Cortical Acetylcholine Release Research Articles

Disruption of Mesolimbic Regulation of Prefrontal Cholinergic Transmission in an Animal Model of Schizophrenia and Normalization by Chronic Clozapine Treatment

Abnormal mesolimbic control of cortical cholinergic activity has been hypothesized to contribute to the cognitive symptoms of schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in prefrontal cortex (PFC), an activation thought to contribute to attentional processing. Thus, the effects of intra-NAC perfusion of NMDA (250–400 μM) on ACh release in PFC were determined in rats receiving lesions of the ventral hippocampus (VH) as neonates (nVHLX), a neurodevelopmental model of schizophrenia, or as adults (aVHLX). NMDA elevated ACh release (100–150% of baseline) in adults sham-lesioned as neonates or in aVHLX rats. Adult nVHLX were unresponsive to NAC NMDA receptor stimulation. The inability of nVHLX to respond to NMDA emerged over development as a separate experiment demonstrated that evoked ACh release was normal prior to puberty (100–150% increase) yet, in these same nVHLX animals, absent after puberty. Amphetamine-evoked ACh release was assessed in nVHLX animals to exclude potential limitations in release capacity. Amphetamine produced greater increases in ACh release than in shams, indicating that nVHLX does not impair the capacity of cholinergic neurons to release ACh. Finally, the ability of 13 days of pretreatment with clozapine (1.25 mg/kg/day) to reinstate NMDA-evoked cortical ACh efflux was determined. Clozapine treatment normalized NMDA-evoked ACh release in nVHLX animals. These experiments reveal that mesolimbic regulation of cortical ACh release is disrupted in post-pubertal nVHLX rats and normalized by low-dose treatment of clozapine; supporting the usefulness of nVHLX animals for research on the neuronal mechanisms underlying the cognitive symptoms of schizophrenia.

Astrocyte‐derived kynurenic acid modulates basal and evoked cortical acetylcholine release

We tested the hypothesis that fluctuations in the levels of kynurenic acid (KYNA), an endogenous antagonist of the alpha7 nicotinic acetylcholine (ACh) receptor, modulate extracellular ACh levels in the medial prefrontal cortex in rats. Decreases in cortical KYNA levels were achieved by local perfusion of S-ESBA, a selective inhibitor of the astrocytic enzyme kynurenine aminotransferase II (KAT II), which catalyses the formation of KYNA from its precursor L-kynurenine. At 5 mm, S-ESBA caused a 30% reduction in extracellular KYNA levels, which was accompanied by a two-threefold increase in basal cortical ACh levels. Co-perfusion of KYNA in the endogenous range (100 nm), which by itself tended to reduce basal ACh levels, blocked the ability of S-ESBA to raise extracellular ACh levels. KYNA perfusion (100 nm) also prevented the evoked ACh release caused by d-amphetamine (2.0 mg/kg). This effect was duplicated by the systemic administration of kynurenine (50 mg/kg), which resulted in a significant increase in cortical KYNA formation. Jointly, these data indicate that astrocytes, by producing and releasing KYNA, have the ability to modulate cortical cholinergic neurotransmission under both basal and stimulated conditions. As cortical KYNA levels are elevated in individuals with schizophrenia, and in light of the established role of cortical ACh in executive functions, our findings suggest that drugs capable of attenuating the production of KYNA may be of benefit in the treatment of cognitive deficits in schizophrenia.

Involvement of Nicotinic and Muscarinic Receptors in the Endogenous Cholinergic Modulation of the Balance between Excitation and Inhibition in the Young Rat Visual Cortex

This study aims to clarify how endogenous release of cortical acetylcholine (ACh) modulates the balance between excitation and inhibition evoked in visual cortex. We show that electrical stimulation in layer 1 produced a significant release of ACh measured intracortically by chemoluminescence and evoked a composite synaptic response recorded intracellularly in layer 5 pyramidal neurons of rat visual cortex. The pharmacological specificity of the ACh neuromodulation was determined from the continuous whole-cell voltage clamp measurement of stimulation-locked changes of the input conductance during the application of cholinergic agonists and antagonists. Blockade of glutamatergic and gamma-aminobutyric acid (GABAergic) receptors suppressed the evoked response, indicating that stimulation-induced release of ACh does not directly activate a cholinergic synaptic conductance in recorded neurons. Comparison of cytisine and mecamylamine effects on nicotinic receptors showed that excitation is enhanced by endogenous evoked release of ACh through the presynaptic activation of alpha(*)beta4 receptors located on glutamatergic fibers. DHbetaE, the selective alpha4beta2 nicotinic receptor antagonist, induced a depression of inhibition. Endogenous ACh could also enhance inhibition by acting directly on GABAergic interneurons, presynaptic to the recorded cell. We conclude that endogenous-released ACh amplifies the dominance of the inhibitory drive and thus decreases the excitability and sensory responsiveness of layer 5 pyramidal neurons.

