Cortical Acetylcholine Release Research Articles

Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh–) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh– ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals’ previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh– group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders.

The dopamine D1 receptor plays an important role in motor activity, reward, and cognition. Efforts to develop D1 agonists have been mixed due to poor drug-like properties, tachyphylaxis, and inverted U-shaped dose-response curves. Recently, positive allosteric modulators (PAMs) for the dopamine D1 receptor were discovered and initial pharmacological profiling has suggested that several of the above issues could be addressed with this mechanism. This paper presents an overview of key findings for DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one), which is currently the only D1 PAM for which published in vivo data is available. In vitro studies showed selective potentiation of the human D1 receptor without significant allosteric agonist effects. Due to a species difference in affinity for DETQ, transgenic mice expressing the human D1 receptor (hD1 mice) were used in vivo. In contrast to D1 agonists, DETQ increased locomotor activity over a wide dose-range without inverted U-shaped dose response or tachyphylaxis. DETQ also reversed hypo-activity in mice with dopamine depletion due to reserpine pretreatment, suggesting potential for treatment of motor symptoms in Parkinson's disease. Potential pro-cognitive effects were supported by improved performance in the novel object recognition task, enhanced release of cortical acetylcholine and histamine, and increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB. In addition, DETQ enhanced wakefulness in EEG studies and decreased immobility in the forced-swim test. Together, these results provide support for potential utility of D1 PAMs in the treatment of several neuropsychiatric disorders. LY3154207, a close analog of DETQ, is currently in phase 2 clinical trials.

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate.

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23μg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3h with 0.3mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate.

Paradoxical Emergence: Administration of Subanesthetic Ketamine during Isoflurane Anesthesia Induces Burst Suppression but Accelerates Recovery.

Promoting arousal by manipulating certain brain regions and/or neurotransmitters has been a recent research focus, with the goal of trying to improve recovery from general anesthesia. The current study tested the hypothesis that a single subanesthetic dose of ketamine during isoflurane anesthesia would increase cholinergic tone in the prefrontal cortex and accelerate recovery. Adult male rats were implanted with electroencephalography electrodes (frontal, parietal, and occipital cortex) and a microdialysis guide cannula targeted for the prefrontal cortex. After establishing general anesthesia with isoflurane, animals were randomly assigned to receive a saline control or ketamine injection. When isoflurane was discontinued nearly 90 min after drug or saline administration, recovery from anesthesia was measured by experimenters and blinded observers. During the entire experiment, electrophysiologic signals were recorded and acetylcholine was quantified by high-performance liquid chromatography with electrochemical detection. A single dose of subanesthetic ketamine caused an initial 125% increase in burst suppression ratio (last isoflurane sample: 37.48 ± 24.11% vs. isoflurane after ketamine injection: 84.36 ± 8.95%; P < 0.0001), but also a significant 44% reduction in emergence time (saline: 877 ± 335 s vs. ketamine: 494 ± 108 s; P = 0.0005; n = 10 per treatment). Furthermore, ketamine caused a significant 317% increase in cortical acetylcholine release (mean after ketamine injection: 0.18 ± 0.16 pmol vs. ketamine recovery: 0.75 ± 0.41 pmol; P = 0.0002) after isoflurane anesthesia was discontinued. Administration of subanesthetic doses of ketamine during isoflurane anesthesia increases anesthetic depth but-paradoxically-accelerates the recovery of consciousness, possibly through cholinergic mechanisms.

Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention.

The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity.

Orexin receptor activity in the basal forebrain alters performance on an olfactory discrimination task

Cholinergic innervation of the prefrontal cortex is critical for various forms of cognition, although the efferent modulators contributing to acetylcholine (ACh) release are not well understood. The main source of cortical ACh, the basal forebrain, receives projections from lateral and perifornical hypothalamic neurons releasing the peptides orexin (orexin A; OxA, and orexin B; OxB), of which OxA is hypothesized to play a role in various cognitive functions. We sought to assess one such function known to be susceptible to basal forebrain cholinergic manipulation, olfactory discrimination acquisition, and reversal learning, in rats following intra-basal forebrain infusion of OxA or the orexin 1 receptor (OxR1) antagonist SB-334867. OxA administration facilitated, while OxR1 antagonism impaired performance on both the acquisition and reversal portions of the task. These data suggest that orexin acting in the basal forebrain may be important for cortical-dependant executive functions, possibly through the stimulation of cortical ACh release.

