Blockade Of Muscarinic Acetylcholine Receptors Research Articles

Muscarinic receptor activation overrides boundary conditions on memory updating in a calcium/calmodulin-dependent manner.

Long-term memory storage is a dynamic process requiring flexibility to ensure adaptive behavioural responding in changing environments. Indeed, it is well established that memory reactivation can "destabilize" consolidated traces, leading to various forms of updating. However, the neurobiological mechanisms rendering long-term memories labile and modifiable remain poorly described. Moreover, boundary conditions, such as the age or strength of the memory, can reduce the likelihood of this destabilization; yet, intuitively, these most behaviourally influential of memories should also be modifiable under appropriate conditions. Here, we provide evidence that salient novelty at the time of memory reactivation promotes integrative updating of resistant object memories in rats. Furthermore, blockade of muscarinic acetylcholine receptors (mAChRs; with pirenzepine) or disruption of calcium/calmodulin (Ca2+/CaM) with KN-93, a Ca2+/CaM-binding molecule that inhibits calcium/calmodulin-dependent protein kinase II (CaMKII) activation, in perirhinal cortex (PRh) prevented novelty-induced destabilization and updating of resistant object memories. Finally, PRh M1 mAChR activation (with CDD-0102A) was sufficient to destabilize resistant object memories for updating, and this effect was blocked by KN-93, possibly via inhibition of CaMKII activity. Thus, mAChRs and activation of CaMKII appear to interact as part of a mechanism to override boundary conditions on resistant object memories to ensure integrative modification with novel information. These findings therefore have important implications for understanding the dynamic nature of long-term memory storage and potential treatments for conditions characterized by maladaptive and inflexible memories.

Pulmonary Microcirculation during Experimental Pulmonary Thromboembolism under Conditions of Activation and Blockade of Muscarinic Acetylcholine Receptors.

Changes in pulmonary microcirculation were studied in isolated perfused rabbit lungs during modelling pulmonary thromboembolism under conditions of acetylcholine infusion against the background of treatment with M1 acetylcholine receptor blocker pirenzepine or blockade of muscarinic acetylcholine receptors with atropine. In the first case, the increase in pulmonary artery pressure was less pronounced than in case of atropine treatment. In response to pulmonary embolism after acetylcholine infusion against the background of pirenzepine pretreatment, the capillary hydrostatic pressure and postcapillary resistance did not change, while after atropine treatment, these parameters increased. In case of pulmonary embolism after acetylcholine infusion combined with selective blockade of M1 muscarinic acetylcholine receptors, the capillary filtration coefficient increased to a greater extent, than in the control and after blockade of muscarinic acetylcholine receptors.

Chlorphenamine for prolonged drug-induced extrapyramidal side effects in a dog

An eight-year-old male entire crossbreed dog, evaluated for resection of a mass at the base of the tail, underwent general anaesthesia for CT. Following preanaesthetic medication of 0.2 mg/kg butorphanol...

Злоупотребление антидепрессантами: причины и возможные последствия

Антидепрессанты традиционно характеризуются низким риском злоупотребления. Однако случаи неконтролируемого применения антидепрессантов представлены в литературе. К возможным механизмам, лежащими в основе злоупотребления антидепрессантами, можно отнести стимуляцию опиоидных рецепторов, блокаду центральных м-холинорецепторов, а также усиление дофаминергической синаптической передачи в мезолимбической системе. В подавляющем большинстве случаев злоупотребления антидепрессантами пациенты имели в анамнезе алкогольную или наркотическую зависимость, либо периодически применяли разнообразные психоактивные вещества с рекреационными целями. Таким образом, применение антидепрессантов у лиц с алкогольной, наркотической или иной зависимостью в анамнезе требует особой осторожности в выборе препарата, а также разработанной терапевтической стратегии для преодоления сформировавшегося пристрастия.

Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation.

Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non-specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort-related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels.