Adenosine A1and A2AReceptors in Mouse Prefrontal Cortex Modulate Acetylcholine Release and Behavioral Arousal

During prolonged intervals of wakefulness, brain adenosine levels rise within the basal forebrain and cortex. The view that adenosine promotes sleep is supported by the corollary that N-methylated xanthines such as caffeine increase brain and behavioral arousal by blocking adenosine receptors. The four subtypes of adenosine receptors are distributed heterogeneously throughout the brain, yet the neurotransmitter systems and brain regions through which adenosine receptor blockade causes arousal are incompletely understood. This study tested the hypothesis that adenosine A(1) and A(2A) receptors in the prefrontal cortex contribute to the regulation of behavioral and cortical arousal. Dependent measures included acetylcholine (ACh) release in the prefrontal cortex, cortical electroencephalographic (EEG) power, and time to waking after anesthesia. Sleep and wakefulness were also quantified after microinjecting an adenosine A(1) receptor antagonist into the prefrontal cortex. The results showed that adenosine A(1) and A(2A) receptors in the prefrontal cortex modulate cortical ACh release, behavioral arousal, EEG delta power, and sleep. Additional dual microdialysis studies revealed that ACh release in the pontine reticular formation is significantly altered by dialysis delivery of adenosine receptor agonists and antagonists to the prefrontal cortex. These data, and early brain transection studies demonstrating that the forebrain is not needed for sleep cycle generation, suggest that the prefrontal cortex modulates EEG and behavioral arousal via descending input to the pontine brainstem. The results provide novel evidence that adenosine A(1) receptors within the prefrontal cortex comprise part of a descending system that inhibits wakefulness.

A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia

The development and validation of animal models of the cognitive impairments of schizophrenia have remained challenging subjects. We review evidence from a series of experiments concerning an animal model that dissociates between the disruption of attentional capacities during acute illness periods and the cognitive load-dependent impairments that characterize periods of remission. The model focuses on the long-term attentional consequences of an escalating-dosing pretreatment regimen with amphetamine (AMPH). Acute illness periods are modeled by the administration of AMPH challenges. Such challenges result in extensive impairments in attentional performance and the "freezing" of performance-associated cortical acetylcholine (ACh) release at pretask levels. During periods of remission (in the absence of AMPH challenges), AMPH-pretreated animals' attentional performance is associated with abnormally high levels of performance-associated cortical ACh release, indicative of the elevated attentional effort required to maintain performance. Furthermore, and corresponding with clinical evidence, attentional performance during remission periods is exquisitely vulnerable to distractors, reflecting impaired top-down control and abnormalities in fronto-mesolimbic-basal forebrain circuitry. Finally, this animal model detects the moderately beneficial cognitive effects of low-dose treatment with haloperidol and clozapine that were observed in clinical studies. The usefulness and limitations of this model for research on the neuronal mechanisms underlying the cognitive impairments in schizophrenia and for drug-finding efforts are discussed.