The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens.

Alpha7 and α4β2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer's disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and γ-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition. Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide], a high-affinity α7 nAChR partial agonist, at 0.1mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1mg/kg, but not 0.03 and 0.3mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other α7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective α7 nAChR antagonist, methyllycaconitine (MLA, 1.0mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to α7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC. These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the α7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.

Cortical Cholinergic Input Is Required for Normal Auditory Perception and Experience-Dependent Plasticity in Adult Ferrets

The nucleus basalis (NB) in the basal forebrain provides most of the cholinergic input to the neocortex and has been implicated in a variety of cognitive functions related to the processing of sensory stimuli. However, the role that cortical acetylcholine release plays in perception remains unclear. Here we show that selective loss of cholinergic NB neurons that project to the cortex reduces the accuracy with which ferrets localize brief sounds and prevents them from adaptively reweighting auditory localization cues in response to chronic occlusion of one ear. Cholinergic input to the cortex was disrupted by making bilateral injections of the immunotoxin ME20.4-SAP into the NB. This produced a substantial loss of both p75 neurotrophin receptor (p75(NTR))-positive and choline acetyltransferase-positive cells in this region and of acetylcholinesterase-positive fibers throughout the auditory cortex. These animals were significantly impaired in their ability to localize short broadband sounds (40-500 ms in duration) in the horizontal plane, with larger cholinergic cell lesions producing greater performance impairments. Although they localized longer sounds with normal accuracy, their response times were significantly longer than controls. Ferrets with cholinergic forebrain lesions were also less able to relearn to localize sound after plugging one ear. In contrast to controls, they exhibited little recovery of localization performance after behavioral training. Together, these results show that cortical cholinergic inputs contribute to the perception of sound source location under normal hearing conditions and play a critical role in allowing the auditory system to adapt to changes in the spatial cues available.

Symmetrical Serotonin Release during Asymmetrical Slow-Wave Sleep: Implications for the Neurochemistry of Sleep–Waking States

On land, fur seals predominately display bilaterally synchronized electroencephalogram (EEG) activity during slow-wave sleep (SWS), similar to that observed in all terrestrial mammals. In water, however, fur seals exhibit asymmetric slow-wave sleep (ASWS), resembling the unihemispheric slow-wave sleep of odontocetes (toothed whales). The unique sleeping pattern of fur seals allows us to distinguish neuronal mechanisms mediating EEG changes from those mediating behavioral quiescence. In a prior study we found that cortical acetylcholine release is lateralized during ASWS in the northern fur seal, with greater release in the hemisphere displaying low-voltage (waking) EEG activity, linking acetylcholine release to hemispheric EEG activation (Lapierre et al. 2007). In contrast to acetylcholine, we now report that cortical serotonin release is not lateralized during ASWS. Our data demonstrate that bilaterally symmetric levels of serotonin are compatible with interhemispheric EEG asymmetry in the fur seal. We also find greatly elevated levels during eating and hosing the animals with water, suggesting that serotonin is more closely linked to bilateral variables, such as axial motor and autonomic control, than to the lateralized cortical activation manifested in asymmetrical sleep.

The Presynaptic Choline Transporter Imposes Limits on Sustained Cortical Acetylcholine Release and Attention

