a 1 -adrenergic receptor enhances cortical excitatory signaling and acute stress-evoked glutamate release (Marek and Aghajanian, 1999;Lupinsky et al, 2010), thereby facilitating the signal-to-noise ratio of evoked synaptic transmission and sharpening cellular responses in cortex (Waterhouse et al, 1981(Waterhouse et al, , 2000. Thus, elevated NE levels may facilitate cognitive flexibility and behavioral adaptation by increasing glutamate neurotransmission in the mPFC circuitry.…”

“…Similar to corticosterone, NE modulates basal excitatory signaling and acute stress-evoked glutamate release in the mPFC (Marek and Aghajanian, 1999;Lupinsky et al, 2010). Therefore, through a process of cumulative excitotoxicity or similar negative consequence of repeated facilitation, repeated stress-induced noradrenergic activity in the mPFC may play a role in the development of CUS-induced ED deficits.…”