Cortical Cholinergic Transmission Research Articles

Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids.

Recent research linking choline-containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration. We examined the neuroprotective potential of sub-chronic treatments with the cannabinoid agonist WIN55,212-2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG-saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [35S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI-mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg-AD mouse model. Degeneration, induced by 192IgG-saporin, of baso-cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212-2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery. We hypothesise that WIN55,212-2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline-containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction.

Role of hippocampal and prefrontal cortical cholinergic transmission in combination therapy valproate and cannabidiol in memory consolidation in rats: involvement of CREB- BDNF signaling pathways.

Cognitive disorders are associated with valproate and drugs used to treat neuropsychological diseases. Cannabidiol (CBD) has beneficial effects on cognitive function. This study examined the effects of co-administration of CBD and valproate on memory consolidation, cholinergic transmission, and cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling pathway in the prefrontal cortex (PFC) and hippocampus (HPC). One-trial, step-through inhibitory test was used to evaluate memory consolidation in rats. The intra-CA1 injection of physostigmine and atropine was performed to assess the role of cholinergic transmission in this co-administration. Phosphorylated CREB (p-CREB)/CREB ratio and BDNF levels in the PFC and HPC were evaluated. Post-training intraperitoneal (i.p.) valproate injection reduced memory consolidation; however, post-training co-administration of CBD with valproate ameliorated memory impairment induced by valproate. Post-training intra-CA1 injection of physostigmine at the ineffective doses in memory consolidation (0.5 and 1µg/rat), plus injection of 10mg/kg of CBD as an ineffective dose, improved memory loss induced by valproate, which was associated with BDNF and p-CREB level enhancement in the PFC and HPC. Conversely, post-training intra-CA1 injection of ineffective doses of atropine (1 and 2µg/rat) reduced the positive effects of injection of CBD at a dose of 20mg/kg on valproate-induced memory loss associated with BDNF and p-CREB level reduction in the PFC and HPC. The results indicated a beneficial interplay between valproate and CBD in the process of memory consolidation, which probably creates this interaction through the BDNF-CREB signaling pathways in the cholinergic transmission of the PFC and HPC regions.

Characterization of vascular dementia with TMS: A systematic review and meta‐analysis

AbstractBackgroundVascular dementia (VaD) is the second most common cause of dementia. However, the variety of lesions in different vessels make VaD heterogeneous. VaD has been studied using transcranial magnetic stimulation (TMS) in patients with multi‐infarct dementia, subcortical ischemic vascular dementia (SIVD), and with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). There is, however, some controversy about the reported impairment in cortical excitability and cortical circuits in VaD(1–5). Therefore, we reviewed systematically TMS characterization in patients with VaD.MethodWe conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to VaD and TMS and was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies, comparing any type of VaD to healthy controls (HC) using TMS. Case reports and series were excluded. Risk of bias was assessed using QUADAS. Meta‐analyses comparing various TMS parameters between VaD and HC were conducted. Demographic data (age, sex, comorbidities, years of education, onset age, diagnosis information), subtype of vascular dementia, reference standard, and TMS parameters were extracted.ResultAfter duplicates were removed our search yielded 216 results. After applying the eligibility criteria, 26 articles were fully screened and finally 8 articles were reviewed and included in the meta‐analysis(4–11). A total of 145 patients with VaD were analyzed, and most of them had SIVD (69.65%) and CADASIL (11.72%); 140 HC were also analyzed. When compared VaD patients to HC, the mean differences of resting motor threshold (RMT) and short‐latency afferent inhibition (SAI) values were statistically significant (Fig 1‐2).ConclusionThis is the first systematic review to describe the differences of TMS parameters between patients with VaD and HC. RMT and SAI values were significantly altered in patients with VaD suggesting that both cortical excitability and cholinergic transmission are affected. These parameters could be further used to understand the impact of vascular events in neurotransmission. Furthermore, because of the difficulty of detecting vascular lesions in structural imaging studies, TMS characterization may allow a clearer diagnosis of VaD.

