Acetylcholine Efflux Research Articles

In vivo neurochemical evidence that delta1-, delta2- and mu2-opioid receptors, but not mu1-opioid receptors, inhibit acetylcholine efflux in the nucleus accumbens of freely moving rats

Cholinergic neurons in the nucleus accumbens express delta- and mu-opioid receptors that are thought to inhibit neural activity. Delta- and mu-opioid receptors are divided into delta1- and delta2-opioid receptors and mu1- and mu2-opioid receptors, respectively. We analysed the roles of delta- and mu-opioid receptor subtypes in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. Other than naloxonazine, given intraperitoneally, delta- and mu-opioid receptor ligands were administered intracerebrally through the dialysis probe. Doses of these compounds indicate total amount (mol) over an infusion time of 30–60min. To monitor basal acetylcholine, a low concentration of physostigmine (50nM) was added to the perfusate. The delta1-opioid receptor agonist DPDPE (3 and 300pmol) and delta2-opioid receptor agonist deltorphin II (3 and 30pmol) decreased accumbal acetylcholine in a dose-related manner. DPDPE (300pmol)- and deltorphin II (3pmol)-induced reductions in acetylcholine were each inhibited by the delta1-opioid receptor antagonist BNTX (0.3pmol) and delta2-opioid receptor antagonist naltriben (15pmol), respectively. The mu-opioid receptor agonists endomorphin-1 and endomorphin-2 (6 and 30nmol) decreased acetylcholine in a dose-related manner. Endomorphin-1- and endomorphin-2 (30nmol)-induced reductions in acetylcholine were prevented by the mu-opioid receptor antagonist CTOP (3nmol). The mu1-opioid receptor antagonist naloxonazine (15mg/kg ip), which inhibits endomorphin-1 (15nmol)-induced accumbal dopamine efflux, did not alter endomorphin-1- or endomorphin-2 (30nmol)-induced reductions in acetylcholine efflux. This study provides in vivo evidence for delta1-, delta2- and mu2-opioid receptors, but not mu1-opioid receptors, that inhibit accumbal cholinergic neural activity.

PM430. Blonanserin reversed phencyclidine-induced novel object recognition deficit and induced cortical dopamine and acetylcholine efflux through dopamine D3 receptor antagonism

PM430. Blonanserin reversed phencyclidine-induced novel object recognition deficit and induced cortical dopamine and acetylcholine efflux through dopamine D3 receptor antagonism

PM319. δ1, δ2 and μ2, but not μ1 receptors, exert an inhibitory role in regulation of acetylcholine efflux in the nucleus accumbens of freely moving rats

PM319. δ1, δ2 and μ2, but not μ1 receptors, exert an inhibitory role in regulation of acetylcholine efflux in the nucleus accumbens of freely moving rats

Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior

Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time points: 24-h or 2-weeks post-exercise. It was found that only after the 2-week adaption period did exercise lead to an interrelated sequence of events in PTD rats that included: (1) restored spatial working memory; (2) rescued behaviorally-stimulated hippocampal acetylcholine efflux; and (3) within the medial septum/diagonal band, the re-emergence of the cholinergic (choline acetyltransferase [ChAT+]) phenotype, with the greatest change occurring in the ChAT+/nestin+ neurons. Furthermore, in control rats, exercise followed by a 2-week adaption period improved hippocampal acetylcholine efflux and increased the number of neurons co-expressing the ChAT and nestin phenotype. These findings demonstrate a novel mechanism by which exercise can modulate the mature cholinergic/nestin neuronal phenotype leading to improved neurotransmitter function as well as enhanced learning and memory.

Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.

