Increase In Cortical Acetylcholine Release Research Articles

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

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

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

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

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.

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

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

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.

Neuronal activity in the nucleus accumbens is necessary for performance-related increases in cortical acetylcholine release

In vivo microdialysis was used to determine the necessity of neuronal activity in the nucleus accumbens (NAC) for task-induced increases in cortical acetylcholine (ACh) efflux. Rats were trained in a behavioral task in which they were required to perform a defined number of licks of a citric acid solution in order to gain access to a palatable, cheese-flavored food. Upon reaching a consistent level of performance, rats were implanted with microdialysis cannula in the medial prefrontal cortex (mPFC) and either the ipsilateral shell of the NAC or in the dorsal striatum (STR; control site). Dialysis samples from the mPFC were analyzed for ACh concentrations and samples from the NAC were analyzed for dopamine (DA) concentrations. Performance in the task was associated with increases in both ACh efflux in the cortex (150–200%) and DA efflux in the NAC (50–75%). These increases were blocked by administration of tetrodotoxin (TTX; 1.0 μM) via reverse dialysis into the NAC. Administration of TTX into the dorsal STR control site was ineffective in blocking performance-associated increases in cortical ACh. The D2 antagonist sulpiride (10 or 100 μM) administered into the NAC via reverse dialysis was ineffective in blocking increases in cortical ACh efflux. The present data reveal that neuronal activity in the NAC is necessary for behaviorally induced increases in cortical ACh efflux and that this activation does not require increases in D2 receptor activity.

Differential cortical acetylcholine release in rats performing a sustained attention task versus behavioral control tasks that do not explicitly tax attention

The present study used microdialysis techniques to compare acetylcholine release in the frontoparietal cortex of rats performing in a task requiring sustained attention with that of rats performing in two control procedures. The two control procedures were a fixed-interval 9-s schedule of reinforcement assessing primarily the effects of operant responding and comparable reward rates, and an operant procedure designed to test the effects of lever extension to prompt responding. These two control procedures involved comparable sensory-motor and motivational variables to those of the sustained attention task, but did not explicitly tax attentional processes. Performance of the sustained attention task was associated with a significant increase in cortical acetylcholine efflux, reaching a maximum of nearly 140%. Performance of the two control procedures was associated with significantly smaller (∼50%) increases in cortical acetylcholine release. This robust dissociation between attentional and control performance-associated increases in cortical acetylcholine release resulted, in part, from the elimination of the pre-task transfer of the animals into the operant chambers and the associated increases in acetylcholine release observed in previous studies. The present results support the hypothesis that demands on attentional performance, as opposed to the frequency of lever pressing, reward delivery and other task-related variables, selectively activate the basal forebrain corticopetal cholinergic system.

The effects of manipulations of attentional demand on cortical acetylcholine release

In vivo microdialysis was used to measure acetylcholine (ACh) efflux in the frontoparietal cortex while rats performed in one of two operant tasks. One task was designed and validated to generate measures of sustained attention, while the other task was designed to minimize explicit demands on sustained attentional resources (low-demand task). Transferring animals from the baseline environment into the operant chambers robustly increased cortical ACh efflux regardless of subsequent task demands. Performance in the sustained attention task further increased frontoparietal ACh efflux, and these increases were not observed when animals were simply exposed to the operant chamber without task performance. Manipulations of the task parameters within a session, to either increase or decrease explicit demands on sustained attention, were not associated with fluctuations in ACh efflux. Unexpectedly, performance in the low-demand task was also associated with significant increases in ACh efflux that were similar to those observed during the sustained attention task. However, widespread depletions of cortical cholinergic inputs produced by intra-basalis infusions of 192 IgG-saporin failed to impair performance in the low-demand task, suggesting that cholinergic transmission is not necessary for performance in this task. The present results indicate that although a wider range of instrumental processes than previously hypothesized are associated with increases in cortical ACh release, the dependence of performance on the integrity of cortical cholinergic inputs may be limited to tasks with explicit attentional demands.

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release.

Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.

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.