The histamine H1‐receptor mediates the motivational effects of novelty

Novelty-induced arousal has motivational effects and can reinforce behavior. The mechanisms by which novelty acts as a reinforcer are unknown. Novelty-induced arousal can be either rewarding or aversive dependent on its intensity and the preceding state of arousal. The brain's histamine system has been implicated in both arousal and reinforcement. Histamine and histamine-1-receptor (H1R) agonists induced arousal and wakefulness in humans and rodents, e.g. by stimulating cortical acetylcholine (ACh) release. The H1R has also been implicated in processes of brain reward via interactions with the nigrostriatal- and mesolimbic dopamine (DA) systems. We asked whether the motivational effects of novelty-induced arousal are compromised in H1R knockout (KO) mice. The H1R-KO mice failed to develop a conditioned place-preference induced by novel objects. Even though they still explore novel objects, their reinforcing value is diminished. Furthermore, they showed impaired novelty-induced alternation in the Y-maze. Rearing activity and emotional behavior in a novel environment was also altered in H1R-KO mice, whereas object-place recognition was unaffected. The H1R-KO mice had higher ACh concentrations in the frontal cortex and amygdala (AMY). In the latter, the H1R-KO mice had also increased levels of DA, but a lower dihydrophenylacetic acid/DA ratio. Furthermore, the H1R-KO mice had also increased tyrosine hydroxylase immunoreactivity in the basolateral anterior, basolateral ventral and cortical AMY nuclei. We conclude that the motivational effects of novelty are diminished in H1R-KO mice, possibly due to reduced novelty-induced arousal and/or a dysfunctional brain reward system.

Cortical Acetylcholine Release Is Lateralized during Asymmetrical Slow-Wave Sleep in Northern Fur Seals

Fur seals are unique in that they display both bilateral slow-wave sleep (BSWS), as seen in all terrestrial mammals, and slow-wave sleep with interhemispheric electroencephalogram (EEG) asymmetry, resembling the unihemispheric slow waves of cetaceans. Little is known about the underlying mechanisms of this phenomenon, which is also termed asymmetrical slow wave sleep (ASWS). However, we may begin to understand the expression of ASWS by studying the neurotransmitter systems thought to be involved in the generation and maintenance of sleep-wake states in terrestrial mammals. We examined bilaterally the release of cortical acetylcholine (ACh), a neurotransmitter implicated in the regulation of cortical EEG and behavioral arousal, across the sleep-wake cycle in four juvenile northern fur seals (Callorhinus ursinus). In vivo microdialysis and high-performance liquid chromatography coupled with electrochemical detection were used to measure cortical ACh levels during polygraphically defined behavioral states. Cortical ACh release was state-dependent, showing maximal release during active waking (AW), similar levels during quiet waking (QW), and rapid eye movement (REM) sleep, and minimal release during BSWS. When compared with BSWS, cortical ACh levels increased approximately 300% during AW, and approximately 200% during QW and REM sleep. During these bilaterally symmetrical EEG states, ACh was synchronously released from both hemispheres. However, during ASWS, ACh release was lateralized with greater release in the hemisphere displaying lower voltage activity, at levels approximating those seen in QW. These findings demonstrate that cortical ACh release is tightly linked to hemispheric EEG activation.

Prefrontal Acetylcholine Release Controls Cue Detection on Multiple Timescales

Cholinergic neurons originating from the basal forebrain innervate the entire cortical mantle. Choline-sensitive microelectrodes were used to measure the synaptic release of cortical acetylcholine (ACh) at a subsecond resolution in rats performing a task involving the detection of cues. Cues that were detected, defined behaviorally, evoked transient increases in cholinergic activity (at the scale of seconds) in the medial prefrontal cortex (mPFC), but not in a nonassociational control region (motor cortex). In trials involving missed cues, cholinergic transients were not observed. Cholinergic deafferentation of the mPFC, but not motor cortex, impaired cue detection. Furthermore, decreases and increases in precue cholinergic activity predicted subsequent cue detection or misses, respectively. Finally, cue-evoked cholinergic transients were superimposed over slower (at the timescale of minutes) changes in cholinergic activity. Cortical cholinergic neurotransmission is regulated on multiple timescales to mediate the detection of behaviorally significant cues and to support cognitive performance.

Food-elicited increases in cortical acetylcholine release require orexin transmission

The corticopetal basal forebrain cholinergic system (BFCS) is crucial for normal attentional function and cortical acetylcholine release is increased by stimuli with high motivational salience. Projections from the lateral hypothalamus to the basal forebrain have been previously described and have been hypothesized to relay interoceptive information to this area but little is known about the phenotypic and functional nature of hypothalamic modulation of the BFCS. We have previously shown that orexin (hypocretin) fibers from the hypothalamus distribute densely among basal forebrain choline acetyltransferase–positive neurons and that intrabasalis administration of orexin A increases cortical acetylcholine release. Here, we used in vivo microdialysis to test the hypothesis that the orexin system is necessary for activation of the BFCS in response to a food-related stimulus in food-restricted rats. Elimination of the majority of orexin neurons with the toxin orexin B–saporin significantly blunted the cholinergic response to presentation of palatable food in these animals. Similar effects were seen in animals acutely pretreated with the orexin 1 receptor antagonist, SB-334867, which also increased feeding latency. Collectively, these data suggest that orexin interactions with the BFCS may be a critical component of the neurobiological substrates by which interoceptive cues bias the allocation of attentional resources toward exteroceptive stimuli related to homeostatic challenges.