Effects of lisdexamfetamine alone and in combination with s-citalopram on acetylcholine and histamine efflux in the rat pre-frontal cortex and ventral hippocampus.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by poor attention, impulse control and hyperactivity. A significant proportion of ADHD patients are also co-morbid for other psychiatric problems including mood disorders and these patients may be managed with a combination of psychostimulants and anti-depressants. While it is generally accepted that enhanced catecholamine signalling via the action of psychostimulants is likely responsible for the cognitive improvement in ADHD, other neurotransmitters including acetylcholine and histamine may be involved. In the present study, we have examined the effect of lisdexamfetamine dimesylate (LDX), an amphetamine pro-drug that is approved for the treatment of ADHD on acetylcholine and histamine efflux in pre-frontal cortex and hippocampus alone and in combination with the anti-depressant s-citalopram. LDX increased cortical acetylcholine efflux, an effect that was not significantly altered by co-administration of s-citalopram. Cortical and hippocampal histamine were markedly increased by LDX, an effect that was attenuated in the hippocampus but not in pre-frontal cortex when co-administered with s-citalopram. Taken together, these results suggest that efflux of acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially influenced by the co-administration of s-citalopram. Attention deficit hyperactivity disorder (ADHD) is characterized by poor attention, impulse control and hyperactivity. Some ADHD patients are also co-morbid for mood disorders and may be managed with psychostimulants (e.g. lisdexamfetamine, LDX) and anti-depressants (e.g. s-citalopram). LDX increased the efflux of acetylcholine and histamine, neurotransmitters involved in cognitive function, which were differentially influenced when co-administered with s-citalopram. Acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially affected by the co-administration of s-citalopram.

The effects of postnatal alcohol exposure and galantamine on the context pre-exposure facilitation effect and acetylcholine efflux using in vivo microdialysis

Fetal alcohol spectrum disorders (FASD) are characterized by damage to multiple brain regions, including the hippocampus, which is involved in learning and memory. The acetylcholine neurotransmitter system provides major input to the hippocampus and is a possible target of developmental alcohol exposure. Alcohol (3.0 g/kg/day) was administered via intubation to male rat pups (postnatal day [PD] 2–10; ethanol-treated [ET]). Controls received a sham intubation (IC) or no treatment (NC). Acetylcholine efflux was measured using in vivo microdialysis (PD 32–35). ET animals were not different at baseline, but had decreased K+/Ca2+-induced acetylcholine efflux compared to NC animals and an enhanced acetylcholine response to galantamine (acetylcholinesterase inhibitor; 2.0 mg/kg) compared to both control groups. A separate cohort of animals was tested in the context pre-exposure facilitation effect task (CPFE; PD 30-32) following postnatal alcohol exposure and administration of galantamine (2.0 mg/kg; PD 11-30). Neither chronic galantamine nor postnatal alcohol exposure influenced performance in the CPFE task. Using immunohistochemistry, we found that neither alcohol exposure nor behavioral testing significantly altered the density of vesicular acetylcholine transporter or alpha7 nicotinic acetylcholine receptor in the ventral hippocampus (CA1). In the medial septum, the average number of choline acetyltransferase (ChAT+) cells was increased in ET animals that displayed the context-shock association; there were no changes in IC and NC animals that learned the context-shock association or in any animals that were in the control task that entailed no learning. Taken together, these results indicate that the hippocampal acetylcholine system is significantly disrupted under conditions of pharmacological manipulations (e.g., galantamine) in alcohol-exposed animals. Furthermore, ChAT was up‑regulated in ET animals that learned the CPFE, which may account for their ability to perform this task. In sum, developmental alcohol exposure may disrupt learning and memory in adolescence via a cholinergic mechanism.

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.

Medial Septum-Diagonal Band of Broca (MSDB) GABAergic Regulation of Hippocampal Acetylcholine Efflux Is Dependent on Cognitive Demands