Implication of cholinergic transmission in rat model of spinal cord injury: A potential therapeutic target

Purpose: To assess the involvement of cholinergic transmission in the etiology of spinal cord injury (SCI) in a rat model.
 Methods: Male adult rats (Wistar) with body weight ranging from 200 to 250 g were equally allocated into 2 groups: test (SCI) and control (non-SCI). Clipping method was used to induce SCI. Thereafter, motor function was measured using rotarod. Each rat was sacrificed by decapitation, and the cortex was excised for use in the study of the involvement of cholinergic transmission in SCI using real time quantitative polymerase chain reaction (RT-PCR) and western blot analysis (WBA).
 Results: Significant upregulation in acetylcholine esterase (AChE) was observed in the cortex of SCI rats, relative to non-SCI rats (p < 0.005). Results from cholinergic receptor binding studies revealed significantly decreased maximum binding (Bmax) and dissociation constant (kd) values for muscarinic receptors in SCI rats, when compared to non-SCI rats. Moreover, the reduction in intensity of cholinergic receptors was significantly greater in the cerebral cortex of SCI group compared to non-SCI group.
 Conclusion: The results of this study suggested that the reduction in cortical cholinergic transmission impairs motor functions in SCI, and plays a major role in motor deficits in SCI.

Cholinergic Signaling Dynamics and Cognitive Control of Attention.

The central cholinergic system is one of the most important modulator neurotransmitter system implicated in diverse behavioral processes. Activation of the basal forebrain cortical cholinergic input system represents a critical step in cortical information processing. This chapter explores recent developments illustrating cortical cholinergic transmission mediate defined cognitive operations, which is contrary to the traditional view that acetylcholine acts as a slowly acting neuromodulator that influences arousal cortex-wide. Specifically, we review the evidence that phasic cholinergic signaling in the prefrontal cortex is a causal mediator of signal detection. In addition, studies that support the neuromodulatory role of cholinergic inputs in top-down attentional control are summarized. Finally, we review new findings that reveal sex differences and hormonal regulation of the cholinergic-attention system.

Dopamine D2-agonist Rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients

Dopamine is a neurotransmitter involved in several brain functions ranging from emotions control, movement organization to memory formation. It is also involved in the regulation of mechanisms of synaptic plasticity. However, its role in Alzheimer's disease (AD) pathogenesis is still puzzling. Several recent line of research instead indicates a clear role for dopamine in both amyloid β formation as well as in cognitive decline progression. In particular it has been shown that dopamine D2-like receptors (namely D3 and D2) could be mostly responsible for dopamine dysfunction in AD. Here we aimed to study the effects of the dopamine agonist Rotigotine on cortical excitability and on central cholinergic transmission in cases of AD. Rotigotine is a dopamine agonist with a pharmacological profile with high affinity for D3 and D2 receptors. We used paired pulse protocols assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF) to asses cortical excitability over the primary motor cortex and Short Latency Afferent Inhibition (SLAI) protocols, to verify the effects of the drug on central cholinergic transmission in a group of AD patients compared to age-matched controls. We observed that rotigotine induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D2-like receptors dysfunction previously described in AD brains. The current findings could indicate that future strategies aimed to ameliorate symptoms of the related AD cognitive decline could also involve some dopaminergic drugs.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia

These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic-cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic-basal forebrain-cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic-cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia.

Drs. Lieberman, Javitch, and Moore Reply

Drs. Lieberman, Javitch, and Moore Reply

Time window in cholinomimetic ability to rescue long-term potentiation in neurodegenerating anti-nerve growth factor mice

A deficit in cortical cholinergic synaptic transmission is a common feature of cognitive and behavioral impairment observed in neurodegenerative pathologies. AD11 transgenic mice producing blocking antibodies against Nerve Growth Factor (NGF) are characterized by a progressive neurodegenerative phenotype defined by the deposition of amyloid peptide, intracellular neurofibrillary tangles and by a marked cholinergic depletion. We exploited AD11 mice to develop a functional assay to investigate the impact of cholinergic deficit on cortical synaptic plasticity impairment at different neurodegenerative stages. In particular, we investigated the time course of long-term potentiation (LTP) impairment in neocortex of AD11 mice and potential rescue by acute pharmacological treatment with Acetylcholine (ACh) or the cholinergic agonist Galantamine (GAL). We showed that LTP starts being absent in AD11 mice at 2 months, an age corresponding to early neurodegenerative stage characterized by the first observed decrease in number of basal forebrain cholinergic neurons (BFCNs) without overt cortical neurodegeneration. We demonstrated that acute ACh or GAL treatment fully reverts LTP impairment in 2 month old AD11 mice. In contrast, cholinergic treatment failed to recover synaptic plasticity deficit in aged (9-10 months) AD11 mice characterized by a severe cortical neurodegeneration.

Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer-like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein

The molecular mechanisms of the interrelationship between cholinergic neurotransmission, processing of amyloid precursor protein (APP) and β-amyloid (Aβ) production in vivo are still less understood. To reveal any effect of cholinergic dysfunction on APP processing in vivo, 11-month-old transgenic Tg2576 mice with Aβ plaque pathology received intraperitoneal injections of scopolamine at a daily dosage of 2mg/kg body weight for 14 days in order to suppress cortical cholinergic transmission by chronic inhibition of muscarinic acetylcholine receptors. Scopolamine treatment of transgenic Tg2576 mice resulted in increased levels of fibrillar Aβ(1–40) and Aβ(1–42), while the soluble, SDS-extractable Aβ level remained unchanged as compared to vehicle-injected Tg2576 mice. α-Secretase activity determined in cortical tissue from scopolamine-treated Tg2576 mice was lower by about 30% as compared to that assayed in control mice, while β-secretase activity and BACE1 protein expression appeared unaffected by scopolamine treatment. The amount of sAPPα, the product secreted by α-secretase-mediated APP cleavage, and the unprocessed APP were assayed in the soluble and membrane fraction, respectively, of cortical tissue preparations from treated and control mice by Western blotting. Using the anti antibody 6E10 which specifically labels human sAPPα and full length APP in transgenic Tg2576, an enhanced APP level was detected in the membrane fraction from treated mice as compared to controls, while in the soluble fraction scopolamine treatment did not affect the protein level of sAPPα. These data indicate an accumulation of APP in cortical membrane fraction in scopolamine-treated Tg2576 mice presumably due to the decreased level of α-secretase-mediated APP cleavage, and further suggest that chronic suppresion of cortical muscarinic cholinergic transmission may alter the balance between α- and β-secretory APP processing by favouring the amyloidogenic route.

NMDA and dopamine interactions in the nucleus accumbens modulate cortical acetylcholine release

The nucleus accumbens (NAC) plays a key role in directing appropriate motor output following the presentation of behaviorally relevant stimuli. As such, we postulate that accumbens efferents also participate in the modulation of neuronal circuits regulating attentional processes directed toward the identification and selection of these stimuli. In this study, N-methyl-d-aspartate (NMDA) and D1 ligands were perfused into the shell region of the NAC of awake rats. Cortical cholinergic transmission, a mediator of attentional processes, was measured via microdialysis probes inserted into the prefrontal cortex (PFC). NMDA perfusions (150 or 250 microm) into NAC resulted in significant increases in acetylcholine (ACh) efflux in PFC (150-200% above baseline levels). Co-administration of the D1 antagonist SCH-23390 (150 microm) markedly attenuated (by approx. 70%) ACh efflux following perfusions of 150 microm NMDA but not following 250 microm NMDA, suggesting that D1 receptor activity contributes to the ability of the lower but not the higher concentration of NMDA to increase cortical ACh release. Collectively, these data reveal a positive modulation of NMDA receptors by D1 receptors in NAC that is expressed trans-synaptically at the level of cortical transmission. This modulation may underlie the coordinated linking of attentional processes and motor output following exposure to salient and behaviorally relevant stimuli.

Cortical Cholinergic Transmission and Cortical Information Processing in Schizophrenia

Models of the neuronal mediation of psychotic symptoms traditionally have focused on aberrations in the regulation of mesolimbic dopaminergic neurons, via their telencephalic afferent connections, and on the impact of abnormal mesolimbic activity for functions of the ventral striatum and its pallidal-thalamic-cortical efferent circuitry. Repeated psychostimulant exposure models major aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. Based on neuroanatomical, neurochemical, and behavioral data, the hypothesis that an abnormally reactive cortical cholinergic input system represents a necessary correlate of a sensitized mesolimbic dopaminergic system is discussed. Moreover, the abnormal cognitive mechanisms that contribute to the development of psychotic symptoms are attributed specifically to the aberrations in cortical cholinergic transmission and to its consequences on the top-down regulation of sensory and sensory-associational input functions. Experimental evidence from studies demonstrating repeated amphetamine-induced sensitization of cortical cholinergic transmission and the ability of antipsychotic drugs to normalize the activity of cortical cholinergic inputs, and from experiments indicating the attentional consequences of manipulations that increase the excitability of cortical cholinergic inputs, supports this hypothesis. Relevant human neuropathological and psychopharmacological data are discussed, and the implications of an abnormally regulated cortical cholinergic input system for pharmacological treatment strategies are addressed. Given the role of cortical cholinergic inputs in gating cortical information processing, even subtle changes in the regulation of this cortexwide input system that represent a necessary transsynaptic consequence of sensitized mesolimbic dopaminergic transmission profoundly contribute to the neuronal mediation of psychotic symptoms.

Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats.

The effects of non-competitive N-methyl- D-aspartate (NMDA) receptor antagonists model aspects of schizophrenic symptomatology. Because effects on both cortical cholinergic transmission and attentional processes have been hypothesized to represent components of the properties of psychotogenic drugs, the present study investigated the effects of ketamine on the activity of cortical cholinergic inputs and attentional performance. To determine the effects of acute and repeated ketamine administration on cortical acetylcholine release and performance of rats in an operant task designed to assess sustained attention performance. Experiment 1 assessed the effects of ketamine (2.0-20.0 mg/kg, i.p.) on medial prefrontal acetylcholine release using in vivo microdialysis. In experiment 2, animals were pretreated with 2.0 mg/kg or 25.0 mg/kg ketamine for 7 days. Cortical acetylcholine release was assessed in these rats following the subsequent administration of a 'challenge' dose of 2.0 mg/kg on days 1, 8, and 15 following completion of the pretreatment regimen. Experiment 3 assessed the effects of acute ketamine administration (2.0, 4.0, and 8.0 mg/kg, i.p.) on sustained attention performance. In experiment 4, animals trained in the sustained attention task were pretreated with 25.0 mg/kg ketamine or vehicle for 7 days. In these animals, the performance effects of 2.0 mg/kg ketamine administered 1, 8, or 15 days after completion of the pretreatment regimen were assessed. The acute administration of ketamine dose dependently increased cortical acetylcholine release by up to 250% above baseline and for over 40 min following the highest dose of ketamine. Pretreatment with 2.0 mg or 25.0 mg/kg did not robustly alter the effects of subsequent ketamine administration on cortical acetylcholine release. In animals performing the sustained attention task, administration of the highest dose of ketamine resulted in high levels of errors of omission, while the administration of the two smaller doses did not affect performance. Pretreatment with 25.0 mg/kg disrupted the attentional performance during the pretreatment period, but it did not affect the baseline performance thereafter. Furthermore, ketamine pretreatment did not systematically alter the performance effects of subsequent ketamine administration. The robust stimulation of cortical acetylcholine release represents a potent component of the pharmacological effects of ketamine. The effects of acute ketamine on attentional performance were limited to high rates of omissions. Repeated ketamine administration 'sensitized' neither cortical acetylcholine release nor attentional performance. These effects of repeated ketamine differ substantially from those of another major psychotogenic drug, amphetamine, and thus support the view that ketamine and amphetamine model fundamentally different aspects of schizophrenia.

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, clozapine (2.5–20 mg/kg), olanzapine (10 mg/kg), risperidone (1 mg/kg), and ziprasidone (3 mg/kg) significantly increased ACh release in rat medial prefrontal cortex (mPFC), whereas the typical APDs, haloperidol (0.1–1 mg/kg), S(-)-sulpiride (10–25 mg/g), and thioridazine (5–20 mg/kg) did not. None of seven APDs increased ACh release in the nucleus accumbens or striatum at the doses effective in the mPFC. Thus, atypical and typical APDs may differ in the ability to increase cortical ACh release, a possible factor contributing to cognitive improvement in schizophrenia. After perfusion with neostigmine, an AChesterase inhibitor, clozapine, but not haloperidol, increased ACh release in all three aforementioned brain regions with an enhanced effect in the mPFC, indicating the importance of studying ACh release in the absence of AChesterase inhibition. Clozapine, and perhaps other atypical APDs, alone or in combination with an AChesterase inhibitor, may improve cognition in schizophrenia, and perhaps other cognitive disorders, e.g., early Alzheimer's disease, by enhancing cortical cholinergic transmission.