Functional variation in the gene encoding the presynaptic choline transporter (CHT) has been linked to attention-deficit/hyperactivity disorder. Here, we report that a heterozygous deletion in the CHT gene in mice (CHT(+/-)) limits the capacity of cholinergic neurons to sustain acetylcholine (ACh) release and attentional performance. Cortical microdialysis and amperometric methods revealed that, whereas wild-type and CHT(+/-) animals support equivalent basal ACh release and choline clearance, CHT(+/-) animals exhibit a significant inability to elevate extracellular ACh following basal forebrain stimulation, in parallel with a diminished choline clearance capacity following cessation of stimulation. Consistent with these findings, the density of CHTs in cortical synaptosomal plasma membrane-enriched fractions from unstimulated CHT(+/-) animals matched those observed in wild-type animals despite reductions in CHT levels in total extracts, achieved via a redistribution of CHT from vesicle pools. As a consequence, in CHT(+/-) animals, basal forebrain stimulation was unable to mobilize wild-type quantities of CHT to the plasma membrane. In behavioral studies, CHT(+/-) mice were impaired in performing a sustained attention task known to depend on cortical cholinergic activity. In wild-type mice, but not CHT(+/-) mice, attentional performance increased the density of CHTs in the synaptosomal membrane in the right frontal cortex. Basal CHT levels in vesicle-enriched membranes predicted the degree of CHT mobilization as well as individual variations in performance on the sustained attention task. Our findings demonstrate biochemical and physiological alterations that underlie cognitive impairments associated with genetically imposed reductions in choline uptake capacity.

CHF5074 restores visual memory ability and pre‐synaptic cortical acetylcholine release in pre‐plaque Tg2576 mice

CHF5074, a new microglial modulator, attenuates memory deficit in Alzheimer's disease transgenic mice. In this study, the effect of an acute or subacute CHF5074 treatment on in vivo novel object recognition test and on [³H]Acetylcholine (ACh) and GABA release in pre-plaque (7-month-old) Tg2576 mice have been compared with those induced by the γ-secretase inhibitor LY450139 (semagacestat). Vehicle-treated Tg2576 mice displayed an impairment of recognition memory compared with wild-type animals. This impairment was recovered in transgenic animals acutely treated with CHF5074 (30 mg/kg), while LY450139 (1, 3, 10 mg/kg) was ineffective. In frontal cortex synaptosomes from vehicle-treated Tg2576 mice, K⁺-evoked [³H]ACh release was lower than that measured in wild-type mice. This reduction was absent in transgenic animals subacutely treated with CHF5074 (30 mg/kg daily for 8 days), while it was slightly, not significantly, amplified by LY450139 (3 mg/kg daily for 8 days). There were no differences between the groups on spontaneous [³H]ACh release as well as spontaneous and K⁺-evoked GABA release. These results suggest that CHF5074 has beneficial effects on visual memory and cortical cholinergic dysfunctions in pre-plaque Tg2576 mice. Together with previous findings, these data suggest that CHF5074 could be a possible candidate for early Alzheimer's disease therapeutic regimens.

The missing link between long-term stimulation of nicotinic receptors and the increases of acetylcholine release and vasodilation in the cerebral cortex of aged rats

In adult rats (4-9 months), chronic nicotine infusion increases the basal level of acetylcholine (ACh) release in the cerebral cortex and enhances responses of cortical ACh release and cortical vasodilation elicited by nucleus basalis of Meynert (NBM) stimulation. In the present study, we examined whether these effects of nicotine are detected in aged rats. Aged rats (27-30 months) received sustained subcutaneous nicotine (100 μg/kg/h) or saline for 14 days. Under urethane anesthesia, ACh release and regional blood flow in the parietal cortex were measured. The basal level of ACh release in the cerebral cortex was not changed by chronic nicotine. In addition, the magnitudes of ACh release and vasodilation by NBM stimulation were similar between the saline-treated and nicotine-treated groups. The lack of an effect of chronic nicotine in aged rats may be due to a decrease in nicotinic receptors in the cerebral cortex during aging (Nordberg et al., J Neurosci Res 31:103-111, 1992).

Olanzapine causes a leptin-dependent increase in acetylcholine release in mouse prefrontal cortex.