Pharmacology of sensory stimulation-evoked increases in frontal cortical acetylcholine release

Recent research has demonstrated that a variety of sensory stimuli can increase acetylcholine release in the frontal cortex of rats. The aim of the present experiments was to investigate the pharmacological regulation of sensory stimulation-induced increases in the activity of basal forebrain cholinergic neurons. To this end, the effects of agonists and antagonists at a variety of neurotransmitter receptors on basal and tactile stimulation-evoked increases in frontal cortical acetylcholine release were studied using in vivo brain microdialysis. Tactile stimulation, produced by gently stroking the rat's neck with a nylon brush for 20 min, significantly increased frontal cortical acetylcholine release by more than 100% above baseline. The noradrenergic α 2 agonist clonidine (0.1 or 0.2 mg/kg) and α 1 antagonist prazosin (1 mg/kg) failed to affect basal cortical acetylcholine release; however, both compounds significantly reduced the increases evoked by sensory stimulation. In contrast, the α 2 antagonist yohimbine (3 mg/kg) increased basal cortical acetylcholine release, thereby preventing meaningful investigation of its effects on tactile stimulation-evoked increases. The benzodiazepine agonist diazepam (5 mg/kg) reduced, and the GABA A receptor antagonist picrotoxin (2 mg/kg) increased basal cortical acetylcholine release; in addition, diazepam attenuated the increases in cortical acetylcholine release evoked by tactile stimulation. While dopaminergic D 1 (SCH 23390, 0.15 mg/kg) and D 2 (raclopride, 1 mg/kg) receptor antagonists did not by themselves significantly influence the increases evoked by tactile stimulation, their co-administration produced a significant reduction. The opioid receptor antagonist naltrexone (1.5 mg/kg) failed to affect either basal or tactile stimulation-evoked increases in acetylcholine overflow. Finally, the non-competitive N-methyl- d-aspartate receptor antagonist, dizocilpine maleate (MK-801; 0.025 and 0.05 mg/kg) increased basal cortical acetylcholine release. These results confirm that cortically projecting cholinergic neurons are activated by sensory stimuli, and indicate that the increases in cortical acetylcholine release produced by tactile stimulation are inhibited by stimulation of α 2 or blockade of α 1 noradrenergic receptors, and by enhanced GABAergic transmission. In addition, simultaneous blockade of dopamine D 1 and D 2 receptors appears necessary to achieve a significant reduction of sensory stimulation-evoked acetylcholine release in the frontal cortex. The results are consistent with the hypothesis that cortical acetylcholine release is a component of the neurochemistry of arousal and/or attention and indicate that this is modulated by GABAergic, noradrenergic and dopaminergic systems. In contrast, endogenous opioid actions do not appear to be involved.

MKC-242, a novel 5-HT 1A receptor agonist, facilitates cortical acetylcholine release by a mechanism different from that of 8-OH-DPAT in awake rats

We have previously reported that 5-{3-[((2 S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole (MKC-242), a potent and selective serotonin (5-HT) 1A receptor agonist, exerts anxiolytic- and antidepressant-like effects in animal models and that the antidepressant-like effect may be mediated by postsynaptic 5-HT 1A receptors. The present study, using a microdialysis technique, was undertaken to characterize in vivo the effect of MKC-242 on cholinergic neurons. Subcutaneous injection of MKC-242 (0.5–1.0 mg/kg), like the typical 5-HT 1A receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), increased extracellular acetylcholine (ACh) levels in the rat cerebral cortex. The increase in ACh release by MKC-242 was also observed in the hippocampus. The effect of MKC-242 on cortical ACh release was attenuated by pretreatment with the 5-HT 1A receptor antagonists (10 mg/kg, s.c.) propranolol and N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide. The increase in cortical ACh release by MKC-242 was blocked by lesion of serotonergic neurons with 5,7-dihydroxytryptamine, whereas that by 8-OH-DPAT was not. Lesion of noradrenergic neurons with N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine did not affect the MKC-242-induced increase in ACh release. These results suggest that systemic injection of MKC-242 facilitates in vivo ACh release via an activation of somadendritic 5-HT 1A autoreceptors, and that MKC-242 and 8-OH-DPAT affect cholinergic neurons in the rat cerebral cortex via different mechanisms.

Cocaine-induced increase in cortical acetylcholine release: interaction with the hypothalamo-pituitary-adrenal axis.