Rat basal forebrain cholinergic lesion affects neuronal nitric oxide synthase activity in hippocampal and neocortical target regions

Nitric oxide (NO)-mediated mechanisms have been assigned a role in cortical perfusion, learning and memory as well as in neuronal plasticity. Dysfunction of cortical cholinergic transmission has also been associated with reduced cortical cerebral blood flow and impaired performance in learning and memory tasks suggesting a link between the basal forebrain cholinergic system and cortical NO-mediated mechanisms. The aim of this study was therefore to study the influence of cholinergic input on neuronal NO-synthase (nNOS) activity in cortical cholinoceptive target neurons. A nearly complete loss of rat basal forebrain cholinergic cells was induced by a single intracerebroventricular application of the cholinergic immunotoxin 192IgG-saporin. Basal forebrain cholinergic hypofunction resulted in reduced catalytic and substrate binding activity of nNOS in a number of hippocampal and neocortical subregions 7 days after lesion as revealed by NADPH-diaphorase enzyme histochemistry and quantitative autoradiography of [ 3H] l- N G-nitro-arginine binding, respectively. The total amount of nNOS protein assayed by Western analysis, was not affected in the cortical and hippocampal regions examined. The data indicate that cortical cholinergic deafferentation results in reduced nNOS activity in select cholinoceptive neocortical and hippocampal neurons. As the total amount of cortical nNOS protein was not affected by basal forebrain cholinergic lesion, the results suggest that the ratio of catalytically active and inactive cortical nNOS is driven by basal forebrain cholinergic input presumably via M1-muscarinic cholinergic receptors.

Increases in cortical acetylcholine release during sustained attention performance in rats

Acetylcholine (ACh) efflux in the frontoparietal cortex was studied with in vivo microdialysis while rats performed in an operant task designed to assess sustained attention. Transferring animals from the baseline environment into the operant chambers elicited a robust increase in cortical ACh efflux that persisted throughout the 18-min pre-task period. Subsequent performance in the 36-min sustained attention task was associated with further significant increases in frontoparietal ACh efflux, while the termination of the task resulted in a delayed decline in ACh levels. Upon the 12-min presentation of a visual distracter (flashing houselight, 0.5 Hz) during task performance, animals initially developed a significant response bias to the left lever in the first 6-min distracter block, reflecting a reduction of attentional effort. Under continued conditions of increased attentional demand, performance recovered during the second 6-min distracter block. This return to attentional processing was accompanied by an increase in cortical ACh efflux, suggesting that the augmentation of attentional demand produced by the distracter elicited further increases in ACh release. The enhancement of cortical ACh efflux observed prior to task performance implies the presence of complex relationships between cortical ACh release and anticipatory and/or contextual factors related to operant performance and attentional processing. This finding, along with the further increases in cortical ACh efflux associated with task performance, extends hypotheses regarding the crucial role of cortical cholinergic transmission for attentional functions. Furthermore, the effects of the distracter stimulus provide evidence for a direct relationship between attentional effort and cortical ACh release.

Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release

Cortical acetylcholine, under resting and stimulated conditions, was measured in frontoparietal and prefrontal cortex using in vivo microdialysis in freely-moving rats. Cortical acetylcholine efflux was stimulated by systemic administration of the benzodiazepine receptor partial inverse agonist FG 7142. Administration of FG 7142 (8.0 mg/kg; i.p.) significantly elevated acetylcholine efflux in both cortical regions (150–250% relative to baseline) for 30 min after drug administration. The ability of endogenous dopamine to regulate cortical acetylcholine efflux under resting or stimulated conditions and the relative contributions of D 1- and D 2-like dopamine receptor activation was also assessed. In a first series of experiments, systemic administration of the antipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142-stimulated acetylcholine efflux in frontoparietal, while the D 1-like antagonist, SCH 23390 (0.1, 0.3 mg/kg), was less effective in attenuating stimulated acetylcholine efflux. In a second series of experiments, the effects of infusions of these antagonists and of the D 2- like antagonist sulpiride (10, 100 μM) into the nucleus accumbens were assessed. Infusions of haloperidol and sulpiride significantly blocked FG 7142-stimulated acetylcholine efflux while SCH 23390 did not. By contrast, a third series of experiments demonstrated that perfusion of these antagonists (100 μM) locally into the cortex (through the probe) did not affect FG 7142-stimulated acetylcholine efflux. Moreover, none of these dopamine receptor antagonists, whether administered systemically or perfused into the nucleus accumbens or cortex, affected basal cortical acetylcholine efflux. These results reveal similarities in stimulated cortical acetylcholine release across frontal cortical regions and suggest a prominent role for D 2-mediated accumbens dopamine transmission in the regulation of cortical acetylcholine release. The findings provide evidence in support of a neural substrate that links dysregulation of mesolimbic dopaminergic transmission to changes in cortical cholinergic transmission. Dysregulation within this circuit is hypothesized to contribute to the etiology of disorders such as schizophrenia, dementia and drug abuse.