Inactivation of prefrontal cortex abolishes cortical acetylcholine release evoked by sensory or sensory pathway stimulation in the rat

Sensory stimulation and electrical stimulation of sensory pathways evoke an increase in acetylcholine release from the corresponding cortical areas. The pathways by which such sensory information reaches the cholinergic neurons of the basal forebrain that are responsible for this release are unclear, but have been hypothesized to pass through the prefrontal cortex (PFC). This hypothesis was tested in urethane-anesthetized rats using microdialysis to collect acetylcholine from somatosensory, visual, or auditory cortex, before and after the PFC was inactivated by local microdialysis delivery of the GABA-A receptor agonist muscimol (0.2% for 10 min at 2 μl/min). Before PFC inactivation, peripheral sensory stimulation and ventral posterolateral thalamic stimulation evoked 60 and 105% increases, respectively, in acetylcholine release from somatosensory cortex. Stimulation of the lateral geniculate nucleus evoked a 57% increase in acetylcholine release from visual cortex and stimulation of the medial geniculate nucleus evoked a 72% increase from auditory cortex. Muscimol delivery to the PFC completely abolished each of these evoked increases (overall mean change from baseline=−7%). In addition, the spontaneous level of acetylcholine release in somatosensory, visual, and auditory cortices was reduced by 15–59% following PFC inactivation, suggesting that PFC activity has a tonic facilitatory influence on the basal forebrain cholinergic neurons. These experiments demonstrate that the PFC is necessary for sensory pathway evoked cortical ACh release and strongly support the proposed sensory cortex-to-PFC-to-basal forebrain circuit for each of these modalities.

Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons

The basal forebrain (BF) contains cholinergic as well as different types of non-cholinergic corticopetal neurons and interneurons, including neuropeptide Y (NPY) containing cells. BF corticopetal neurons constitute an extrathalamic route to the cortex and their activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with low voltage fast cortical EEG activity. It has been shown in previous studies (Duque et al. in J Neurophysiol 84:1627-1635, 2000) that in anesthetized rats BF cholinergic neurons fire mostly during low voltage fast cortical EEG epochs, while increased NPY neuronal firing is accompanied by cortical slow waves. In this paper, electrophysiologically and neurochemically characterized cholinergic and NPY-containing neurons were 3D reconstructed from serial sections and morphometrically analyzed. Cholinergic and NPY-containing neurons, although having roughly the same dendritic surface areas and lengths, were found to differ in dendritic thickness and branching structure. They also have distinct patterns of dendritic endings. The subtle differences in dendritic arborization pattern may have an impact on how synaptic integration takes place in these functionally distinct neuronal populations. Cholinergic neurons exhibited cortically projecting axons and extensive local axon collaterals. Elaborate local axonal arbors confined to the BF also originated from NPY-containing neurons. The presence of local axon collaterals in both cholinergic and NPY neurons indicates that the BF is not a mere conduit for various brainstem inputs to the cortex, but a site where substantial local processing must take place.

Does Aripiprazole Have a Role in Treating Cognitive Impairment in Parkinson’s Disease?