Blockade of muscarinic acetylcholine receptors in the ventral tegmental area blocks the acquisition of reward-related learning

In the present study we investigated whether stimulation of muscarinic acetylcholine (mACh) receptors in the ventral tegmental area (VTA) plays a role in the acquisition of food-based conditioned approach learning. Rats were exposed to 3 (in Experiment 1) or 7 (in Experiment 2) conditioning sessions in which 30, randomly presented light (CS) presentations were paired with delivery of food pellets (US), followed by one session with no light or food and finally one CS-only test session with only light stimulus presentations. Bilateral microinjections of scopolamine (a mACh receptor antagonist) were made either prior to each conditioning session (Experiment 1; to test effects on acquisition) or prior to the CS-only test (Experiment 2; to test effects on performance of the learned response). Scopolamine produced a dose-related significant reduction in the acquisition of conditioned approach but had no effect on its performance. These results suggest that mACh receptor stimulation in the VTA plays a necessary role in the acquisition of reward-related learning.

Orexin in Rostral Hotspot of Nucleus Accumbens Enhances Sucrose ‘Liking’ and Intake but Scopolamine in Caudal Shell Shifts ‘Liking’ Toward ‘Disgust’ and ‘Fear’

The nucleus accumbens (NAc) contains a hedonic hotspot in the rostral half of medial shell, where opioid agonist microinjections are known to enhance positive hedonic orofacial reactions to the taste of sucrose ('liking' reactions). Within NAc shell, orexin/hypocretin also has been reported to stimulate food intake and is implicated in reward, whereas blockade of muscarinic acetylcholine receptors by scopolamine suppresses intake and may have anti-reward effects. Here, we show that NAc microinjection of orexin-A in medial shell amplifies the hedonic impact of sucrose taste, but only within the same anatomically rostral site, identical to the opioid hotspot. By comparison, at all sites throughout medial shell, orexin microinjections stimulated 'wanting' to eat, as reflected by increases in intake of palatable sweet chocolates. At NAc shell sites outside the hotspot, orexin selectively enhanced 'wanting' to eat without enhancing sweetness 'liking' reactions. In contrast, microinjections of the antagonist scopolamine at all sites in NAc shell suppressed sucrose 'liking' reactions as well as suppressing intake of palatable food. Conversely, scopolamine increased aversive 'disgust' reactions elicited by bitter quinine at all NAc shell sites. Finally, scopolamine microinjections localized to the caudal half of medial shell additionally generated a fear-related anti-predator reaction of defensive treading and burying directed toward the corners of the transparent chamber. Together, these results confirm a rostral hotspot in NAc medial shell as a unique site for orexin induction of hedonic 'liking' enhancement, similar to opioid enhancement. They also reveal distinct roles for orexin and acetylcholine signals in NAc shell for hedonic reactions and motivated behaviors.

Grid cell firing properties vary as a function of theta phase locking preferences in the rat medial entorhinal cortex.

Theta rhythmic fluctuations in the hippocampal–entorhinal circuit are believed to reflect rapid transitions between modes of mnemonic processing. Specifically, activity at the trough and peak of CA1 pyramidal layer theta is thought to correspond to retrieval and encoding related processing, respectively. Spatially tuned “grid cells” in layers II and III of the medial entorhinal cortex preferentially spike during the trough and peak phases of theta, respectively. Such differences suggest differential involvement of these layers to the processes of retrieval and encoding. It remains unknown, however, if the properties of grid cells that spike preferentially at the trough vs. the peak of theta differ systematically. Such putative differences would offer insights into the differential processing that occurs during these two phases. The goal of the present work was to contrast these types of grid cells. We found that significant functional dissociations do exist: trough locked grid cells carried more spatial information, had a higher degree of head direction tuning, and were more likely to phase precess. Thus, grid cells that activate during the putative retrieval phase of theta (trough) have a greater degree of location, orientation, and temporal tuning specificity relative to grid cells that activate during the putative encoding phase (peak), potentially reflecting the influence of the retrieved content. Additionally, trough locked grid cells had a lower average firing rate, were more likely to burst, and were less phase locked to high-gamma (∼80 Hz). Further analyses revealed they had different waveforms profiles and that systemic blockade of muscarinic acetylcholine receptors reduced the spatial tuning of both types, although these differences were only significant for the peak locked grid cells. These differences suggest that trough and peak locked grid cells are distinct populations of neurons.

