Neuroscience
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Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. ⋯ Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.
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Patients with post-traumatic stress disorder (PTSD) present hippocampal (HPC) dysfunction, which may facilitate fear-related phenomena such as fear learning sensitization (i.e. potentiation of fear acquisition by initial fear conditioning (FC1)) and fear return (i.e. reactivation of extinguished fear). Fear return is sensitive to HPC high-frequency stimulation (HFS) in rats. The goal of the present study was to examine whether fear learning sensitization is also sensitive to HPC HFS in rats. ⋯ We also found that the effect of HPC HFS on fear learning sensitization required initial extinction. These findings suggest a pivotal role of the HPC in preventing proactive and retroactive effects of successive fear conditionings. These data also support the concept that HPC deactivation may be involved in fear learning sensitization and fear return in PTSD patients.
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The visceral insular cortex (VIC) has previously been shown to play a critical role during acute nausea-induced conditioned gaping in rats. Specifically, localized administration of the conventional anti-emetic, ondansetron or the synthetic cannabinoid, HU210, interferes with the establishment of conditioned gaping, likely by reducing the effects of an illness-inducing treatment. However the precise role of the VIC in endocannabinoid-suppression of nausea remains unknown; thus we investigated the potential of localized intra-VIC endocannabinoid administration to interfere with acute nausea-induced conditioned gaping behavior in male Sprague-Dawley rats. ⋯ Bilateral intra-VIC infusions of 2-AG (1 μg, but not 0.5 μg) dose-dependently suppressed conditioned gaping, whereas exogenous AEA was without effect. Interestingly, 2-AG reduced conditioned gaping despite additional pretreatment with the selective cannabinoid receptor type 1 (CB1) antagonist, AM-251; however, concomitant pretreatment with the cyclooxygenase inhibitor, indomethacin (0.5 μg), blocked the suppressive effects of intra-VIC 2-AG. These findings suggest that the modulatory role of the endocannabinoid system during nausea is driven largely by the endocannabinoid, 2-AG, and that its anti-nausea effects may be partly independent of CB1-receptor signaling through metabolic products of the endocannabinoid system.
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The endogenous tetrapeptide endomorphin-2 (EM2) participates in pain modulation by binding to pre- and/or post-synaptic μ opioid receptor (MOR). In the present study, pathological expression and antinociceptive effects of EM2 at the spinal level were investigated in a rat model of bone cancer pain. The model was established by introducing Walker 256 mammary gland carcinoma cells into the tibia medullary cavity. ⋯ Furthermore, topical application of EM2 dose-dependently inhibited the electrically evoked C-fiber responses and postdischarge of wide dynamic range (WDR) neurons within the spinal cord (p < 0.05), and pretreatment with β-FNA abolished the hyperactivity of these neurons. Compared with the antinociception of morphine which took effect from 40 min to 100 min post application, the analgesic action of EM2 was characterized by quick onset and short-lived efficacy (p < 0.05), being most potent at 10 min and lasting about 20 min. These findings indicate that the down-regulated spinal EM2 is an important contributor to the neuropathological process of bone cancer pain and enhancing activation of EM2/μ receptor signaling might provide a therapeutic alternative to optimizing the treatment of cancer-induced bone pain.
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We have previously reported a time-dependent increase in melatonin (MLT) and decrease in dopamine (DA) in striatal dialysate 3 weeks after unilateral 6-hydroxydopamine (6-OHDA) lesioning in the rat substantia nigra pars compacta (SNc) and medial forebrain bundle (MFB). This study aimed to investigate dynamic and circadian variations in DA, MLT, glutamate (Glu) and γ-aminobutyric acid (GABA) in striatal dialysates in the same 6-OHDA animal model. These neurotransmitters were determined using high-performance liquid chromatography (HPLC). ⋯ Six weeks post-treatment, MLT levels correlated well with Glu and GABA levels at corresponding time-points in the striatum ipsilateral to the injected side in both groups, and increased MLT levels also correlated well with changes in Glu and GABA in the striatum in 6-OHDA-lesioned rats. These data suggest that 6-OHDA lesioning affects the endogenous productions of DA, MLT, Glu and GABA, and changes the MLT secretion pattern. Augmented striatal MLT levels and advanced MLT secretion pattern caused by unilateral intracerebral injection of 6-OHDA may influence the variations in Glu and GABA between day and night.