Back to table of contents Previous article Next article LETTERFull AccessDoes Aripiprazole Have a Role in Treating Cognitive Impairment in Parkinson’s Disease?Sarbjot Singh Ajit,Sarbjot Singh AjitSearch for more papers by this author,Published Online:1 Apr 2007https://doi.org/10.1176/jnp.2007.19.2.205AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Case reports of aripiprazole treating psychosis in Parkinson’s disease have been reported. 1 We present a case in which aripiprazole, an atypical antipsychotic with 5HT2A antagonist, 5HT1A partial agonist activity, improved cognitive functioning in a 57-year-old veteran with a recent diagnosis of Parkinson’s disease and depression. 2Case ReportThe patient had marked cognitive impairment confirmed by neuropsychiatric testing, indicating slowing in processing information (bradyphrenia), with learning and memory deficits. The patient presented to scheduled appointments along with a social worker because of difficulty in expressing himself. Medications comprised paxil, 20mg, and his antiparkinsons medications (sinemet and artane). He continued to do poorly in the subsequent months, with increasing episodes of confusion, depression, apathy, social isolation, and decline in working memory. Residential care was being considered. After several failed attempts in adjusting medications, the patient was started on a regimen of aripiprazole, 5 mg and increased to 15 mg, in the hopes of improving cognition. When the patient presented subsequently for his appointment, he showed marked signs of cognitive improvement. His memory, mood, verbal fluency, processing speed, alertness, and interaction dramatically improved. In the past, he was unable to drive a vehicle but since being on aripiprazole, he has been driving his vehicle with no further episodes of confusion. He continues to do well on aripiprazole.Comment Early cognitive impairment with five times the risk of developing dementia is noted in Parkinson’s patients due to dopamine and cholinergic deficits in the prefrontal cortex 3 , 4 with frontal and hippocampal atrophy noted in imaging studies of nondemented Parkinson’s patients. 3 Rivastigmine was shown to improve cognitive slowing in Parkinson’s disease, suggesting acetylcholine is involved in processing information speed. 3 Aripiprazole partial agonist action on 5HT1A may increase cortical acetylcholine release, improving cognition. 5 Loss of pigmented neurons in the ventral tegmental area in a small group of patients with Parkinson’s disease have been reported. 3 Systemic administration of the 5-HT2A receptor antagonist enhances activity of midbrain dopamine neurons, increasing dopamine in the prefrontal cortex. 6 , 7 5HT1A and 5HT2A receptors are located primarily on the pyramidal cortical neurons (5HT2A receptors excitatory and 5HT1A receptors inhibitory), mediating a physiological balance between excitatory and inhibitory inputs onto prefrontal pyramidal neurons. 2 Aripiprazole’s unique actions on D2 receptors possibily depend upon the cellular milieu of D2 receptors (receptor and G protein complement and concentration) eliciting agonist, antagonist, partial agonist activity, 2 which may enhance cognitive function. The most common psychiatric disturbance in Parkinson’s disease is depression with a frequency of approximately 40%, occurring usually in the early and late stages of the disease. 4 , 8 A significant correlation exists between cognitive deficits and severity of depression. 4 Depression and dementia, not motor symptoms, were associated with increased mortality in Parkinson’s disease. 2 Aripiprazole is a unique atypical which may have a role in improving mood and cognition in Parkinson’s disease. University of Missouri, Columbia, Mo.

Orexin transmission is required for food‐related increases in cortical acetylcholine release

Orexin transmission is required for food‐related increases in cortical acetylcholine release

Electrical stimulation of the pedunculopontine tegmental nucleus in freely moving awake rats: Time- and site-specific effects on two-way active avoidance conditioning

The pedunculopontine tegmental nucleus (PPTg) is involved in the regulation of thalamocortical transmission and of several functions related to ventral and dorsal striatal circuits. Stimulation of the PPTg in anesthetized animals increases cortical arousal, cortical acetylcholine release, bursting activity of mesopontine dopaminergic cells, and striatal dopamine release. It was hypothetized that PPTg stimulation could improve learning by enhancing cortical arousal and optimizing the activity of striatal circuits. We tested whether electrical stimulation (ES) of the PPTg, applied to freely-moving awake rats previously implanted with a chronic electrode, would improve the acquisition and/or the retention of two-way active avoidance conditioning, and whether this effect would depend on the specific PPTg region stimulated (anterior vs posterior) and on the time of ES: just before (pre-training) or after (post-training) each of three training sessions. The treatment consisted of 20 min of ES (0.2 ms pulses at 100 Hz; current intensity: 40–80 μA). The results showed that (1) this stimulation did not induce either any signs of distress nor abnormal behaviors, apart from some motor stereotyped behaviors that disappeared when current intensity was lowered; (2) pre-training ES applied to the anterior PPTg improved the acquisition of two-way active avoidance, (3) no learning improvement was found after either post-training ES of the anterior PPTg, or pre- and post-training ES of the posterior PPTg. The results give support to a role of PPTg in learning-related processes, and point to the existence of functional PPTg regions.

