Dopamine Modulates Adaptive Forgetting in Medial Prefrontal Cortex.

Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. We observed a bidirectional modulation of retrieval-induced forgetting by agonists and antagonists of D1 receptors in the medial prefrontal cortex. These findings establish the essential role of prefrontal dopamine in the active forgetting of competing memories, contributing to the shaping of retention in response to the behavioral goals of an organism.SIGNIFICANCE STATEMENT Forgetting is a ubiquitous phenomenon that is actively promoted in many species. The very act of remembering some experiences can cause forgetting of others, in both humans and rats. This retrieval-induced forgetting process is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where the memories are stored. Here we started disentangling the neurochemical signals in the prefrontal cortex that are essential to retrieval-induced forgetting. We found that, in rats, the release of dopamine in this area, acting through D1 receptors, was essential to causing active forgetting of competing memories. Inhibition of D1 receptors impaired forgetting, while activation increased forgetting. These findings are important, because the mechanisms of active forgetting and their linkage to goal-directed behavior are only beginning to be understood.

Increased Retinal Ganglion Cell Survival by Exogenous IL-2 Depends on IL-10, Dopamine D1 Receptors, and Classical IL-2/IL-2R Signaling Pathways.

Interleukin-2 (IL-2) is a classical pro-inflammatory cytokine known to display neuroprotective roles in the central nervous system including the retina. In the present study, we investigate the molecular targets involved in the neurotrophic effect of IL-2 on retinal ganglion cells (RGC) after optic nerve axotomy. Analysis of retrograde labeling of RGC showed that common cell survival mediators, as Trk receptors, Src, PI3K, PKC, and intracellular calcium do not mediate the neurotrophic effect of IL-2 on RGC. No involvement of MAPK p38 was also observed. However, other MAPKs as MEK and JNK appear to be mediating this IL-2 effect. Our data also indicate that JAK2/3 are important intracellular proteins for the IL-2 effect. Interestingly, we demonstrate that the IL-2 effect depends on dopamine D1 receptors (D1R), the cAMP/PKA pathway, interleukin-10 (IL-10), and NF-κB, suggesting that RGC survival induced by IL-2 encompasses a molecular network of major complexity. In addition, treatment of retinal cells with recombinant IL-10 or 6-Cl-pb (D1R full agonist) was able to increase RGC survival similar to IL-2. Taken together, our results suggest that after optic nerve axotomy, the increase in RGC survival triggered by IL-2 is mediated by IL-10 and D1R along with the intracellular pathways of MAPKs, JAK/STAT, and cAMP/PKA.

Blockade of the dopaminergic neurotransmission with AMPT and reserpine induces a differential expression of genes of the dopaminergic phenotype in substantia nigra.

Dopaminergic neurons have the ability to release Dopamine from their axons as well as from their soma and dendrites. This somatodendritically-released Dopamine induces an autoinhibition of Dopaminergic neurons mediated by D2 autoreceptors, and the stimulation of neighbor GABAergic neurons mediated by D1 receptors (D1r). Here, our results suggest that the somatodendritic release of Dopamine in the substantia nigra (SN) may stimulate GABAergic neurons that project their axons into the hippocampus. Using semiquantitative multiplex RT-PCR we show that chronic blockade of the Dopaminergic neurotransmission with both AMPT and reserpine specifically decreases the expression levels of D1r, remarkably this may be the result of an antagonistic effect between AMPT and reserpine, as they induced the expression of a different set of genes when treated by separate. Furthermore, using anterograde and retrograde tracing techniques, we found that the GABAergic neurons that express D1r also project their axons in to the CA1 region of the hippocampus. Finally, we also found that the same treatment that decreases the expression levels of D1r in SN, also induces an impairment in the performance in an appetitive learning task that requires the coding of reward as well as navigational skills. Overall, our findings show the presence of a GABAergic interconnection between the SNr and the hippocampus mediated by D1r.

GABAergic imbalance is normalized by dopamine D1 receptor activation in the striatum contralateral to the cortical injury in motor deficit-recovered rats.

RATIONALE: The sensorimotor cortex and the striatum are interconnected by the corticostriatal pathway, suggesting that cortical injury alters the striatal function, which may be modulated by dopamine. OBJECTIVES: We studied whether the activation of dopamine D1 receptors (D1Rs) modulates the γ-aminobutyric acid (GABA) and glutamate levels in the striatum of recovered rats at 192 h after cortical injury. METHODS: The D1R agonist SKF-38393 (0, 2, 3, or 4 mg/kg) was administered at 24, 48, 96, and 192 h post-injury, and then rats were decapitated to determine GABA and glutamate levels and the levels of D1R mRNA on both sides of the striatum. RESULTS: GABAergic imbalance in the striatum contralateral to the injury site was normalized by the administration of the D1R agonist, but this treatment did not produce a significant effect on glutamate levels, suggesting that glutamate was metabolized into GABA. The administration of SKF-38393 (2 mg/kg) decreased the levels of D1R mRNA in the striatum contralateral to the injury, and this effect was blocked by the coadministration of the D1R antagonist SCH-23390 (2 mg/kg). In the striatum ipsilateral to the injury, the D1R agonist increased the D1R mRNA levels, an effect that was blocked by SCH-23390. CONCLUSION: The reversal of the GABAergic imbalance in the striatum contralateral to the cortical injury can be modulated by extrastriatal D1R activation, and the D1R agonist-induced increases in the D1R mRNA levels in the striatum ipsilateral to the injury suggest that the striatum may be necessary to achieve functional recovery.

Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition.

The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure.

Effects of dopamine D1 receptor activation and blockade on dopamine and noradrenaline levels in the rat brain.

The noradrenergic and dopaminergic systems are associated with the motor system and have anatomical and functional connections that have not yet been studied. The present study aimed to examine the specific role of D1 receptors (D1Rs) on noradrenergic and dopaminergic responses in the rat brain. Male Wistar rats were assigned to eight groups to receive systemic injection of a D1R agonist (SKF-38393) at 0, 1, 5 or 10mg/kg or injection of a D1R antagonist (SCH-23390) at 0, 0.25, 0.5 or 1mg/kg. Dopamine (DA) and noradrenaline (NA) levels were measured using high-performance liquid chromatography. Injection of SKF-38393 alone at 1, 5 and 10mg/kg did not alter DA levels in the midbrain, cerebral cortex or pons, while it significantly increased these levels in the striatum (at 1 and 10mg/kg), hippocampus (at 1mg/kg) and cerebellum (at 1 and 5mg/kg). Administration of SKF-38393 at 1, 5, and 10mg/kg decreased the NA levels in the midbrain, pons, hippocampus (except at 1mg/kg) and cortex (except at 5mg/kg), whereas the opposite effect was observed in the striatum. SCH-23390 decreased the DA levels in the cortex (at 0.25 and 0.5mg/kg) and pons (at 0.5mg/kg). In contrast, 0.25, 0.5 and 1mg/kg SCH-23390 increased the DA levels in the cerebellum, whereas no differences from the control levels were observed for the DA levels in the striatum, midbrain and hippocampus. SCH-23390 at 0.5 and 1mg/kg increased the NA levels in the striatum. In contrast, the midbrain, hippocampus, cortex, pons and cerebellum did not exhibit altered NA levels. Our results demonstrate that the activation of D1Rs modulates the response of the noradrenergic system in nearly all of the investigated brain structures; thus, the blockade of D1Rs attenuates the effects induced by D1R activation.

Renal dopaminergic system: Pathophysiological implications and clinical perspectives.

Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent.