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PubMed1995

Effect of repeated methamphetamine administrations on dopamine and glutamate efflux in rat prefrontal cortex.

Pretreatment with psychostimulants such as methamphetamine (METH) results in augmented mesostriatal dopamine transmission upon a challenge administration of the drug. This effect can be blocked by dopamine antagonists and excitatory amino acid antagonists. However, no direct comparisons have been made with respect to the effects of a low-dose pretreatment regimen of METH on impulse and transporter-mediated dopamine release or to what extent glutamate release is altered by a pretreatment regimen with METH. The purpose of this study was to examine dopamine and glutamate efflux in the prefrontal cortex and striatum in rats pretreated with METH following either high potassium (80 microM) infusion or after a systemic injection of a low dose of METH. Extracellular dopamine and glutamate concentrations in the prefrontal cortex and striatum were measured in vivo by microdialysis. Potassium infusion increased extracellular dopamine and glutamate concentrations to a greater extent in the prefrontal cortex than in the striatum of METH-pretreated rats compared to saline-pretreated controls. A low dose METH challenge significantly increased extracellular dopamine but not glutamate concentrations in both prefrontal cortex and striatum of all animals. Moreover, the acute METH-induced increased in cortical dopamine efflux was significantly greater in rats pretreated with METH. Overall, these data are the first evidence that repeated METH administrations can enhance cortical glutamate efflux and indicate that a low dose pretreatment regimen of METH enhances dopamine transmission in the prefrontal cortex through both transporter and depolarization-induced mechanisms.

Analysis of Variance↗

PubMed1979

Facilitation of self-stimulation of the prefrontal cortex in rats following chronic administration of spiroperidol or amphetamine.

The effect of chronic administration of spiroperidol, a dopaminergic antagonist, on self-stimulation of the prefrontal cortex was investigated. When spiroperidol was administered either before or after daily self-stimulation tests for 9 days, self-stimulation rates were significantly elevated for several weeks following withdrawal of the drug. Self-stimulation of the nucleus accumbens, supracallosal bundle, and other forebrain sites was not altered, suggesting that the increased self-stimulation of the prefrontal cortex was not due to increased motor activity. Self-stimulation of the prefrontal cortex was also facilitated by chronic administration of d-amphetamine whereas self-stimulation of the supracallosal bundle was suppressed and self stimulation of the nucleus accumbens was unchanged. The results suggest that dopamine modulates self-stimulation of the prefrontal cortex. Additionally, the effects of chronic spiroperidol on self-stimulation of this structure may model the therapeutic effects of neuroleptics in humans.

Amphetamine↗

PubMed2000

Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on In vivo 1H-MRS signals.

The rat medial prefrontal cortex (mPFC) regulates subcortical dopamine transmission via projections to the striatum and ventral tegmental area. We used in vivo proton magnetic resonance spectroscopy (1H-MRS) at 4.7 T to determine whether excitotoxic lesions of the mPFC result in alterations of N-acetylaspartate (NAA), a marker of neuronal integrity, both locally and downstream in the striatum. Lesioned rats exhibited persistent reductions of NAA and other metabolites within the prefrontal cortex; selective reductions of NAA were seen in the striatum, but not in the parietal cortex. Consistent with earlier reports, lesioned rats exhibited a transient enhancement in amphetamine-induced hyperlocomotion. Prefrontal NAA losses correlated with lesion extent. In the striatum, while there was no change in tissue volume, expression of striatal glutamic acid decarboxylase-67 mRNA was significantly reduced. In vivo NAA levels thus appear sensitive to both local and downstream alterations in neuronal integrity, and may signal meaningful effects at cellular and behavioral levels.

Amphetamine↗

PubMed1975

Preliminary evidence for a direct projection of the prefrontal cortex to the hippocampus in the squirrel monkey.

Unilateral partial ablations in the medial prefrontal cortex of six squirrel monkeys led to fiber degeneration which followed cingulate and uncinate routes to the hippocampal region. Degenerating fibers were observed primarily in the alvear, but also in the perforant, bundle. Preterminal and terminal debris was seen on basket cells of the stratum oriens and pyramidal cells within the sratum pyramidalis of CA1-3. Since the prefrontal cortex has been shown to receive convergent sensory inputs from both external and internal milieu, this projection may represent the anatomical substrate for the essential influence of this information on the hippocampus proper, and also explain data which show the prefrontal cortex and hippocampus to be integrally related to mechanisms of learning and memory behavior.

Animals↗

PubMed2005

Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex.

Structures of the cerebral cortex expressing the D2 dopamine receptor subtype (D2) are important sites of action of antipsychotic drugs. It has also been repeatedly suggested that the prefrontal cortex plays a significant role in neuropsychiatric disorders, including schizophrenia. Here, by using single and double immunohistochemical techniques with electron microscopy, we investigated in the primate prefrontal cortex the ultrastructural localization of D2 and we compared it with that of the neuronal calcium sensor-1 (NCS-1), a neuron-specific calcium-binding and D2-interacting protein. D2 immunoreactivity, revealed with preembedding immunoperoxidase in single labeling and with preembedding immunogold for double labeling, was localized in cell bodies with ultrastructural characteristics of both neurons and astroglia. D2 was localized in pre- and postsynaptic structures, including spines and dendrites, and in both excitatory- and inhibitory-like axon terminals. Immunogold labeling revealed peri- and extrasynaptic localization of D2 in postsynaptic structures, whereas extrasynaptic labeling was typically found in boutons. NSC-1 immunoreactivity was abundant in pre- and postsynaptic structures, in which it was also colocalized with D2. With the present strategy (that has high resolution but relatively limited sensitivity), NSC-1 was observed in about 10% of the D2-immunopositive spines and in a lower proportion of D2-immunopositive dendrites and boutons. The data demonstrate the localization of D2 in pre- and postsynaptic as well as extra- and perisynaptic structures of the primate prefrontal cortex. The data also show the coexistence of NCS-1 and D2 at the ultrastructural level. The latter finding suggests a role for NCS-1 in desensitization of D2 in the prefrontal cortex.

Animals↗

PubMed1989

In vivo electrochemical studies of monoamine release in the medial prefrontal cortex of the rat.

The magnitude and duration of release of monoamines evoked by local applications of potassium were measured in vivo in the medial prefrontal cortex using high-speed chronoamperometry. Typical electrochemical signals reflecting released of electroactive species ranging from 0.5 to 3.0 microM and lasting 90-120 s were detected at a variety of dorsal-ventral and anterior-posterior electrode placements in the medial prefrontal cortex. The magnitude of the reduction current measured following the oxidation reaction suggests a contribution of both serotonin and dopamine to the electrochemical signal, dopamine serving as the predominant monoamine in the medial prefrontal cortex proper and serotonin appearing to predominant in the more posterior regions of the frontal cortex. This conclusion was reinforced by the fact that unilateral 6-hydroxydopamine lesions of ascending dopamine fibers almost completely abolished electrochemical signals in the ipsilateral but not in the contralateral medial prefrontal cortex. The present study provides an in vivo characterization of monoamine release in the mesocortical dopamine terminal field, where it has been suggested that psychomotor stimulants may produce some of their positive reinforcing effects.

Dopamine↗

PubMed2006

Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder.