Glutamate receptors in nucleus accumbens mediate regionally selective increases in cortical acetylcholine release

The basal forebrain cortical cholinergic system (BFCS) is critical for the regulation of attentional information processing. BFCS activity is regulated by several cortical and subcortical structures, including the nucleus accumbens (NAC) and prefrontal cortex (PFC). GABAergic projection neurons from NAC to basal forebrain are modulated by Glu receptors within NAC. We previously reported that intra-NAC perfusions of NMDA or its antagonist CPP stimulate ACh release in PFC. In this experiment we determined whether this trans-synaptic modulation of cortical ACh release is evident in multi-sensory associational areas like the posterior parietal cortex (PPC). Artificial cerebrospinal fluid (aCSF, control), NMDA (250 or 400 muM), or CPP (200 or 400 muM) were perfused into the NAC shell and ACh was measured in the ipsilateral PPC. Amphetamine (2.0 mg/kg, i.p), was systemically administered as a positive control in a fourth session, since it also stimulates cortical ACh release but via mechanisms known to not necessitate transmission within the NAC. Neither NMDA nor CPP increased ACh efflux in the PPC, yet both drugs increased ACh release in PFC, suggesting that NMDA receptor modulation in the NAC increases ACh in the cortex in a regionally-specific manner. Systemic amphetamine administration significantly increased (100-200%) ACh in the PPC, suggesting that levels of ACh in the PPC can be increased following certain pharmacological manipulations. The cortical region-specific modulation of ACh by NAC may underlie the linkage of motivational information with top-down controls of attention as well as guide appropriate motor output following exposure to salient and behaviorally relevant stimuli.

Orexins Increase Cortical Acetylcholine Release and Electroencephalographic Activation through Orexin-1 Receptor in the Rat Basal Forebrain during Isoflurane Anesthesia

Cholinergic arousal system plays an important role in the maintenance of consciousness. The authors investigated whether the intrabasalis injection of orexin-A or orexin-B and the electrically stimulated pedunculopontine tegmentum nuclei (PPTg: the origin of cholinergic ascending pathways) may alter acetylcholine efflux and electroencephalographic activity in the somatosensory cortex in relation to the orexinergic system in isoflurane-anesthetized rats. Either orexin-A (10, 30, or 100 pmol) or orexin-B (10, 30, or 100 pmol) (n = 6 each) was injected into the basal forebrain while the electroencephalogram was measured during 1.0 minimum alveolar concentration (1.2%) isoflurane anesthesia. Injection of Ringer's solution was used as a control. The PPTg was electrically stimulated twice with the following conditions: 1-s stimulus train (0.2 ms, 100 Hz, 400 microA) per min for 20 min. Twenty minutes before the second PPTg stimulation, Ringer's solution or 20 microg SB334867, an orexin-1 receptor antagonist (n = 5 each) was injected into the basal forebrain. Injection of orexin-A (30 and 100 pmol) and orexin-B (100 pmol) significantly increased the acetylcholine efflux in the somatosensory cortex (P < 0.05). Injection of orexin-A (10, 30, 100 pmol) and orexin-B (30, 100 pmol) changed the burst and suppression patterns to arousal electroencephalogram. Compared with orexin-B, injection of a lower dose of orexin-A induced increase in the acetylcholine efflux and arousal electroencephalogram. SB334867 significantly attenuated the increases in the acetylcholine efflux and electroencephalographic activation evoked by PPTg stimulation. The authors demonstrated that orexin-A was more potent than orexin-B in producing alteration of cholinergic basal forebrain neuronal activity and that the cortical activation induced by the PPTg stimulation against isoflurane anesthesia may be mediated through the orexin-1 receptors in the basal forebrain.