Cortical Acetylcholine, Reality Distortion, Schizophrenia, and Lewy Body Dementia: Too Much or Too Little Cortical Acetylcholine?

Aberrations in cortical cholinergic transmission have been hypothesized to mediate the development and manifestation of psychotic cognition. Based primarily on hypotheses about mesolimbic dopaminergic hyperactivity in schizophrenia, the actions of antipsychotic drugs, the trans-synaptic regulation of the excitability of basal forebrain corticopetal cholinergic neurons, and the role of cortical cholinergic inputs in attentional functions, we hypothesized that persistent disinhibition of cortical cholinergic inputs mediates the fundamental cognitive dysfunctions which form the basis for the development of positive symptoms in schizophrenia. In contrast to this hypothesis, Perry and Perry (1995), based on evidence from hallucinating patients with Lewy Body Dementia (LBD), concluded that the extensivelossof cortical acetylcholine allows irrelevant information to enter “conscious awareness” and thus hallucinations to emerge. The discussion of these contrasting hypotheses highlights the need for more dynamic and precise theories describing the cognitive variables and neuronal processes which contribute to the development and manifestation of psychotic cognition. While the hypothesis that a disinhibited cholinergic system mediates the evolution of psychotic symptoms corresponds more convincingly with current theories about the cognitive functions of cortical cholinergic inputs, both hypotheses stress the critical role of cortical acetylcholine in the highest levels of cognitive functioning.

Expression of amyloid precursor protein mRNA isoforms in rat brain is differentially regulated during postnatal maturation and by cholinergic activity

Pathological processing of the amyloid precursor protein (APP) is assumed to be responsible for the amyloid deposits in Alzheimer-diseased brain tissue, but the physiological function of this protein in the brain is still unclear. The aim of this study is to reveal whether the expression of different splicing variants of APP transcripts in distinct brain regions is driven by postnatal maturation and/or regulated by cortical cholinergic transmission, applying quantitative in situ hybridization histochemistry using 35S-labeled oligonucleotides as specific probes to differentiate between APP isoforms. In cortical brain regions, the expression of both APP695 and APP751 is high at birth and exhibits nearly adult levels. The developmental expression pattern of cortical APP695 displays a peak value around postnatal day 10, while the age-related expression of APP751 demonstrates peak values on postnatal days 10 and 25, with the highest steady state levels of APP751 mRNA on day 25. During early development, the cortical laminar distribution of the APP695, but not APP751, mRNA transiently changes from a more homogeneous distribution at birth to a pronounced laminar pattern with higher mRNA levels in cortical layer III/IV detectable at the age of 4 days and persisting until postnatal day 10. The distinct age-related changes in cortical APP695 and APP751 mRNA levels reflect the functional alterations during early brain maturation and suggest that APP695 might play a role in establishing the mature connectional pattern between neurons, whereas APP751 could play a role in controlling cellular growth and synaptogenesis.Lesion of basal forebrain cholinergic system by the selective cholinergic immunotoxin 192IgG-saporin resulted in decreased levels of APP695 but not APP751 and APP770 transcripts by about 15–20% in some cortical (cingulate, frontal, parietal, piriform cortex), hippocampal regions (CA1, dentate gyrus), and basal forebrain nuclei (medial septum, vertical limb of diagonal band), detectable not earlier than 30 days after lesion and persisting until 90 days postlesion, suggesting that the nearly complete loss of cortical cholinergic input does not have any significant impact on the expression of APP mRNA isoforms in cholinoceptive cortical target regions.

Cognitive functions of cortical ACh: lessons from studies on trans-synaptic modulation of activated efflux

Trans-synaptic modulation of cortical ACh efflux is a useful approach for determining the functions of cortical ACh. Bilateral modulation of basal forebrain GABAergic transmission by benzodiazepine-receptor agonists and inverse agonists decreases and increases, respectively, activated cortical ACh efflux. The determination of behavioral functions which are mediated via activated cortical ACh efflux, and therefore subject to the effects of basal forebrain GABA—cholinergic manipulations, should promote analyses of the functions of cortical ACh. Trans-synaptic approaches to enhance activated cortical ACh efflux offer some potential for the treatment of cognitive dysfunctions associated with impaired cortical cholinergic transmission.