M5 Muscarinic Receptors Mediate Striatal Dopamine Activation by Ventral Tegmental Morphine and Pedunculopontine Stimulation in Mice

Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects. M5 muscarinic receptors are the only muscarinic receptor subtype associated with VTA and SN dopamine neurons. Here we tested the contribution of M5 muscarinic receptors to morphine-induced dopamine elevations by measuring nucleus accumbens dopamine efflux in response to intra-VTA morphine infusion using in vivo chronoamperometry. Intra-VTA morphine increased nucleus accumbens dopamine efflux in urethane-anesthetized wildtype mice starting at 10 min after infusion. These increases were absent in M5 knockout mice and were similarly blocked by pre-treatment with VTA scopolamine in wildtype mice. Furthermore, in wildtype mice electrical stimulation of the PPT evoked an initial, short-lasting increase in striatal dopamine efflux, followed 5 min later by a second prolonged increase in dopamine efflux. In M5 knockout mice, or following systemic pre-treatment with scopolamine in wildtype mice, the prolonged increase in striatal dopamine efflux was absent. The time course of increased accumbal dopamine efflux in wildtype mice following VTA morphine was consistent with both the prolonged M5-mediated excitation of striatal dopamine efflux following PPT electrical stimulation and accumbal dopamine efflux following LDT electrical stimulation. Therefore, M5 receptors appear critical for prolonged PPT excitation of dopamine efflux and for dopamine efflux induced by intra-VTA morphine.

Muscarinic Acetylcholine Receptor Localization and Activation Effects on Ganglion Response Properties

The activation and blockade of muscarinic acetylcholine receptors (mAChRs) affects retinal ganglion cell light responses and firing rates. This study was undertaken to identify the full complement of mAChRs expressed in the rabbit retina and to assess mAChR distribution and the functional effects of mAChR activation and blockade on retinal response properties. RT-PCR, Western blot analysis, and immunohistochemistry were used to identify the complement and distribution of mAChRs in the rabbit retina. Extracellular electrophysiology was used to determine the effects of the activation or blockade of mAChRs on ganglion cell response properties. RT-PCR of whole neural retina resulted in the amplification of mRNA transcripts for the m1 to m5 mAChR subtypes. Western blot and immunohistochemical analyses confirmed that all five mAChR subtypes were expressed by subpopulations of bipolar, amacrine, and ganglion cells in the rabbit retina, including subsets of cells in cholinergic and glycinergic circuits. Nonspecific muscarinic activation and blockade resulted in the class-specific modulation of maintained ganglion cell firing rates and light responses. The expression of mAChR subtypes on subsets of bipolar, amacrine, and ganglion cells provides a substrate for both enhancement and suppression of retinal responses via activation by cholinergic agents. Thus, the muscarinic cholinergic system in the retina may contribute to the modulation of complex stimuli. Understanding the distribution and function of mAChRs in the retina has the potential to provide important insights into the visual changes that are caused by decreased ACh in the retinas of Alzheimer's patients and the potential visual effects of anticholinergic treatments for ocular diseases.

Temporal resolution and temporal transfer properties: Gabaergic and cholinergic mechanisms

Temporal resolution is a basic property of the visual system and critically depends upon retinal temporal coding properties which are also of importance for directional coding. Whether the temporal coding properties for directional coding derive form inherent properties or critically depend upon the temporal coding mechanisms is unclear. Here, the influence of acetylcholine and GABA upon photopic temporal coding was investigated in goldfish, using flicker stimuli, in a behavioral and an electrophysiological (ERG) approach. The goldfish temporal resolution ability decreased from more than 90% correct choices at 20 Hz flicker frequency to about 65% at 45 Hz flicker frequency with a flicker fusion frequency of approximately 39 Hz. Blockade of GABAa-receptors reduced the flicker fusion frequency to about 23 Hz, not affecting temporal resolution below 20 Hz flicker frequency. Partial blockade of nicotinic acetylcholine receptors reduced the flicker fusion frequency slightly and lowered the temporal resolution ability in the 25-30 Hz range. Blockade of muscarinic acetylcholine receptors had a smaller effect than the partial blockade of nicotinic acetylcholine receptors. In ERG-recordings, blocking GABAa-receptors increased the a- and b-wave amplitude, induced a delay, an increase and a slow fall-off of the d-wave. Blocking GABAc-receptors had little effect. Blocking GABAa- or GABAa/c-receptors changed the temporal resolution, when expressed as a linear filter, from a 3rd degree filter with resonance to a low order low-pass filter with a low upper limit frequency. The temporal transfer properties were barely changed by blocking either nicotinic or muscarinic acetylcholine receptors, although ERG-components increased in amplitude to varying degrees. The behavioral and electrophysiological data indicate the important role of GABA for temporal processing but little involvement of the cholinergic system. It is proposed that the interaction of the GABAergic amacrine cell network and bipolar cells determines the gain of the retinal temporal coding in the upper frequency range.

