Continuous production of endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. NO is also formed in the brain upon activation of glutamate receptors, which are thought to mediate central autonomic reflexes. In the present study we assessed whether NO plays a role in central autonomic regulation. For this, we have investigated the effects of NG-methyl-L-arginine (NMA), a selective inhibitor of NO synthesis from L-arginine, on sympathetic renal nerve activity (RNA), blood pressure, and heart rate in the anesthetized rat. NMA elicited a dose-dependent sustained increase in blood pressure (approximately 20 and 30 mm Hg, 5 minutes after 10 and 50 mumol/kg i.v., respectively). Heart rate and RNA decreased transiently (15 beats per minute and 40%, respectively); RNA subsequently increased (100%) while blood pressure remained elevated. Baroreceptor deafferentation markedly altered these responses to NMA; the transient decreases in heart rate and RNA were abolished, whereas the increases in RNA and blood pressure were significantly potentiated. After spinal C-1-C-2 transection, there was no increase in RNA, and blood pressure increased to a smaller extent. L-Arginine blocked the NMA-induced increases in blood pressure and RNA. Thus, in addition to modulating vascular resistance by a peripheral action, NO may also play a role in the central regulation of sympathetic tone.

The neural mechanisms underlying memory regulation during sleep are not yet fully understood. We found that melanin concentrating hormone–producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs. Wake- and REM sleep–active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state–dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep–active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.

2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression of synaptic transmission in the brain. 2-AG is synthesized in activated postsynaptic neurons by sn-1-specific diacylglycerol lipase (DGL), binds to presynaptic cannabinoid CB 1 receptors, suppresses neurotransmitter release, and is degraded mainly by monoacylglycerol lipase (MGL). In the basolateral amygdala complex, it has been demonstrated that CB 1 is particularly enriched in axon terminals of cholecystokinin (CCK)-positive GABAergic interneurons, induces short-and long-term depression at inhibitory synapses, and is involved in extinction of fear memory. Here, we clarified a unique molecular convergence of DGLα, CB 1 , and MGL at specific inhibitory synapses in the basal nucleus (BA), but not lateral nucleus, of the basolateral amygdala. The synapses, termed invaginating synapses, consisted of conventional symmetrical contact and unique perisynaptic invagination of nerve terminals into perikarya. At invaginating synapses, DGLα was preferentially recruited to concave somatic membrane of postsynaptic pyramidal neurons, whereas invaginating presynaptic terminals highly expressed CB 1 , MGL, and CCK. No such molecular convergence was seen for flat perisomatic synapses made by parvalbumin-positive interneurons. On the other hand, DGLα and CB 1 were expressed weakly at axospinous excitatory synapses. Consistent with these morphological data, thresholds for DGLα-mediated depolarizationinduced retrograde suppression were much lower for inhibitory synapses than for excitatory synapses in BA pyramidal neurons. Moreover, depolarization-induced suppression was readily saturated for inhibition, but never for excitation. These findings suggest that perisomatic inhibition by invaginating synapses is a key target of 2-AGmediated control of the excitability of BA pyramidal neurons.retrograde signaling | metabotropic glutamate receptor | muscarinic acetylcholine receptor | depolarization-induced suppression of inhibition | depolarization-induced suppression of excitation M arijuana and other derivatives of the plant Cannabis sativa exert diverse neuropsychopharmacological actions, such as hallucination, euphoria, sedation, memory impairment, anxiolytic effect, appetite stimulation, motor deficit, and pain relief. These actions are mediated by Δ9-tetrahydrocannabinol (Δ9-THC), an active component of cannabis, through its binding to cannabinoid CB 1 receptors (1). CB 1 is particularly abundant in specific types of neurons, is selective to presynaptic elements, and induces shortand long-term forms of retrograde suppression of neurotransmitter release (1). In the brain, 2-arachidonoylglycerol (2-AG) is the major endogenous cannabinoid, synthesized in postsynaptic neurons by sn-1-specific diacylglycerol lipase (DGL) (2), and degraded mainly by monoacylglycerol lipase (MGL) (3, 4). 2-AG synthesis is facilitated when depolarization of postsynaptic neurons is combined with G q/11 -coupled receptor activation (1). Selective postsynaptic expression...

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Whether increased serotonin (5-HT) release in the forebrain attenuates or enhances anxiety has been controversial for over 25 yr. Although there is considerable indirect evidence, there is no direct evidence that indicates a relationship between acute 5-HT release and anxiety. In particular, there is no known method that can reversibly, selectively, and temporally control serotonergic activity. To address this issue, we generated transgenic animals to manipulate the firing rates of central 5-HT neurons by optogenetic methods. Activation of serotonergic neurons in the median raphe nucleus was correlated to enhanced anxiety-like behaviour in mice, whereas activation of serotonergic neurons in the dorsal raphe nucleus had no effect on anxiety-like behaviour. These results indicate that an acute increase in 5-HT release from the median raphe nucleus enhances anxiety.

The present study evaluates juvenile stroke-prone spontaneously hypertensive rats (SHRSP) as an animal model of a developmental disorder, which is diagnosed according to hyperactivity-impulsivity and/or inattention. To characterize behavioural alterations, we studied motor activity, as well as emotional and cognitive behaviours in juvenile SHRSP, with and without methylphenidate, a psychostimulant. Ambulatory and rearing activities in the open-field environment were significantly higher in SHRSP than in Wistar-Kyoto rats (WKY). In the elevated plus maze task, the entries into open arms, as an index of impulsivity, were significantly increased in SHRSP. In the Y-maze task, spontaneous alternation behaviour, as an index of attention, was significantly lowered in the male SHRSP, but not in the female SHRSP, indicating that spontaneous alternation deficit is gender specific. Methylphenidate (0.01-1 mg/kg, i.p.) significantly attenuated locomotor hyperactivity at low doses and dose-dependently improved the spontaneous alternation deficit in SHRSP. Our findings reveal that juvenile SHRSP manifest problematic behaviours resembling a developmental disorder, attention-deficit/hyperactivity disorder (ADHD), namely hyperactivity-impulsivity and/or inattention. Methylphenidate alleviated the behavioural symptoms of hyperactivity and inattention. We propose that juvenile SHRSP are an appropriate animal model of a developmental disorder resembling ADHD, from behavioural and pharmacological perspectives.

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