The atypical antipsychotic olanzapine is used effectively for treating symptoms of schizophrenia and bipolar disorder. Unwanted effects of olanzapine include slowing of the electroencephalogram (EEG) during wakefulness and increased circulating levels of leptin. The mechanisms underlying the desired and undesired effects of olanzapine are poorly understood. Sleep and wakefulness are modulated by acetylcholine (ACh) in the prefrontal cortex, and leptin alters cholinergic transmission. This study tested the hypothesis that olanzapine interacts with leptin to regulate ACh release in the prefrontal cortex. Within/between subjects. University of Michigan. Adult male C57BL/6J (B6) mice (n = 33) and B6.V-Lep(ob) (leptin-deficient) mice (n = 31). Olanzapine was delivered to the prefrontal cortex by microdialysis. Leptin-replacement in leptin-deficient mice was achieved using subcutaneous micro-osmotic pumps. Olanzapine caused a concentration-dependent increase in ACh release in B6 and leptin-deficient mice. Olanzapine was 230-fold more potent in leptin-deficient than in B6 mice for increasing ACh release, yet olanzapine caused a 51% greater ACh increase in B6 than in leptin-deficient mice. Olanzapine had no effect on recovery time from general anesthesia. Olanzapine increased EEG power in the delta (0.5-4 Hz) range. Thus, olanzapine dissociated the normal coupling between increased cortical ACh release, increased behavioral arousal, and EEG activation. Leptin replacement significantly enhanced (75%) the olanzapine-induced increase in ACh release. Replacing leptin by systemic administration restored the olanzapine-induced enhancement of ACh release in the prefrontal cortex of leptin-deficient mouse.

Adult mouse basal forebrain harbors two distinct cholinergic populations defined by their electrophysiology

We performed whole-cell recordings from basal forebrain (BF) cholinergic neurons in transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the choline acetyltransferase promoter. BF cholinergic neurons can be differentiated into two electrophysiologically identifiable subtypes: early and late firing neurons. Early firing neurons (∼70%) are more excitable, show prominent spike frequency adaptation and are more susceptible to depolarization blockade, a phenomenon characterized by complete silencing of the neuron following initial action potentials. Late firing neurons (∼30%), albeit being less excitable, could maintain a tonic discharge at low frequencies. In voltage clamp analysis, we have shown that early firing neurons have a higher density of low voltage activated (LVA) calcium currents. These two cholinergic cell populations might be involved in distinct functions: the early firing group being more suitable for phasic changes in cortical acetylcholine release associated with attention while the late firing neurons could support general arousal by maintaining tonic acetylcholine levels.

Cholinergic Enhancement Augments Magnitude and Specificity of Visual Perceptual Learning in Healthy Humans

Learning through experience underlies the ability to adapt to novel tasks and unfamiliar environments. However, learning must be regulated so that relevant aspects of the environment are selectively encoded. Acetylcholine (ACh) has been suggested to regulate learning by enhancing the responses of sensory cortical neurons to behaviorally relevant stimuli. In this study, we increased synaptic levels of ACh in the brains of healthy human subjects with the cholinesterase inhibitor donepezil (trade name: Aricept) and measured the effects of this cholinergic enhancement on visual perceptual learning. Each subject completed two 5 day courses of training on a motion direction discrimination task, once while ingesting 5 mg of donepezil before every training session and once while placebo was administered. We found that cholinergic enhancement augmented perceptual learning for stimuli having the same direction of motion and visual field location used during training. In addition, perceptual learning with donepezil was more selective to the trained direction of motion and visual field location. These results, combined with previous studies demonstrating an increase in neuronal selectivity following cholinergic enhancement, suggest a possible mechanism by which ACh augments neural plasticity by directing activity to populations of neurons that encode behaviorally relevant stimulus features.

Microinjection of Propofol into the Perifornical Area Induces Sedation with Decreasing Cortical Acetylcholine Release in Rats