OBJECTIVE: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies have explored their brain physiology. Using event-related functional magnetic resonance imaging (fMRI) and a behavioral measure of attention to angry faces, the authors evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder. METHOD: In the primary trials of interest, 18 adolescents with generalized anxiety disorder and 15 comparison subjects of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to indicate whether a subsequent asterisk appeared on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face trials provided a measure of attention bias to angry faces. RESULTS: Relative to the comparison subjects, patients with generalized anxiety disorder manifested greater right ventrolateral prefrontal cortex activation to trials containing angry faces. Patients with generalized anxiety disorder also showed greater attention bias away from angry faces. Ventrolateral prefrontal cortex activation differences remained evident when differences in attention bias were covaried. Finally, in an examination among patients of the association between degree of anxiety and brain activation, the authors found that as ventrolateral prefrontal cortex activation increased, severity of anxiety symptoms diminished. CONCLUSIONS: Adolescents with generalized anxiety disorder show greater right ventrolateral prefrontal cortex activation and attentional bias away from angry faces than healthy adolescents. Among patients, increased ventrolateral prefrontal cortex activation is associated with less severe anxiety, suggesting that this activation may serve as a compensatory response.

Adolescent↗

PubMed2004

Anterior prefrontal cortex contributions to attention control.

In a series of event-related functional magnetic resonance studies, we consistently found activation in anterior prefrontal cortex related to visual dimension changes in singleton search tasks. I review these data and discuss possible contributions of anterior prefrontal cortex to attention control in visual search. It is proposed that anterior prefrontal cortex may detect task-relevant stimulus changes when the target is ambiguously defined. This process may occur in the absence of awareness and may support visual dimension weighting by inhibition of the old relevant dimension in favor of the new dimension.

Attention↗

PubMed1997

Increase of extracellular dopamine in primate prefrontal cortex during a working memory task.

Increase of extracellular dopamine in primate prefrontal cortex during a working memory task. J. Neurophysiol. 78: 2795-2798, 1997. The dopamine innervation of the prefrontal cortex is involved importantly in cognitive processes, such as tested in working memory tasks. However, there have been no studies directly investigating prefrontal dopamine levels in relation to cognitive processes. We measured frontal extracellular dopamine concentration using in vivo microdialysis in monkeys performing in a delayed alternation task as a typical working memory paradigm and in a sensory-guided control task. We observed a significant increase in dopamine level in the delayed alternation task as compared both with the sensory-guided control task and the basal resting level. The increase was seen in the dorsolateral prefrontal but not in the arcuate or orbitofrontal areas. The increase appeared to reflect the working memory component of the task and was observed mainly in the lip areas of principal sulcus. Although there was no significant difference in dopamine level between delayed alternation and sensory-guided control tasks in the premotor area, significant increases in dopamine concentration were observed during both tasks as compared with the basal resting level, indicating the importance of premotor dopamine for the motor response itself.

Animals↗

PubMedDate not supplied

[Prefrontal cortex in memory and attention processes].

INTRODUCTION: The role of the prefrontal cortex still remains poorly understood. Only after 1970, the functions of the frontal lobes have been conceptualized from different points of view (behaviorism, cognitivism). DEVELOPMENT: Recently,different parallel circuits connecting discrete cortical and subcortical regions of the frontal lobes have been described. Three of these circuits are the most relevant to understanding of behavior: the dorsolateral prefrontal circuit, that mediates executive behavior; the orbitofrontal prefrontal circuit, mediating social behavior, and the medial frontal circuit, involved in motivation. Damage to the frontal cortex impairs planning, problem solving, reasoning, concept formation, temporal ordering of stimuli, estimation, attention, memory search, maintaining information in working memory, associative learning,certain forms of skilled motor activities, image generation and manipulation of the spatial properties of a stimulus, metacognitive thinking, and social cognition. Several theories have been proposed to explain the functions of the prefrontal cortex. Currently,the most influential cognitive models are: the Norman and Shallice supervisory attentional system, involved in non-routine selection; the Baddeley working memory model with the central executive as a supervisory controlling system, in which impairment leads to a 'dysexecutive syndrome'; and the Grafman's model of managerial knowledge units, stored as macrostructured information in the frontal cortex. CONCLUSION: The prefrontal cortex is essential for attentional control, manipulation of stored knowledge and modulation of complex actions, cognition, emotion and behavior.