Muscarinic blockade weakens interaction of gamma with theta rhythms in mouse hippocampus

theta (4-12 Hz) and gamma (40-90) oscillations are prominent rhythms in the mammalian brain. A striking feature of these rhythms, possibly vital to memory encoding, is their specific coordination in a manner that has been termed 'nesting', i.e. the preferred occurrence of bouts of gamma activity during specific phases of theta. Both rhythms are shaped by the neuromodulator acetylcholine, but it is unknown to what degree their coordination is influenced by cholinergic neuromodulation. Here, we investigated the effects of a blockade of muscarinic acetylcholine receptors by atropine on theta and gamma oscillations, and their interaction, in mouse hippocampus in vivo. Multi-site recordings from area CA1 of freely moving mice showed that under control conditions gamma activity was amplitude-modulated at theta frequencies. This coordination of theta and gamma oscillations, as assessed by cross-correlation of theta with the gamma envelope, was prominent in basal and apical dendritic laminae but not in intermediate laminae. It was stronger during active exploration than during awake immobility. Atropine (50 mg/kg intraperitoneal) altered several aspects of the individual and nested rhythms. It rendered theta activity irregular, decreased theta oscillation frequency and reduced gamma power. Atropine also reduced the amplitude-modulation of gamma oscillations at theta frequencies, in part by perturbing the coordination of the rhythms on a short time scale. Thus, our findings demonstrate that phase locking of the amplitude of gamma oscillations to theta in hippocampal area CA1 is partially governed by neuronal elements harbouring muscarinic receptors.

Effects of right-hemisphere cortical infarction and muscarinic acetylcholine receptor blockade on spatial visual attention performance in rats

The syndrome of hemispatial neglect is defined as an inability to report, respond or orient to stimuli contralateral to a cerebral lesion despite intact elementary sensory or motor function. This syndrome is typically observed after lesions of the right cerebral cortex, and has been associated with impairment of attention. We studied whether visual attention performance is impaired after right-hemisphere infarction in rats. Using a behavioural paradigm measuring spatial visual attention, we tested the effects of photothrombotic infarction to either the frontal cortex or the parietal cortex on attention performance. Since the cholinergic system is known to modulate attention performance, we additionally evaluated the role of cholinergic receptor blockade with scopolamine in our task paradigm. Our results show a transient response bias immediately after cortical infarction, with a decrease in contralesional responses and an increase in contralesional omissions after frontal infarction. Parietal infarction and systemic administration of scopolamine also resulted in a decrease in correct responses and an increase in omissions, but without a difference in side responding. In conclusion, right frontal infarction induces a transient impairment in contralesional spatial visual attention that we explain as left-sided neglect. Right parietal infarction and cholinergic blockade shows non-lateralized deficits in spatial visual attention, suggestive of global attentional impairment. We postulate that both effects of cortical infarction on attention performance may be related to cholinergic dysfunction. Our study confirms the role of frontal and parietal cortices in attention performance in rats, and corroborates the theory that attention performance is impaired in hemispatial neglect in human stroke patients.

Blockade of muscarinic acetylcholine receptors in the ventral tegmental area prevents acquisition of food-rewarded operant responding in rats

We recently found that muscarinic receptor (mAChR) stimulation in the ventral tegmental area (VTA) is involved in the acquisition of a feeding task. To investigate the involvement of VTA mAChR and nicotinic receptors (nAChR) in the acquisition and performance of a food-rewarded lever-pressing task. In experiment 1 (N=54), rats were trained under a fixed ratio 1 schedule of reinforcement and received bilateral intra-VTA microinjections of scopolamine (0, 2.5 or 5 microg/0.5 microl) or mecamylamine (0, 5 or 10 microg/0.5 microl) before each of the first four sessions. Before session 10, all rats that initially received a dose of either compound now received the vehicle and vice versa. In experiment 2 (N=14), rats were tested with scopolamine or mecamylamine while lever pressing under a progressive ratio schedule of reinforcement. In experiment 1, lever pressing by rats initially treated with any mecamylamine dose or the scopolamine vehicle rose to and stayed at maximal levels for the remaining sessions. Responding by rats initially treated with the 2.5- or 5-microg dose of scopolamine remained low, even after the cessation of scopolamine treatment, and gradually rose to maximal levels by the final sessions. Injections of scopolamine 1 to 2 mm dorsal to the VTA had no significant effect on responding. In experiment 2, neither of the compounds significantly affected break points. Stimulation of VTA mAChR, but not of nAChR, is necessary for the acquisition of a food-rewarded lever-pressing task and neither is necessary for the performance of the task.