The septohippocampal pathway contains cholinergic, GABAergic, and glutamatergic projections and has an established role in learning, memory, and hippocampal theta rhythm. Both GABAergic and cholinergic neurons in the medial septum-diagonal band of Broca (MSDB) have been associated with spatial memory, but the relationship between the two neuronal populations is not fully understood. The present study investigated the effect of selective GABAergic MSDB lesions on hippocampal acetylcholine (ACh) efflux and spatial memory during tasks that varied in memory demand. Male Sprague Dawley rats were given GABAergic lesions of the MSDB using GAT1-saporin (GAT1-SAP) and examined on spontaneous exploration (Experiment 1) and non-matching to position without (NMTP; Experiment 2) and with a delay (DNMTP; Experiment 3), while concurrently using in vivo microdialysis to measure hippocampal ACh efflux. Intraseptal GAT1-SAP treatment did not alter baseline or behaviorally stimulated hippocampal ACh efflux or maze exploration (Experiment 1). Moreover, GAT1-SAP did not alter evoked hippocampal ACh efflux related to NMTP nor did it impair working memory in NMTP (Experiment 2). In contrast, both ACh efflux and performance in DNMTP were impaired by intraseptal GAT1-SAP. Thus, GABAergic MSDB neurons are important for spatial working memory and modulate hippocampal ACh efflux under conditions of high memory load. The relationship between the septohippocampal cholinergic and GABAergic systems and working memory will be discussed.

The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission. In the current study, the effects of partial nAChR agonist and 5-HT3 receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats. R3487/MEM3454, at doses of 0.1-10mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose-response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0mg/kg), completely blocked RG3487-induced (0.45mg/kg) DA but not ACh efflux, while the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (1.0mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1mg/kg), but not typical APD haloperidol (0.1mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3mg/kg), olanzapine (1.0mg/kg), and quetiapine (30mg/kg), also produced additive effects on DA efflux. These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5‐HT)2A and DA D2 antagonism and 5‐HT1A partial agonism

Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine.

Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration

The Alzheimer's disease (AD) mouse model Tg2576 overexpresses an AD associated mutant variant of human APP and accumulates amyloid beta (Aβ) in an age-dependent manner. Using the selective cholinergic immunotoxin mu p75-saporin (SAP), we induced a partial basal forebrain cholinergic degeneration (BFCD) in 3 months old male Tg2576 mice to co-express cholinergic degeneration with Aβ overexpression as these characteristics constitutes key hallmarks of AD. At 9 months, SAP lesioned Tg2576 mice were cognitively impaired in two spatial paradigms addressing working memory and mid to long-term memory. Conversely, there was no deterioration of cognitive functioning in sham lesioned Tg2576 mice or wild type littermates (wt) receiving the immunotoxin. At 10 months of age, release of acetylcholine (ACh) was addressed by microdialysis in conscious mice. Scopolamine-induced increases in hippocampal ACh efflux was significantly reduced in SAP lesioned Tg2576 mice compared to sham lesioned Tg2576 mice. Intriguingly, there was no significant difference in ACh efflux between wt treatment groups. Following SAP treatment, choline acetyltransferase activity was reduced in the hippocampus and frontal cortex and the reduction was comparable between groups. Our results suggest that partial BFCD acts collectively with increased levels of Aβ to induce cognitive decline and to compromise cholinergic release. Tg2576 mice with BFCD may constitute a new and suitable AD mouse model to study the interrelations between cholinergic deficits and amsyloid deposition.

Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia

The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.

Clonidine Induces Sedation Through Acting on the Perifornical Area and the Locus Coeruleus in Rats

The main target site of action for the sedative clonidine (CLO), an α2 adrenoceptor agonist, has been considered to be the locus coeruleus (LC). However, previous reports suggest other sites of action of CLO than the LC. Our previous studies suggested that the neuronal activities in the perifornical area (Pef) could influence the sedative or the anesthetic level induced by anesthetics. Therefore, we examined whether microinjection of CLO into the Pef might induce sedation in rats. Fifty-five Wistar rats were used. The cortical norepinephrine (NE) and acetylcholine (ACh) effluxes were detected using microdialysis and measured by high-performance liquid chromatography in samples collected every 20 minutes. First, we injected CLO (100, 300, and 1000 μg/kg cumulative doses) intraperitoneally (IP) and observed the changes in NE or ACh efflux. Second, we injected CLO (4.8 μg in 0.2 μL) or saline (0.2 μL) into the LC or the Pef and observed the changes in NE or ACh efflux for 2 hours. Finally, a sedative/anesthetic score was obtained after IP, LC or Pef microinjection of CLO. IP injection of CLO induced sedation and resulted in a dose-dependent attenuation of the cortical effluxes of both NE and ACh (P<0.001). Microinjection of CLO either into the LC or the Pef induced sedation and significantly decreased the cortical NE efflux (P<0.001). Cortical ACh efflux was significantly reduced by microinjection of CLO into the Pef but not by microinjection into the LC (P<0.05). The Pef and the LC are responsible for the sedative action of CLO in rats.