Animals↗

PubMed1997

Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth.

Epidemiological evidence indicates a higher incidence of pregnancy and birth complications among individuals who later develop schizophrenia, a disorder linked to alterations in mesolimbic dopamine (DA) function. Two birth complications usually included in these epidemiological studies, and still frequently encountered in the general population, are birth by Caesarean section (C-section) and fetal asphyxia. To test the hypothesis that birth complications can produce long-lasting changes in DA systems, the present study examined the effects of Caesarean birth, with or without an added period of anoxia, on steady state monoamine levels and metabolism in various brain regions in a rat model. Pups born vaginally served as controls. At 2 months of age, in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally born group. DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no significant change in the striatum, in the C-section group. Thus, birth by a Caesarean procedure produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and prefrontal cortex. This is consistent with the known inhibitory effect of increased prefrontal cortex DA activity on DA release in the nucleus accumbens. By contrast to birth by rapid C-section alone, young adult animals, that had been born by C-section with 15 min of added anoxia, showed no change in steady state DA levels in the prefrontal cortex, nucleus accumbens, or striatum and a significant decrease in DA turnover only in the nucleus accumbens, in comparison to the vaginally born group. Levels of norepinephrine, serotonin, and its metabolite, 5-hydroxyindole acetic acid, were unchanged in all groups, indicating relatively specific effects on DA systems. Although appearing robust at birth on gross observation, more subtle measurements revealed that rat pups born by C-section show altered respiratory rates and activity levels and increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of life, in comparison to vaginally born controls. Pups born by C-section with 15 min of added acute anoxia were pale, hypotonic, and inactive at birth and showed reduced respiration and high brain lactate levels. However, these alterations resolved by 1-5 h after birth and, with few exceptions, animals in the anoxic group remained normal with respect to these parameters during the remainder of the first 24 h of life. Immediately after birth, levels of plasma epinephrine, a hormone known to play a role in neonatal adaptation to extrauterine life and protection against hypoxia, were decreased in pups born by C-section but increased in pups born by C-section with 15 min added anoxia, in comparison to levels measured in vaginally born controls. These early developmental alterations could contribute to long-term alterations in dopaminergic parameters observed in rats born by C-section, with or without added anoxia. It is concluded that C-section birth is sufficient perturbation to produce long-lasting effects on DA levels and metabolism in the central nervous system of the rat. These findings highlight the sensitivity of DA pathways to variations in birth procedure and support the notion that birth complications might contribute to the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Relationship between the thymus and neurochemical changes in the hypothalamus-preoptic area and prefrontal cortex in female rats with delayed puberty.

In female rats, aged 55-58 days with delayed puberty due to deficient growth and environmental stress, 5-hydroxyindoleacetic acid levels and serotonin turnover rate in the hypothalamus-preoptic area as well as body weight, body weight gain and relative weight of ovaries, uterus, adrenals and preputial glands were lower while serotonin and 5-hydroxyindoleacetic acid levels in the prefrontal cortex were higher when compared to normal rats with the latest onset of puberty aged 42-52 days. In rats with delayed puberty, multiple regression analysis revealed a significant negative dependence on dopamine turnover in the hypothalamus-preoptic area for body weight gain and, of all organs, for the relative weight of the thymus. A similar negative significant dependence on serotonin turnover rate in the prefrontal cortex was also found for the relative weight of thymus and spleen. The same analysis in the opposite direction revealed a significant negative dependence of 3,4-dihydroxyphenylacetic acid levels and dopamine turnover rate in the hypothalamus-preoptic area as well as serotonin turnover rate in the prefrontal cortex only on thymus weight. After separation of delayed pubertal rats into two groups, based on absolute ovarian weight, the rats in the low ovarian weight range and no signs of puberty exhibited: lower body weight gain, lower body weight, and lower relative weight only of thymus, ovaries and preputial glands in parallel with an increased dopamine turnover rate in the hypothalamus-preoptic area and serotonin turnover rate in the prefrontal cortex compared to the delayed pubertal rats in the high ovarian weight range and early signs of puberty. The results suggest that in rats with delayed puberty: (1) serotonergic activation in the hypothalamus-preoptic area is lower compared to normal puberty rats; (2) dopaminergic activation in the hypothalamus-preoptic area negatively affects body weight gain, thymus weight and initiation of puberty and (3) thymus weight is negatively implicated in dopaminergic activation in the hypothalamus-preoptic area and serotonergic activation in the prefrontal cortex and positively related to ovarian weight and early signs of puberty.