Blockade of muscarinic acetylcholine receptors in the ventral tegmental area disrupts food-related learning in rats

Stimulation of ventral tegmental area (VTA) muscarinic acetylcholine receptors (mAChRs) is implicated in feeding. To investigate the effects of mAChR blockade in the VTA on food-related learning. In experiment 1, rats (N=12) were placed in chambers containing food and received microinjections of 0 or 5 microg/0.5 microl scopolamine prior to the first four feeding sessions and the alternate dose prior to the tenth feeding session. In experiment 2 (N=9), the effects of daily microinjections of scopolamine on lever pressing under a progressive ratio schedule of food reinforcement were tested. In experiment 3 (N=34), the effects of daily microinjections of scopolamine on lever pressing maintained by conditioned reward were investigated. In experiment 1, all rats demonstrated low consumption during session 1. However, pellet consumption for rats initially pretreated with the 0-microg dose rose to and stayed at maximal levels for the remaining sessions, even when pretreated with the 5-microg dose during the tenth session. Pellet consumption for rats initially pretreated with the 5-microg dose remained low, even for the first two sessions following the cessation of scopolamine pretreatment, and gradually rose to maximal levels by the eighth session. In experiment 2, scopolamine significantly decreased break points. In experiment 3, scopolamine failed to significantly decrease responding specifically on the lever producing the conditioned reward. Altogether, these data suggest that VTA mAChR stimulation is involved in feeding and food-related learning but may not be involved in responding maintained by conditioned reward.

Central muscarinic blockade interferes with retrieval and reacquisition of active allothetic place avoidance despite spatial pretraining

Animal navigation to hidden goals (place navigation) ranks among the most intensively studied types of behaviour because it requires brain representations of environments in the form of cognitive maps, demonstrated to depend on hippocampal function. Intact function of muscarinic receptors in the brain was originally assumed to be crucial for place navigation, however, recent studies using non-spatial pretraining demonstrated that animals with central blockade of muscarinic acetylcholine receptors can also learn and retrieve spatial memory engrams. In the present study we addressed whether navigation in the active allothetic place avoidance (AAPA) task, which requires animals to separate spatial stimuli into coherent representations and navigate according to the representation relevant for the task, is dependent on intact muscarinic receptors in the brain. We studied the effect of three doses of scopolamine (0.5, 1.0 and 2.0 mg/kg) administered 20 min prior to training on the retention of the AAPA and re-acquisition of the AAPA in a new environment. The dose of 2.0 mg/kg was found to impair both AAPA retention and re-acquisition of the AAPA in a new environment, whereas the 1.0 mg/kg dose only impaired the reinforced retention of AAPA. It is concluded that, unlike navigation in classic paradigms, efficient orientation in the AAPA task is critically dependent on muscarinic receptors in the brain.

Nigrostriatal dopamine release modulated by mesopontine muscarinic receptors

The present study investigated the regulation of substantia nigra pars compacta (SNc) dopamine neuronal activity by pedunculopontine (PPT) cholinergic neurons. Changes in dopamine efflux following chemical activation or blockade of muscarinic acetylcholine receptors in the PPT were measured at stearate-carbon paste electrodes in the striatum of urethane (1.5 g/kg) anaesthetized male rats using in vivo chronoamperometry (30 s sampling rate). Intra-PPT infusions of a mixed muscarinic/nicotinic (carbachol 8 microg/microl) or M2/4-selective muscarinic (oxotremorine 0.5 microg/microl) receptor agonist attenuated striatal dopamine efflux, whereas a non-selective (scopolamine 100 microg/microl) or M2/4-selective (methoctramine 50 microg/microl) muscarinic receptor antagonist enhanced striatal dopamine efflux. These results suggest that M2/4 muscarinic receptors in the mesopontine tonically influence SNc basal dopamine cell activity and striatal dopamine release.

Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats.