An influence on drug-taking behaviours of the stress-related hypothalamo-pituitary-adrenal (HPA) axis and its final hormonal mediator, corticosterone, has previously been demonstrated. A role for cortically projecting cholinergic neurons in these behaviours can also be proposed. The experiments presented here examine the effect of the drug of abuse cocaine (15 mg/kg) on the release of acetylcholine (ACh) in the cortex of freely moving rats, using the technique of in vivo microdialysis. To assess a possible modulatory influence of the HPA axis via its final hormonal mediator corticosterone, the cocaine-induced effect on cortical ACh release in intact rats was compared to that in adrenalectomized (ADX) rats, which thus lacked their endogenous source of corticosterone, and in ADX rats in which the cocaine-induced corticosterone peak and/or the basal circadian concentrations of serum corticosterone were simulated by replacement treatments. The results reported here demonstrate that cortical ACh release is greatly increased by cocaine in intact rats; ADX prolongs the return to basal levels of cortical ACh, and the chronic replacement of circadian levels of corticosterone normalizes this effect. In contrast, during the plateau period of cocaine-induced increased cortical ACh release, where no effect of ADX is evident, rats with chronic replacement of corticosterone show an attenuated cocaine-induced cortical ACh release, and the acute replacement of the cocaine-induced corticosterone secretion further attenuates this response. These results demonstrate that cocaine stimulates cortically projecting cholinergic neurons, and that the HPA hormone corticosterone modulates this interaction in a complex manner which merits further investigation.

Differential control of cortical activity by the basal forebrain in rats: a role for both cholinergic and inhibitory influences

Using microdialysis and high-performance liquid chromatography, we measured acetylcholine (ACh) release simultaneously from two cortical sites in anesthetized rats. One site was always in the somatosensory cortex, and the other was in either the visual or the motor cortex. After baseline measurements were obtained, selected sites in the basal forebrain (BF) were stimulated to increase ACh release. Some BF sites provoked more release in one microdialysis probe than in the other, suggesting some degree of corticotropic organization of the cholinergic projections from the BF. BF sites optimal for release from the visual cortex were separated from optimal sites for release from the somatosensory cortex by greater distances than were the best sites for release from the somatosensory and the motor cortex. Stimulation of a single BF site often provoked similar release from the latter two cortical areas. Electrical stimulation of the BF also modified cortical neuronal activity. Activation of some BF sites provoked an intense discharge of many neurons in the vicinity of the cortical recording electrode, and the same stimulus site in the BF provoked release of large amounts of ACh in the cortex. Stimulation of other BF sites produced strong inhibition of ongoing cortical activity and no increase in cortical ACh release. When other sites were stimulated, they had no effect or they generated stereotyped bursting patterns in the cortex without any observable effect on ACh release. BF sites that generated inhibition of cortical neural activity were generally located near the sites that activated the cortex and provoked release of ACh. These data suggest an elaborate control of the sensory cortex by a mechanism involving both gamma-aminobutyric acid-containing and cholinergic neurons of the BF.

Differential effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptor antagonists applied to the basal forebrain on cortical acetylcholine release and electroencephalogram desynchronization.

It is known that glutamatergic tracts activated from the pedunculopontine tegmentum represent a major input to the nucleus basalis magnocellularis. To establish the role of different ionotropic glutamate receptors in synaptic transmission in the basal forebrain, the pedunculopontine tegmentum was stimulated in urethane-anesthetized rats and the resulting increases in cortical acetylcholine release and desynchronization of the electroencephalogram were monitored. R(-)-3-(2-carboxypiperazine-4-yl)-propyl-I-phosphonic acid (CPP), an antagonist at N-methyl-D-aspartate-type glutamate receptors, and 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), an antagonist at alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, were delivered through a microdialysis probe placed in the basal forebrain. The N-methyl-D-aspartate antagonist preferentially inhibited cortical acetylcholine release, while the AMPA antagonist was more powerful in reducing desynchronization. A combination of both N-methyl-D-aspartate and AMPA antagonists abolished the increase in cortical acetylcholine release without reducing desynchronization. The dissociation between increased cortical acetylcholine release and electroencephalogram desynchronization suggests that the activity of corticopetal basal forebrain cholinergic neurons is neither necessary nor sufficient to produce electroencephalogram desynchronization. Rather, the nucleus basalis can probably affect the electroencephalogram by its projections to the thalamus. The reversal of the inhibitory effect of DNQX on the electroencephalogram by CPP may be due to the blockade of N-methyl-D-aspartate receptors on the GABAergic projection from the basal forebrain to the thalamus.

