Cholinergic Agonist Arecoline Research Articles

Heat Stress and Agonists of Muscarinic Cholinergic Receptors Modulate Sensitivity of Nicotinic Cholinergic Receptors in Soil Nematode Caenorhabditis elegans.

We studied the effect of moderate heat stress (30oC) and muscarinic cholinergic receptor agonists arecoline and pilocarpine on sensitivity of the behavior of the nematode Caenorhabditis elegans of N2 line to the action of the agonist of nicotinic cholinergic receptor agonist levamisole. Heat stress and muscarinic cholinergic receptor agonists increased the sensitivity of swimming induced by mechanical stimulation to levamisole (32-64 μM), which manifested in dyscoordination of locomotor muscles during swimming and complete loss of ability to swim. Combined exposure to heat stress and muscarinic cholinergic receptor agonists revealed their synergism in the influence on sensitivity of swimming behavior to levamisole: heating to 30oC potentiated the effect of arecoline and arecoline potentiated the effect of heat stress. It is assumed, that the effect of heat stress on the sensitivity of nicotinic receptors is mediated by its effect on muscarinic receptors.

Availability and Characteristics of Betel Products in the U.S.

Betel use involves oral placement of shards of areca nut (Areca catechu palm seed containing the cholinergic agonist arecoline) wrapped with slaked lime in a betel leaf (Piper betle plant) or various chopped or powdered products containing areca nut and/or parts of the betel plant. Additives to this mixture include catechu (areca palm extract), spices/sweeteners (e.g., saccharin, cloves), and/or tobacco. Betel use is most common in Asia and East India; however, little is known about the availability and characteristics of these products outside of this region. Thus, a representative sample of betel products and additives was purchased in the Richmond, Virginia area. Five venues were visited between March and May, 2006. Products successfully purchased were those containing betel alone (seven), betel/tobacco (three), tobacco alone (four), and additives (four). Most betel products listed ingredients on the packaging, though some did not explicitly distinguish between those with versus without tobacco. Importantly, seven of seven betel alone and one of three betel/tobacco products omitted any health-related warnings. All products were inexpensive and relatively obtainable in the groceries visited. More research is warranted in order to accurately estimate product emergence into the U.S. and other world markets, and the consequent impact on public health.

A 24-h access I.V. self-administration schedule of morphine reinforcement and the estimation of recidivism: Pharmacological modification by arecoline

Central cholinergic neurons are known to play a role in the pharmacological actions of opiates. The purpose of the study was to determine whether the muscarinic receptor agonist arecoline, administered during morphine self-administration, would mitigate the subsequent return to self-administration behavior. Rats self-administered increasing concentrations of morphine in operant chambers according to a schedule that permitted unlimited access to lever-activated i.v. infusions on a continuous 24 h basis from 10 to 14 days. Abstinence was induced by discontinuation of the morphine solution and mild withdrawal symptoms were evident from 14 to 74 h. Thereafter the rats remained in their home cages for a 6-week period of protracted abstinence. They were then returned to the operant chambers where lever responding had no reward consequence. The cholinergic muscarinic agonist arecoline was administered twice daily (0.25 or 1 mg/kg, s.c.) throughout the self-administration schedule of morphine. Arecoline treatment partly decreased the self-administration of morphine, it prevented the abstinence-induced decrease in body weight, and it reduced lever responding after protracted withdrawal (by 56%). In animals already dependent on morphine, arecoline failed to alter ongoing self-administration behavior, but responding induced by lever reinstatement 6 weeks after withdrawal was significantly reduced (by 33%). There was a significant relationship between the degree of self-administration activity and the degree of lever responding during reinstatement after protracted abstinence. The results of this study support the role of cholinergic systems in self-administration behavior and context-induced post-withdrawal drug seeking.