Animals↗

PubMed1999

Memory retrieval under the control of the prefrontal cortex.

Memory retrieval is a process wherein a distributed neural network reactivates the brain's representation of past experiences. Sensory long-term memory is represented among a population of neurones in the modality-specific posterior association cortex. The coded representation of memory can be retrieved by interactions of hierarchically different cortical areas along bottom-up and top-down anatomical connections. We examined the function of the prefrontal cortex in memory retrieval by two different approaches. Firstly, a meta-analysis of brain imaging studies revealed that the prefrontal cortex is reliably activated by memory retrieval in humans. Secondly, in order to determine the causal relationship between the prefrontal activations and memory retrieval, we designed a new experimental paradigm using posterior-split-brain monkeys. Following section of the splenium of the corpus callosum and the anterior commissure, visual stimulus-stimulus association learning within one hemisphere did not transfer to the other. Nevertheless, when a visual cue was presented to one hemisphere, the prefrontal cortex could instruct the contralateral hemisphere to retrieve the correct stimulus specified by the cue. These findings suggest that the prefrontal cortex can regulate the recall of long-term memory in the absence of bottom-up sensory inputs.

Animals↗

PubMed2005

High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase.

This study aims to investigate whether or not long-term statin treatment causes upregulation of D1 and D2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague-Dawley rats. Serum triglyceride levels were dose dependently reduced in the simvastatin-treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses. Simvastatin, 10 or 30 mg kg(-1) day(-1), increased D1 and D2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions. Simvastatin (10 mg kg(-1) day(-1)) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. D1 receptor activation by chloro-APB (5 microM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D1 antagonist SCH-23390 (25 microM). D2 receptor activation by quinpirole (5 microM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats, while the same concentration of quinpirole completely abolished the D1 receptor-mediated increase. These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.

Animals↗

PubMed2005

Local glutamate receptor antagonism in the rat prefrontal cortex disrupts response inhibition in a visuospatial attentional task.

RATIONALE: Converging evidence implicates discrete areas of the rat prefrontal cortex in the modulation of different aspects of attention and executive control. Furthermore, the pharmacology of these behaviours has been relatively well characterised for the monoamine systems in a task of visuospatial attention, but it is not known how glutamate receptor antagonism in discrete regions of the prefrontal cortex affects attentional performance. OBJECTIVES: To investigate the role of N-methyl-D-aspartate (NMDA) receptor antagonism in the prelimbic and infralimbic cortices (within the same animals) on performance of the five-choice serial reaction time task (5CSRTT), which assesses visuospatial attention and response inhibition. METHODS: Following training on the 5CSRTT, rats were implanted with bilateral guide cannulae aimed at the medial prefrontal cortex (mPFC). Rats received micro infusions of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid [(R)-CPP; dissolved in saline to give 10 ng and 50 ng per side] into the prelimbic cortex, then three more infusions (saline, 10 ng and 50 ng per side) into the infralimbic cortex, in a counterbalanced design. They were then tested on a version of the task identical to that used in training. RESULTS: (R)-CPP microinfusions impaired accuracy and increased omissions across both cortical regions. (R)-CPP microinfusions robustly increased premature responding only when infused into the infralimbic, but not prelimbic, cortex. CONCLUSIONS: These results indicate that NMDA receptor neurotransmission in the infralimbic cortex is necessary for control of impulsive responding on the 5CSRTT. These results suggest a dissociable role for prefronto-cortical glutamatergic systems in response inhibition, which appear to be functionally localised to the ventromedial infralimbic area of the mPFC.