Among many neurotransmitter systems in the central nervous system, the cholinergic system has been shown to contribute to propofol's sedative/anesthetic effects, because it has been shown that cholinesterase inhibitor reverses the level of propofol-induced unconsciousness in humans. It has been reported that intraperitoneal injection of propofol induced sedative/anesthetic actions and decreased the release of acetylcholine (Ach) from the rat cortex. However, the sites of action of propofol in the cholinergic pathway and its related pathways remain unresolved. We studied whether microinjection of propofol into the nuclei in the cholinergic pathway and its related pathways may induce sedation and decrease Ach from the cortex. Thirty-seven male Wistar rats weighing 270 to 320 g were used. Almost 5 days before the experiments, 23 rats anesthetized with pentobarbital (50 mg/kg) were outfitted with an electroencephalogram (EEG) socket, a microdialysis cannula in the cortex, and an intraperitoneal tube or a microinjection tube into the basal forebrain (BF), the perifornical area (Pef), or the striatum. The Ach effluxes in the somatosensory cortex were detected using in vivo intracerebral microdialysis in freely moving rats. Once basal levels of Ach were stabilized, samples were collected every 20 minutes and measured by high-performance liquid chromatography. In the intraperitoneal group, propofol was cumulatively administered (10, 30, and 100 mg/kg) into the peritoneal cavity. In the microinjection groups, propofol (40 ng in 0.2 microL) was administered into the BF, the Pef, or the striatum (control), and the cortical changes in Ach efflux and EEG were observed for 2 hours. In another 14 rats, the sedative/anesthetic score was obtained after intraperitoneal, Pef, or striatal injection of propofol. The placement of the tip of the microdialysis probe and the microinjection tube was confirmed by histological examination. Intraperitoneal injection of propofol dose-dependently decreased the Ach efflux and induced light sedative to moderate anesthetic states. Loss of righting reflex was observed with significant increases in the relative alpha-power band at 100 mg/kg propofol. Microinjection of propofol into the BF significantly decreased the cortical Ach efflux to -40.2% + or - 19.9% at 40 to 60 minutes. However, there was no difference in the total Ach efflux for 2 hours between BF and control groups. In contrast, microinjection of propofol into the Pef immediately decreased the Ach efflux at 0 to 20 min and maximally to -59.3 + or - 20.4 at 100 to 120 minutes. The total Ach efflux in the Pef microinjection group was significantly less than that in the control group. The same dose of propofol injected into the Pef induced light to deep sedation. There was no significant change in the relative EEG power band between BF or Pef and control groups. The nuclei in the Pef are, at least in part, responsible for the sedative action of propofol in rats.

Pattern visual stimulation elicits cortical acetylcholine release with regional specificity in the anesthetized rat

Pattern visual stimulation elicits cortical acetylcholine release with regional specificity in the anesthetized rat

Activation of the basal forebrain by the orexin/hypocretin neurones

The orexin neurones play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurones promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurones may promote arousal by exciting cortically projecting neurones of the BF. Orexin fibres synapse on BF cholinergic neurones and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurones, induces cortical release of acetylcholine and promotes wakefulness. The orexin neurones also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurones that project to the cortex. Cholinergic neurones were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurones that project to the cortex seem to comprise at least two populations with some directly excited by orexin-A that may represent wake-active, GABAergic neurones, whereas others did not respond to orexin-A but were inhibited by dynorphin and may be sleep-active, GABAergic neurones. This evidence suggests that the BF is a key site through which orexins activate the cortex and promote behavioural arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance.

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

After oral administration, the nonimidazole histamine H(3) receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H(3) receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components.

Orexin/hypocretin modulation of the basal forebrain cholinergic system: Role in attention

The basal forebrain cholinergic system (BFCS) plays a role in several aspects of attentional function. Activation of this system by different afferent inputs is likely to influence how attentional resources are allocated. While it has been recognized for some time that the hypothalamus is a significant source of projections to the basal forebrain, the phenotype(s) of these inputs and the conditions under which their regulation of the BFCS becomes functionally relevant are still unclear. The cell bodies of neurons expressing orexin/hypocretin neuropeptides are restricted to the lateral hypothalamus and contiguous perifornical area but have widespread projections, including to the basal forebrain. Orexin fibers and both orexin receptor subtypes are distributed in cholinergic parts of the basal forebrain, where application of orexin peptides increases cell activity and cortical acetylcholine release. Furthermore, disruption of orexin signaling in the basal forebrain impairs the cholinergic response to an appetitive stimulus. In this review, we propose that orexin inputs to the BFCS form an anatomical substrate for links between arousal and attention, and that these interactions might be particularly important as a means by which interoceptive cues bias allocation of attentional resources toward related exteroceptive stimuli. Dysfunction in orexin–acetylcholine interactions may play a role in the arousal and attentional deficits that accompany neurodegenerative conditions as diverse as drug addiction and age-related cognitive decline.