The 5-HT6 antagonist Lu AE58054 potentiates the effects of the acetylcholinesterase inhibitor donepezil on hippocampal extracellular acetylcholine efflux and oscillatory activity

The 5-HT6 antagonist Lu AE58054 potentiates the effects of the acetylcholinesterase inhibitor donepezil on hippocampal extracellular acetylcholine efflux and oscillatory activity

Aging-related deficits in orexin/hypocretin modulation of the septohippocampal cholinergic system.

The medial septum (MS) of the basal forebrain contains cholinergic neurons that project to the hippocampus, support cognitive function, and are implicated in age-related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate basal forebrain cholinergic neurons and provide direct inputs to the hippocampus. However, the precise role of orexin in modulating hippocampal cholinergic transmission--and how these interactions are altered in aging--is unknown. Here, orexin A was administered to CA1 and the MS of young (3-4 months) and aged (27-29 months) Fisher 344/Brown Norway rats, and hippocampal acetylcholine efflux was analyzed by in vivo microdialysis. At both infusion sites, orexin A dose-dependently increased hippocampal acetylcholine in young, but not aged rats. Moreover, immunohistochemical characterization of the MS revealed no change in cholinergic cell bodies in aged animals, but a significant decrease in orexin fiber innervation to cholinergic cells. These findings indicate that: (1) Orexin A modulates hippocampal cholinergic neurotransmission directly and transsynaptically in young animals, (2) Aged animals are unresponsive to orexin A, and (3) Aged animals undergo an intrinsic reduction in orexin innervation to cholinergic cells within the MS. Alterations in orexin regulation of septohippocampal cholinergic activity may contribute to age-related dysfunctions in arousal, learning, and memory.

Hippocampal neurotransmitter efflux during one-trial novel object recognition in rats

Several lines of evidence point to a role for the hippocampal formation and contiguous temporal lobe structures in a variety of learning and memory paradigms. Presumably, these cognitive phenomena are mediated (and accompanied) by dynamic changes in neurochemical transmission that may differ between learning and recall phases. However, the neurotransmitter correlates of most memory-related tasks have not been thoroughly investigated. Here we used a one-trial object recognition paradigm paired with in vivo microdialysis to assess hippocampal acetylcholine (ACh), glutamate and GABA efflux when rats were exposed to familiar objects, and when given the option to explore familiar and novel objects. Rats preferentially explored the novel object over the familiar one when presented with the option. Regardless of object familiarity, object exploration was accompanied by an increase in hippocampal ACh efflux, while GABA efflux was unaffected. However, glutamate efflux was not increased above baseline levels by presentation of familiar objects, but was significantly enhanced in the presence of the novel object. These data suggest that the hippocampus, and in particular, hippocampal glutamate, may be involved in memory processes during novelty recognition paradigms.

Sustaining high acetylcholine levels in the frontal cortex, but not retrosplenial cortex, recovers spatial memory performance in a rodent model of diencephalic amnesia.