Animals↗

PubMed2003

Perfusion of melatonin into the prefrontal cortex disrupts the circadian rhythm of acetylcholine but not of locomotor activity.

Extracellular concentrations of acetylcholine (ACh) in the prefrontal cortex displayed a circadian rhythm, with a maximum increase in the dark phase of the light:dark cycle. The increase in ACh related well to the circadian rhythm of the same rats in which a maximal increase of locomotor activity in the dark phase also was observed. Local perfusion of melatonin (200-500 microm), in a dose-dependent manner, disrupted the ACh rhythm in the prefrontal cortex but did not affect the circadian rhythm of locomotor activity. It is suggested that the change in the cholinergic transmission during a circadian period in the prefrontal cortex may be under the control of the biological clock through the action of melatonin; however, the prefrontal cortical ACh cycle seems not to be related to the regulation of locomotor activity.

Acetylcholine↗

PubMed2000

Nicotinic receptor-mediated regulation of dopamine transporter activity in rat prefrontal cortex.

The objective of this study was to determine whether nicotine could selectively influence dopamine levels in the prefrontal cortex as compared with other dopaminergic areas of brain. Using a superfusion system, we found that nicotine and other agonists at nicotinic acetylcholine receptors enhanced the release of radiolabeled dopamine that was stimulated by 10 microM amphetamine from slices prepared from rat prefrontal cortex. In contrast, nicotine had no effect on amphetamine-stimulated [(3)H]dopamine release from slices of nucleus accumbens nor striatum. Under the conditions used, which included no added calcium to exclude contribution by exocytotic release, nicotine had no effect on basal release of [(3)H]dopamine. The enhancement by nicotine was concentration-dependent, reaching a maximum at 5 microM, and producing less release at higher concentrations. Enhancement by nicotine was fully reversed by 30 microM dihydro-beta-erythroidine, and by 10 microM mecamylamine, but was not affected by alpha-bungarotoxin. The potencies of nicotine, epibatidine, cytisine, and A85380 to enhance amphetamine-stimulated dopamine release, as well as the sensitivity of nicotine enhanced release to antagonists, are consistent with mediation via a high-affinity nicotinic acetylcholine receptor containing alpha 4 and beta 2 subunits, the major species of nicotinic receptor in forebrain. Since low dopaminergic activity in prefrontal cortex is correlated with cognitive deficits in schizophrenia, our findings may help explain why these deficits are improved in schizophrenics by smoking or nicotine administration.

Amphetamine↗

PubMed2001

Memory-related acetylcholine efflux from rat prefrontal cortex and hippocampus: a microdialysis study.

To investigate the relationship between the prefrontal and hippocampal acetylcholine (ACh) systems and working memory, an in vivo microdialysis study was conducted. A group of rats was trained to perform a working memory task, delayed alternation, in an operant chamber for food reinforcement. The rats had to choose one of two response levers in an alternative manner in each trial, with a certain interval between trials. They had to remember which lever they chose in the previous trial without the assistance of external cues. Another group was trained to perform a reference memory task, cued alternation, in which the behavioral sequence was identical, but an external cue was provided. After stable behavior was established, a dialysis probe was implanted into the prefrontal cortex or the hippocampus of each rat. The extracellular concentration of ACh in the dialysates from the prefrontal cortex increased during performance of the delayed alternation task, while the hippocampal ACh showed a more distinct increase during performance of the cued alternation task. These results suggest that the prefrontal ACh is mainly related to working memory, whereas the hippocampal ACh is mainly related to reference memory.

Acetylcholine↗