Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens

Abstract

The present study investigated the effects of excitotoxic lesions of the prefrontal cortex (PFC) on dopamine (DA) and excitatory amino acid (EAA) function in the nucleus accumbens core using in vivo microdialysis in freely moving rats. As a postsynaptic marker of neuronal function, the nuclear levels of the transcriptional factor CREB and its active phosphorylated form, CREB-P, were measured in the ventral tegmental area (VTA), and in the core and shell subregions of the nucleus accumbens of sham and lesioned animals. PFC-lesioned animals exhibited a greater locomotor response to novelty and amphetamine administration (125-500 microg/kg i.v.). No change was observed in extracellular levels of glutamate or saturable d-aspartate binding (a marker for the high-affinity EAA transporter) in the nucleus accumbens of PFC-lesioned animals. Extracellular levels of DA were comparable in sham and lesioned animals under tonic conditions, however, following amphetamine administration, DA efflux was significantly attenuated in lesioned animals. No correlation was observed between microdialysate levels of amino acids and the attenuated dopaminergic response to amphetamine in lesioned animals. Further, no effect of the lesion was found on nuclear CREB protein in saline- and amphetamine-treated rats. The density of CREB-P immunoreactive nuclei, while remaining unchanged in the VTA, increased in the nucleus accumbens shell following amphetamine treatment in lesioned animals. The results show that an important modulatory role of the PFC on the behavioural response to novelty and amphetamine is associated with the level of immediate-early gene regulation rather than levels of extracellular DA and amino acids in the ventral striatum.

Remediation of attentional dysfunction in rats with lesions of the medial prefrontal cortex by intra-accumbens administration of the dopamine D2/3 receptor antagonist sulpiride

“…This is a striking result, replicating the amelioration also found by Passetti and colleagues (2003) but now highlighting the NAC as a likely site of action, based on the findings of Dalley et al (1999) concerning prefrontal cortex-nucleus accumbens interactions. There are several implications of these findings, perhaps the most important being that modulation of dopamine D 2/3 receptors at the level of the NAC significantly blocked the 'impulsive' responding induced by the mPFC lesion.…”

“…(Braun et al 1993;Iversen 1971;Jaskiw et al 1990;Roberts et al 1994;Wilkinson et al 1997). Moreover, previous evidence following similar mPFC lesions had shown that there were enhanced cellular and behavioural responses to d-amphetamine in the nucleus accumbens (NAC) (Dalley et al 1999), suggesting the latter to be the key striatal site mediating the ameliorative effects of sulpiride. Consequently, in this study we directly tested the hypothesis that this amelioration is mediated by dopamine D 2/3 receptors in the NAC by infusing sulpiride there in rats with deficits in 5CSRTT performance produced by mPFC lesions.…”

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

“…Previous work has associated CREBactivated transcriptional processes with learning and memory (Bourtchuladze et al, 1994;Liu and Graybiel, 1996;Silva et al, 1998;Dalley et al, 1999;Kogan et al, 2000;Genoux et al, 2002), but the role of such processes in perirhinal-dependent recognition memory has not been investigated. Additionally, previous work implicates CREB-activated pathways in synaptic plasticity (Deisseroth et al, 1996;Silva et al, 1998;Ahn et al, 1999), but their role in perirhinal plasticity is unknown.…”

CREB Protein Expressed Differently in the Frontal Cortices of <i>Datura stramonium</i> Treated Rats: Implication for Addiction and Neurodegeneration

“…Studies employing both lesioning experiments [13] [14] and pharmacological manipulations [15] [16] have collectively demonstrated the importance of certain structures including the prefrontal cortex (PFC) of the frontal lobe, nucleus accumbens (NAcc), dorsal striatum, hippocampus and amygdaloid nuclei in relation to drug-seeking behaviours and drug-induced plasticity. The frontal cortex has been majorly used for such studies because it contains network of neurons as the substrate for functions that include: comprehension, cognition, communication, reasoning, problem-solving, abstraction, imagination, planning and memory.…”