Functional MHCI deficiency induces ADHD-like symptoms with increased dopamine D1 receptor expression.

Inappropriate synaptic development has been proposed as a potential mechanism of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD). Major histocompatibility complex class I (MHCI), an immunity-associated molecule expressed by neurons in the brain, regulates synaptic development; however, the involvement of MHCI in these disorders remains elusive. We evaluated whether functional MHCI deficiency induced by ß2m-/-Tap1-/- double-knockout in mice leads to abnormalities akin to those seen in neurodevelopmental disorders. We found that functional MHCI deficiency induced locomotor hyperactivity, motor impulsivity, and attention deficits, three major symptoms of ADHD. In contrast, these mice showed normal spatial learning, behavioral flexibility, social behavior, and sensorimotor integration. In the analysis of the dopamine system, upregulation of dopamine D1 receptor (D1R) expression in the nucleus accumbens and a greater locomotor response to D1R agonist SKF 81297 were found in the functional MHCI-deficient mice. Low-dose methylphenidate, used for the treatment of ADHD patients, alleviated the three behavioral symptoms and suppressed c-Fos expression in the D1R-expressing medium spiny neurons of the mice. These findings reveal an unexpected role of MHCI in three major symptoms of ADHD and may provide a novel landmark in the pathogenesis of ADHD.

Involvement of hippocampal NMDA receptors in encoding and consolidation, but not retrieval, processes of spontaneous object location memory in rats.

The hippocampus is thought to be involved in object location recognition memory, yet the contribution of hippocampal NMDA receptors to the memory processes, such as encoding, retention and retrieval, is unknown. First, we confirmed that hippocampal infusion of a competitive NMDA receptor antagonist, AP5 (2-amino-5-phosphonopentanoic acid, 20-40nmol), impaired performance of spontaneous object location recognition test but not that of novel object recognition test in Wistar rats. Next, the effects of hippocampal AP5 treatment on each process of object location recognition memory were examined with three different injection times using a 120min delay-interposed test: 15min before the sample phase (Time I), immediately after the sample phase (Time II), and 15min before the test phase (Time III). The blockade of hippocampal NMDA receptors before and immediately after the sample phase, but not before the test phase, markedly impaired performance of object location recognition test, suggesting that hippocampal NMDA receptors play an important role in encoding and consolidation/retention, but not retrieval, of spontaneous object location memory.

Neuropeptide W stimulates adrenocorticotrophic hormone release via corticotrophin-releasing factor but not via arginine vasopressin.

Neuropeptide W (NPW) was isolated as an endogenous ligand for NPBWR1, an orphan G protein-coupled receptor localized in the rat brain, including the paraventricular nucleus. It has been reported that central administration of NPW stimulates corticosterone secretion in rats. We hypothesized that NPW activates the hypothalamic-pituitary-adrenal (HPA) axis via corticotrophin-releasing factor (CRF) and/or arginine vasopressin (AVP). NPW at 1 pM to 10 nM did not affect basal or ACTH-induced corticosterone release from dispersed rat adrenocortical cells, or basal and CRF-induced ACTH release from dispersed rat anterior pituitary cells. In conscious and unrestrained male rats, intravenous administration of 2.5 and 25 nmol NPW did not affect plasma ACTH levels. However, intracerebroventricular (icv) administration of 2.5 and 5.0 nmol NPW increased plasma ACTH levels in a dose-dependent manner at 15 min after stimulation (5.0 vs. 2.5 nmol NPW vs. vehicle: 1802 ± 349 vs. 1170 ± 204 vs. 151 ± 28 pg/mL, respectively, mean ± SEM). Pretreatment with astressin, a CRF receptor antagonist, inhibited the increase in plasma ACTH levels induced by icv administration of 2.5 nmol NPW at 15 min (453 ± 176 vs. 1532 ± 343 pg/mL, p<0.05) and at 30 min (564 ± 147 vs. 1214 ± 139 pg/mL, p<0.05) versus pretreatment with vehicle alone. However, pretreatment with [1-(ß-mercapto-ß, ß-cyclopentamethylenepropionic acid), 2-(Ο-methyl)tyrosine]-arg-vasopressin, a V1a/V1b receptor antagonist, did not affect icv NPW-induced ACTH release at any time (p>0.05). In conclusion, we suggest that central NPW activates the HPA axis by activating hypothalamic CRF but not AVP.