Effect of a serotonin depleting regimen of 3,4-methylenedioxymethamphetamine (MDMA) on the subsequent stimulation of acetylcholine release in the rat prefrontal cortex

The amphetamine analog 3,4-methylenedioxymethamphetamine (MDMA) is considered to be selectively neurotoxic to serotonergic nerve terminals. Although the long term effects of MDMA on serotonin (5-HT) terminals have been well studied, other potential neurochemical consequences associated with MDMA-induced 5-HT depletion have been less well investigated. In view of the cognitive impairments in human MDMA abusers and the role of acetylcholine (ACh) in learning and memory, it was of interest to determine the influence of a 5-HT depleting regimen of MDMA on subsequent stimulation of ACh release in the prefrontal cortex (PFC). Male rats received vehicle or MDMA (10 mg/kg, i.p. every 2 h for four injections) and underwent in vivo microdialysis 7 days later to assess the subsequent drug- (e.g., MDMA, 5-HT 1A agonist) or stress- (e.g., tail pinch, presence of an intruder rat) induced stimulation of ACh release. The increase in the extracellular concentration of ACh in the PFC produced by MDMA (10 mg/kg, i.p.) was significantly less in rats previously exposed to the neurotoxic regimen of MDMA than that in control animals. In contrast, there was no difference in the magnitude of the stimulation of cortical ACh release elicited by the 5-HT 1A agonist, 8-hydroxy-2-(di- n-propyl-amino)tetralin (8-OH-DPAT, 0.3 mg/kg, s.c.), tail pinch (30 min) or the presence of an intruder rat (40 min) between control animals and animals previously exposed to a neurotoxic regimen of MDMA. These results suggest that although MDMA-induced 5-HT depletion diminishes subsequent MDMA-induced ACh release, there is little impact on cortical ACh release elicited by the stress of pain or the novelty of an environmental intruder.

Rapid induction of specific associative behavioral memory by stimulation of the nucleus basalis in the rat

Hypothesized circuitry enabling behavioral memory formation can be tested by its direct activation in the absence of normal experience. Neuromodulation via the cortical release of acetylcholine by the nucleus basalis (NB) is hypothesized to be sufficient to induce specific, associative behavioral memory. Previously, we found that tone paired with stimulation of the nucleus basalis (NBs) for 3000 trials over 15 days induced such memory, supporting the hypothesis. However, as standard associative memory can be established much more rapidly, we asked whether NB-induced memory develops rapidly. Adult male Sprague–Dawley rats, trained and tested in the same calm, waking state, were divided into Paired ( n = 5) and control ( n = 4) groups, each of which received a single session of 200 trials of an 8.0 kHz conditioned stimulus (CS) either paired with NBs or with unpaired presentation of NBs. Respiration, cardiac activity, and evoked potentials in the primary auditory cortex (ACx) were recorded. Memory and its degree of specificity were assessed 24 h later by presenting tones of various frequencies (1–15 kHz) in the absence of NBs to yield behavioral frequency generalization gradients. Behavioral responses to test tones consisted of interruption of ongoing respiration and changes in heart rate. Post-training behavioral generalization gradients exhibited response peaks centered on the CS frequency for the Paired group alone. Tone evoked potentials from the ACx also developed CS-specific plasticity. The findings indicate that NB induction of specific behavioral associative memory, like normal memory, can develop rapidly and is accompanied by specific cortical plasticity, supporting the view that NB engagement during normal learning produces memory.

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine

Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

3,4‐Methylenedioxymethamphetamine (MDMA) enhances the release of acetylcholine by 5‐HT4 and D1 receptor mechanisms in the rat prefrontal cortex

3,4-Methylenedioxymethamphetamine (MDMA), an amphetamine analog, has been shown recently to increase the release of acetylcholine (ACh) in the prefrontal cortex (PFC). The present study further characterizes the stimulatory effect of MDMA on cortical ACh release and examines the role of serotonin (5-HT) and dopamine (DA) receptors in this response. The extracellular concentration of ACh was increased dose-dependently and similarly by the (+) and (-) enantiomers of MDMA (5 and 20 mg/kg, i.p.). The systemic administration of the 5-HT(4) antagonist SDZ 205,557 (1 mg/kg, i.p.), but not the 5-HT(2A/2B/2C) antagonist LY-53,857 (3 mg/kg, i.p.), significantly decreased cortical ACh release induced by MDMA. The MDMA-induced increase in the extracellular concentration of ACh also was significantly blunted in rats treated with the D(1) receptor antagonist SCH 23390 (0.5 mg/kg, i.p.). The extent to which the coadministration of SDZ 205,557 and SCH 23390 suppressed the MDMA-induced release of ACh in the PFC was no greater than that produced by either antagonist alone. These results suggest that the 5-HT(4) and D(1) receptor subtypes contribute to the mechanism by which MDMA increases ACh release in the PFC.