Activation of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II in response to Morris water maze learning in rats.

This study investigates the interactive roles of nitric oxide (NO) and CaM-kinase II (calcium/calmodulin-dependent protein kinase II) in Morris water maze learning. In Experiment I, experimental rats received 5 days of training on a Morris water maze, where the controls were trained in the water maze with no spatial cue condition or were trained via a visually guided landmark condition. The experimental rats showed improvement in their rate of spatial learning in the water maze. The escape latencies were significantly correlated with the Ca2+-independent activity of the hippocampal CaM-kinase II. Moreover, there was a significant increase in the endogenous phosphorylation of neuronal NOS and CaM-kinase II in the experimental group when compared to the controls. The intra-hippocampal infusion of 7-NI, KN-93, or AP5 did disrupt water maze learning. SDS-PAGE analysis showed that these drugs significantly depressed phosphorylation of hippocampal NOS. The Ca2+-independent activity of hippocampal CaM-kinase II was significantly lower in the KN-93 or the AP5 infused group when compared to the controls. Although these depressed activities were not reversed by the infusion of NO donor (sodium nitroprusside, SNP), the rats' water maze learning behavior were ameliorated significantly. These results, taken together, indicate that the NOS activation is essential for water maze learning, which may be triggered via the CaM-kinase II activation in hippocampus.

Roles of hippocampal NMDA receptors and nucleus accumbens D1 receptors in the amphetamine-produced conditioned place preference in rats.

There are glutamatergic projections from the hippocampus to the nucleus accumbens (NAc), which regulate DA transmission in this structure. To be precise, the ventral hippocampal (VH) glutamatergic neurons project to the nucleus accumbens shell region (NAcSh), whereas the dorsal hippocampus (DH) sends glutamatergic projections to the nucleus accumbens core region (NAcC). This study investigates the roles of hippocampal N-methyl-D-aspartate (NMDA) glutamate receptors and NAc type 1 dopamine receptor (D1) in amphetamine-produced conditioned place preference (AMPH-CPP) in rats. Our earlier reports showed that AMPH-CPP results in the enhancement of hippocampal CaMKII activity and it can be impaired by NMDA antagonist (AP5). In this study AMPH-CPP did not alter the NAc CaMKII activity, although AMPH-CPP was impaired by a blockade of D1 receptors (SCH23390) during conditioning. Moreover, inactivation of hippocampal area (dorsal hippocampus or ventral hippocampus) impaired AMPH-CPP, but its effect was diminished by the activation of D1 receptors in accumbal region (NAc core or NAc shell). By inactivating both DH and NAc core resulted in the disruption of rat's CPP expression. However, the impaired CPP expression was recovered during the next testing session, suggesting the disruption of CPP expression was a short term effect. Moreover, the disruption of CPP expression was not exhibited if NAc core was not inactivated. Interestingly, the rats that received activation in VH but an inactivation in NAc shell before testing show impaired CPP expression compared to those received inactivation in both VH and NAc shell. DH activation plus an inactivation in NAc core before testing show a significantly higher rate of the weakening of AMPH-CPP expression. Similarly, an activation of VH plus an inactivation of NAc shell before testing also show a statistically significant lower CPP score on tests 3 and 4. These results, taken together, indicate that NMDA receptor activation in DH and VH have different enhancing effects on the AMPH-CPP as their innervations onto the different NAc regions are essential for AMPH-CPP establishment. If the deterioration of AMPH-CPP expression (or extinction process) resembles the formation of new learning, then this active process might have been facilitated by the hippocampal NMDA receptor activations during testing.

Roles of hippocampal N-methyl-D-aspartate receptors and calcium/calmodulin-dependent protein kinase II in amphetamine-produced conditioned place preference in rats.

This study investigates the roles of hippocampal N-methyl-D-aspartate (NMDA) glutamate receptors and CaMKII (calcium/calmodulin-dependent protein kinase II) in amphetamine-produced conditioned place preference (AMPH-CPP) in rats. An earlier report showed that AMPH-CPP resulted in the enhancement of hippocampal CaMKII activity. In this study, AMPH-CPP significantly increased hippocampal GluR1 receptors, though AMPH-CPP was impaired by either blockade of NMDA receptors (AP5) or inhibition of CaMKII (KN-93) during conditioning. These treatments also impaired CPP if administered before testing, but CPP recovered during the next testing session. Therefore, these treatments had no effect on the extinction of CPP. If the conditioned rats were, however, reexposed to AMPH-CPP after a hippocampal-infusion of AP5 or KN-93, the extinction of the original CPP was greater than that seen in the controls. The hippocampal-infusion of D-cycloserine before CPP testing enhanced the extinction of CPP. These results, taken together, indicate that NMDA receptor activation and CaMKII activity are essential for the AMPH-CPP. AMPH-CPP reexposure is similar to the memory reconsolidation process, being disrupted by either a blockade of the NMDA receptor or an inhibition of CaMKII. Furthermore, the extinction of CPP resembles new learning, which is an active process and is facilitated by a partial NMDA agonist.

Roles of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II in inhibitory avoidance learning in rats.

This study investigated the interactive roles of nitric oxide and calcium/calmodulin-dependent protein kinase II in inhibitory avoidance learning. In Experiment I, rats were trained on a one-trial step-through inhibitory avoidance learning task, whereas the controls were trained in a noncontingent stimulus-pairing condition. The experimental rats showed significantly higher retention scores than the control rats. Correspondingly, the rats in the experimental group showed significantly higher Ca2+-independent activity of the hippocampal calcium/calmodulin-dependent protein kinase II and a significant increase in the endogenous phosphorylation of neuronal nitric oxide synthase. The intrahippocampal infusion of 7-nitro-indazole, 2-[N-(2-hidroxyethyl)-N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, or 2-amino-5-phosphonopentanoic acid disrupted inhibitory avoidance learning. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that these drugs significantly depressed phosphorylation of hippocampal nitric oxide synthase. The Ca2+-independent activity of hippocampal calcium/calmodulin-dependent protein kinase II was significantly lower in the 2-[N-(2-hidroxyethyl)-N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine or the 2-amino-5-phosphonopentanoic acid-infused group compared with the controls. Although these depressed activities were not reversed by the infusion of a nitric oxide donor (sodium nitroprusside), this did significantly improve the rats' inhibitory avoidance deficit. These results, taken together, indicate that the nitric oxide synthase activation is essential for inhibitory avoidance learning, which may be triggered via the calcium/calmodulin-dependent protein kinase II activation in the hippocampus.

Prenatal amphetamine exposure alters behavioral reactivity to amphetamine in rats.

In utero exposure to psychostimulants produces neurobehavioral alterations in the offspring of laboratory animals. Most amphetamine-related behavioral changes have been related to changes in the monoamine transmission levels, where monoamines may act as developmental regulatory substances for maturation of neuronal population. This study investigates the effect of prenatal-amphetamine exposure on the offspring's behavioral responses under amphetamine conditioning settings. Pregnant female rats were injected (subcutaneous) with amphetamine or saline during the pregnancy [gestation day (GD) 8 until parturition day]. The prenatal amphetamine exposure resulted in significantly decreased birth weights. The offspring from the saline group displayed a significantly lower number of stereotyped behaviors across the four challenge doses of amphetamine injections. Offspring from the amphetamine-treated prenatal group displayed significantly increased average startle amplitude compared to the controlled offspring. Moreover, offspring from amphetamine-treated prenatal group showed significantly less inhibition for the prepulse startle trials compared to those of the offspring from saline group. These results, taken together, indicate that the prenatally exposed rats displayed a significantly different profile of behavioral reactivity upon amphetamine challenges.