Dopaminergic regulation of cortical acetylcholine release: Effects of dopamine receptor agonists

The regulation of the basai forebrain cholinergic system by D 1 and D 2 dopamine receptors was assessed in the rat using in vivo microdialysis of cortical acetylcholine. The D 1 agonist CY 208–243 significantly increased cortical acetylcholine release; in contrast, the D 2 agonists quinpirole and (+)-4-propyl-9-hydroxynaphthoxazine were without significant effects. Moreover, when administered in combination with CY 208–243, quinpirole failed to potentiate the D 1 agonist-induced increases in cortical acetylcholine release. The non-selective dopamine receptor agonist apomorphine also increased cortical acetylcholine release, and this was completely blocked by the selective D 1 receptor antagonist SCH 23390 and slightly, but not signincantly attenuated by the D 2 antagonist raclopride. The present results indicate that stimulation of D 1 receptors activates cortically-projecting cholinergic neurons; however, a minor contribution of D 2 receptors cannot be excluded.

Dopaminergic regulation of cortical acetylcholine release.

The extent to which the activity of basal forebrain cholinergic neurons is influenced by dopamine (DA) was investigated using in vivo microdialysis of cortical acetylcholine (ACh). Systemic administration of the DA receptor agonist apomorphine significantly increased dialysate concentrations of ACh. Systemic, but not local, administration of d-amphetamine produced similar effects. Both D1 (SCH 23390) and D2 (haloperidol, raclopride) DA receptor antagonists attenuated the amphetamine-induced increase in cortical ACh release; however, only the D1 antagonist significantly reduced basal output of cortical ACh. These findings suggest that the activity of cortically projecting cholinergic neurons in the nucleus basalis is regulated in an excitatory manner by central dopaminergic neurons and that both D1 and D2 receptors are involved.

Frequency-dependent increase in cortical acetylcholine release evoked by stimulation of the nucleus basalis magnocellularis in the rat

Acetylcholine was collected from the somatosensory cortex of anesthetized rats, using the microdialysis technique. Electrical stimulation of the nucleus basalis magnocellularis (NBM) with trains of 10 pulses at 100 Hz delivered every second produced a 3–4-fold increase in acetylcholine release. Stimulation with an intratrain frequency of 10, 50, 100 or 200 Hz demonstrated that 100 Hz trains produced the greatest increase, while the other frequencies were about half as effective. The cortical release of acetylcholine in this paradigm supports the hypothesis that the previously demonstrated enhancement by NBM stimulation of cortical sensory inputs is due to cholinergic activation.

Effects of treatment with microencapsulated monosialoganglioside GM1 on cortical and striatal acetylcholine release in rats with cortical devascularizing lesions

The present study shows a novel administration form of the monoganglioside GM1, which following microencapsulation in human serum albumin was topically applied on cortical regions damaged by devascularization in rats. The effects of microencapsulated GM1 on extracellular levels of acetylcholine, choline and dopamine in the cortex and in the striatum were analyzed using in vivo microdialysis. Cholinergic neurons in the nucleus basalis magnocellularis were studied immunohistochemically using monoclonal antibodies raised against choline acetyltransferase (ChAT). It was found that cortical devascularizing lesions produced a decrease in extracellular levels of cortical acetylcholine and choline, and retrograde morphological changes in cholinergic neurons in the nucleus basalis magnocellularis. GM1 promoted (1) recovery of the retrograde morphological changes produced by the decortication in the nucleus basalis magnocellularis and (2) a parallel increase in cortical acetylcholine release. No changes were observed in the striatum, nor on cortical or striatal dopamine levels simultaneously measured in the same perfusates.

α1Adrenoreceptpr‐Mediated Increase in Acetylcholine Release in Braip Slices During Morphine Tolerance

Norepinephrine, clonidine, and phenylephrine increased the electrically evoked release of endogenous acetylcholine in cortical slices taken from morphine-tolerant guinea pigs. This effect was alpha 1-adrenoreceptor mediated and was opposite to the alpha 2-adrenoreceptor-mediated inhibition of acetylcholine release, normally elicited by norepinephrine and clonidine. In the presence of prazosin, clonidine recovered its normal inhibitory properties, suggesting that morphine tolerance induced the appearance of an alpha 1-adrenoreceptor-mediated response that overshadowed, but did not cancel, the still present alpha 2-adrenoreceptor inhibitory control. The attempt to prove the presence of alpha-adrenoreceptors on the nerve endings by testing the effect of norepinephrine in synaptosomal preparations (preloaded with [3H]choline and depolarized with KCl and veratridine) was unsuccessful. Therefore the problem of the exact location of this excitatory input remains to be solved. These results confirm previous findings reporting the increase in cortical acetylcholine release induced by the alpha-adrenoreceptor agonists in morphine-tolerant, freely moving guinea pigs and demonstrate that opiate tolerance inverts the direction of the noradrenergic modulation even in the isolated intracortical cholinergic structures.