Sex-specific effects of prenatal stress on neuronal development in the medial prefrontal cortex and the hippocampus.

Evidence suggests that maternal stress during gestation in humans and animals can cause emotional and cognitive dysfunction in the offspring. In the present study, we examined neurons of the hippocampus and the medial prefrontal cortex of adult rats exposed to prenatal stress. Using a revised Golgi-Cox staining method, we found decreases in dendritic length and complexity in area CA3 and the dentate gyrus of male rats exposed to prenatal stress compared with the controls, as well as decreased dendritic complexity in the prelimbic cortex. In contrast, we did not detect any changes in dendrites of female rats exposed to prenatal stress. Our results suggest that prenatal stress can induce long-lasting morphological changes in the medial prefrontal cortex and the hippocampus that are sex specific.

Cocaine enhances resistance to extinction of responding for brain-stimulation reward in adult prenatally stressed rats.

The present experiment assessed whether prenatal stress (PS) can alter the ability of acute and chronic cocaine administration to increase and decrease the rewarding effectiveness of the medial forebrain bundle (MFB) using intracranial self-stimulation (ICSS), and also whether PS can affect the extinction of the MFB stimulation response. Adult male offspring of female rats that received PS or no PS (nPS) were implanted with MFB stimulating electrodes, and were then tested in ICSS paradigms. In both nPS and PS offspring, acute cocaine injection decreased ICSS thresholds dose-dependently. However, the threshold-lowering effects at any dose were not significantly different between groups. There was also no group-difference in the threshold-elevating effects of chronic cocaine administration. Nevertheless, chronically drug-administered PS rats exhibited a resistance to the extinguishing of the response for brain-stimulation reward when acutely treated with cocaine, as compared to extinction without cocaine treatment. The results suggest that PS may weaken the ability for response inhibition under cocaine loading in male adult offspring.

Effects of intrahippocampal cannabinoid receptor agonist and antagonist on radial maze and T-maze delayed alternation performance in rats.

Brain cannabinoid receptors are abundantly distributed in the hippocampus, however their detailed role in learning and memory remains unclear. This study investigated the role of hippocampal cannabinoid receptors for performing two kinds of working memory tasks. In experiment 1, intrahippocampal infusion of cannabinoid receptor agonist WIN 55,212-2 (1-2 microg/side) dose-dependently disturbed radial maze performance in rats. In experiment 2, WIN 55,212-2 (2 microg/side) disturbed the performance of delayed alternation in a T-maze by increasing the errors and successive errors, and on the other hand, a cannabinoid receptor antagonist AM 281 (1 microg/side) did not have any significant effects. Disruptive effect of WIN 55,212-2 on the number of errors in delayed alternation was blocked by the pretreatment with intraperitoneal AM 281 (2 mg/kg). Results suggest that hippocampal cannabinoid receptors are involved in the performance of working memory tasks. A possible role of endogenous cannabinoid system in the hippocampus was discussed in terms of an inhibitory adjustment of behavior based on the outcome of animals' previous response.

Effects of hippocampal administration of a cannabinoid receptor agonist WIN 55,212-2 on spontaneous object and place recognition in rats.

Involvement of hippocampal cannabinoid receptors in short-term memory was investigated in rats using spontaneous object and place recognition memory tasks. Rats were allowed to explore the field in which two identical objects were presented. Then after a delay period, they were placed again in the same field in which one of the two objects was replaced by another object (object recognition task) or moved to another place (place recognition task), and their exploration behavior to these objects were analyzed. Activation of hippocampal cannabinoid receptors by an agonist WIN 55,212-2 (1-2 microg/side) dose-dependently decreased the exploration of object in a new place, while it did not affect the exploration of a new object. Disruptive effect of WIN 55,212-2 on place recognition was antagonized by the pretreatment with a cannabinoid receptor antagonist AM 281 (2mg/kg, i.p.). Results suggest that hippocampal cannabinoid receptors play an important role in place recognition or spatial memory.