Although the thalamus and/or mammillary bodies are the primary sites of neuropathology in cases of diencephalic amnesia such as Wernicke Korsakoff Syndrome (WKS), there is also functional deactivation of certain cortical regions that contribute to the cognitive dysfunction. Acetylcholine (ACh) is a key neurotransmitter that modulates neural processing within the cortex and between the thalamus and cortex. In the pyrithiamine-induced thiamine deficiency (PTD) rat model of WKS, there are significant reductions in cholinergic innervation and behaviorally stimulated ACh efflux in the frontal (FC) and retrosplenial (RSC) cortices. In the present study, ACh released levels were site-specifically amplified with physostigmine (0.5 μg, 1.0 μg) in the FC and the RSC, which was confirmed with in vivo microdialysis. Although physostigmine sustained high ACh levels in both cortical regions, the effects on spatial memory, assessed by spontaneous alternation, were different as a function of region (FC, RSC) and treatment (PTD, pair-fed [PF]). Higher ACh levels in the FC recovered the rate of alternation in PTD rats as well as reduced arm-reentry perseverative errors. However, higher ACh levels within the FC of PF rats exacerbated arm-reentry perseverative errors without significantly affecting alternation rates. Maintaining high ACh levels in the RSC had no procognitive effects in PTD rats, but rather impaired alternation behavior in PF rats. These results demonstrate that diverse cortical regions respond differently to intensified ACh levels-and the effects are dependent on thalamic pathology. Thus, pharmacotherapeutics aimed at enhancing cognitive functions must account for the unique features of cortical ACh stimulation and the connective circuitry with the thalamus.

The human OCTN1 (SLC22A4) reconstituted in liposomes catalyzes acetylcholine transport which is defective in the mutant L503F associated to the Crohn's disease

The organic cation transporter (OCTN1) plays key roles in transport of selected organic cations, but understanding of its biological functions remains limited by restricted knowledge of its substrate targets. Here we show capacity of human OCTN1-reconstituted proteoliposomes to mediate uptake and efflux of [3H]acetylcholine, the Km of transport being 1.0mM with Vmax of 160nmol⋅mg−1protein⋅min−1. OCTN1-mediated transport of this neurotransmitter was time-dependent and was stimulated by intraliposomal ATP. The transporter operates as uniporter but translocates acetylcholine in both directions. [3H]acetylcholine uptake was competitively inhibited by tetraethylammonium, γ-butyrobetaine and acetylcarnitine, and was also inhibited by various polyamines. Decreasing intraliposomal ATP concentrations increased OCTN Km for acetylcholine, but Vmax was unaffected. Evaluation of the acetylcholine transporter properties of a variant form of OCTN1, the Crohn's disease-associated 503F variant, revealed time course, Km and Vmax for acetylcholine uptake to be comparable to that of wild-type OCTN1. Km for acetylcholine efflux was also comparable for both OCTN1 species, but Vmax of OCTN1 503F-mediated acetylcholine efflux (1.9nmol⋅mg−1protein⋅min−1) was significantly lower than that of wild-type OCTN1 (14nmol⋅mg−1protein⋅min−1). These data identify a new transport role for OCTN1 and raise the possibility that its involvement in the non-neuronal acetylcholine system may be relevant to the pathogenesis of Crohn's disease.

Anterior thalamic lesions alter both hippocampal-dependent behavior and hippocampal acetylcholine release in the rat

The anterior thalamic nuclei (ATN) are important for learning and memory as damage to this region produces a persistent amnestic syndrome. Dense connections between the ATN and the hippocampus exist, and importantly, damage to the ATN can impair hippocampal functioning. Acetylcholine (ACh) is a key neurotransmitter in the hippocampus, and in vivo measures of ACh are correlated to learning and memory performance. In the present study, complete lesions of the ATN impaired performance on two measures of hippocampal-dependent learning and memory (spontaneous alternation and delayed alternation) and severely disrupted behaviorally evoked ACh efflux within the hippocampus of adult male rats. In contrast, incomplete ATN lesions did not impair spontaneous alternation performance but did impair delayed alternation performance while blunting hippocampal ACh efflux. Interestingly, ATN lesions of any size did not affect basal concentrations of ACh in the hippocampus. These results demonstrate that the ATN have the capacity to modulate behaviorally relevant neuronal transmission within the hippocampus.