We investigated the effects of NMDA and muscarinic acetylcholine receptor blockade in the rostral part of dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC) on spatial working memory (SWM) (delayed non-matching to position task (DNMTP)). The NMDA antagonist, CPP (0.01, 0.03, 0.1 and 0.3 microg/hemisphere) and the muscarinic antagonist, scopolamine (10 microg/hemisphere) were locally infused into the brain of male Wistar rats. In the mPFC CPP 0.1 microg disrupted SWM delay-dependently and CPP 0.3 microg caused a delay-independent performance deficit. Scopolamine disrupted non-cognitive performance, but did not affect SWM accuracy. In the dlPFC, scopolamine or lower doses of CPP did not affect SWM accuracy, but CPP 0.3 microg disrupted non-cognitive performance. We concluded that the NMDA receptors in the dmPFC regulate SWM processes, whereas the muscarinic receptors in the dmPFC mediate non-cognitive performance in the DNMTP task.

Cigarette smoke-induced bronchoconstriction: cholinergic mechanisms, tachykinins, and cyclooxygenase products.

The mechanisms underlying cigarette smoke-induced bronchoconstriction were studied by using selective blockade of muscarinic acetylcholine receptors, neurokinin receptors and production of eicosanoids of the cyclooxygenase pathway in anesthetized guinea pigs. Inhalation of three breaths of cigarette smoke (University of Kentucky research series 2R1; 2.45 mg of nicotine and 35.3 mg of tar per cigarette) reproducibly induced an immediate bronchoconstriction; total pulmonary resistance increased from 0.24 +/- 0.02 to 1.44 +/- 0.21 cmH2O.ml-1.s (P < 0.01) and dynamic lung compliance decreased from 0.53 +/- 0.03 to 0.39 +/- 0.06 ml/cmH2O (P < 0.05) in 10-15 breaths after the smoke inhalation. Atropine pretreatment (50 micrograms/kg i.v.) prevented the immediate decrease in dynamic lung compliance and reduced the immediate increase in total pulmonary resistance by approximately 55%. The atropine-resistant bronchoconstriction occurring immediately after smoke inhalation was completely blocked by a pretreatment with a combination of CP-99994 (0.3 mg/kg i.v.) and SR-489668 (0.3 mg/kg i.v.), the antagonists of neurokinin-1 and neurokinin-2 receptors, respectively. However, a delayed and sustained bronchoconstriction still persisted and reached a plateau in 45-55 breaths after smoke inhalation challenge. This delayed response was completely prevented by pretreatment with indomethacin (5 mg/kg i.v.). We conclude that the smoke-induced bronchoconstriction in guinea pigs consists of an early phase induced by both a cholinergic reflex and tachykinin release, probably evoked by the activation of bronchopulmonary C fibers, and a late phase caused by the action of arachidonic acid metabolite(s) of the cyclooxygenase pathway.

Dissimilarities between cholinergic and dopaminergic turning elicited by nucleus accumbens stimulation in freely moving rats

Contralateral turning was produced by unilateral injection of carbachol (0.5, 2.5, 5 μg) into the nucleus accumbens, but not into the dorsal or ventral striatum. This behaviour was inhibited by muscarinic M 1 acetylcholine receptor blockade in the nucleus accumbens, and less effectively by blockade of muscarinic M 2 and nicotinic acetylcholine receptors. Unilateral injection of a mixture of the dopamine D 1 receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7,8-diol (SKF 38393, 5 μg) and the dopamine D 2 receptor agonist quinpirole (10 μg) also produced contralateral turning. The stepping pattern, however, completely differed from that induced by carbachol. The number of carbachol-induced turnings was reduced by dopamine D 1 or D 2 receptor blockade (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol (SCH 23390) and l-sulpiride, respectively) in the nucleus accumbens. However, the reduction was due to a change in the turning pattern. Blockade of muscarinic acetylcholine receptors in the nucleus accumbens did not change the contralateral turning induced by unilateral injection of dopamine receptor agonists into the nucleus accumbens. The results demonstrate that there is no functional interaction between the cholinergic and dopaminergic substrates involved, although blockade of the dopamine receptors elicited behavioural deficits that competed with the turning elicited by carbachol. The contralateral turning elicited by carbachol injection into the nucleus accumbens requires an intact dopamine activity at the level of dopamine D 1 and D 2 receptors in the ipsilateral, but not contralateral, ventrolateral striatum.