The effects of dopamine agonists on fixed interval schedule-controlled behavior are selectively altered by low-level lead exposure

A previous report of differential effects of catecholaminergic compounds, but not other classes of compounds, on FI (fixed interval) response rates of lead (Pb)-treated pigeons suggests that catecholamine system disturbances might play a role in lead (Pb)-induced changes in FI performance. The current study sought to extend those findings using more selective dopaminergic (DA) D1 and D2-like receptor agonists, Pb-treated rats, and additional classes of compounds. Drug-induced changes in FI performance of rats exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate in drinking water were compared following the administration of drugs known to impact various neurotransmitter systems altered by Pb exposure, including the selective D2-like agonist quinpirole, the D1 agonists SKF38393 and SKF82958, the mu-opioid agonist morphine, the muscarinic cholinergic agonist arecoline, the glutamate agonist NMDA, and the noncompetitive NMDA antagonist MK-801. All drugs except NMDA significantly altered FI performance, but only the effects of DA agonists differed in control and Pb-exposed rats. Pb exposure attenuated the decrements in rates produced by D1 agonists and at 150 ppm modestly altered the rate changes associated with low doses of quinpirole. These data demonstrate functional DA alterations in response to Pb exposure and provide further evidence for the selective involvement of such effects in FI performance.

Differential response to the cholinergic agonist arecoline among different cognitive modalities in Alzheimer's disease

Nine patients with possible or probable dementia of the Alzheimer type were tested on nine cognitive tests prior to (two times) and during continuous intravenous administration of five different doses of the muscarinic cholinergic agonist arecoline (1, 4, 16, 28, and 40 mg/day). The present analysis examined whether improvement on cognitive testing for each patient during arecoline treatment was most likely to occur at the same dose for all tests or whether different test scores improved at different doses of arecoline. Results indicated there were significant differences among tests in the dose at which most patients showed improved cognitive performance. These differences may have therapeutic significance, as verbal ability tended to improve at low doses of arecoline, whereas attention and visuospatial ability tended to improve at higher doses of arecoline.

Selective immunolesioning of the basal forebrain cholinergic system disrupts short-term memory in rats.

Selective depletion of nerve growth factor receptor-bearing neurons in the basal forebrain cholinergic system nuclei by the immunotoxin 192 IgG-saporin offers a new and highly useful tool for the study of the role of the forebrain cholinergic system in cognitive functions. In the present study, we have tested the effects of 192 IpG-saporin in an operant delayed matching-to-position task which has previously been used to discriminate between delay-dependent learning impairments and delay-independent disturbances of non-mnemonic processes. Rats were first trained to criterion performance and then received intraventricular injections of 5 microg of 192 IgG-saporin 4 weeks prior to a second testing session. Rats with 192 IgG-saporin lesions displayed a significant delay-dependent decline in performance compared to normal controls, indicating a deficit in short-term memory. Administration of the muscarinic blocker scopolamine (0.5 mg/kg, i.p.) produced more pronounced impairment in the performance of the normal control rats across all delays, and induced further impairment also in animals with 192 IgG-saporin lesions. These effects were not observed following control injections of methyl scopolamine, suggesting that the impairment induced by scopolamine was due to the blockade of central muscarinic receptors. No improvement in performance was observed in either group following systemic treatment with the muscarinic cholinergic agonist arecoline (1.00 mg/kg). Biochemical and morphological analyses confirmed the selective and severe (>90-95%) depletion of cholinergic neurons throughout the septal-diagonal band area and the nucleus basalis region by the intraventricular 192 IgG-saporin treatment. Although the immunotoxin was observed to produce additional damage to the cerebellar Purkinje cells, no gross motor abnormalities were observed that could contribute to the effects on accuracy in the task used here. In conclusion, the results show that selective combined lesions of the basal forebrain cholinergic neurons in the septal-diagonal band area and nucleus basalis produce long-lasting impairments in short-term memory, thus providing further support for a role of this system in cognitive functions.

Intrathecal Cholinergic Agonists Lessen Bupivacaine Spinal-Block-Induced Hypotension in Rats

Hypotension is an important side effect of spinal anesthesia. Intrathecal (IT) cholinergic agonists, including neostigmine (NEO), increase arterial blood pressure by stimulating spinal sympathetic neurons. Therefore, we tested the ability of IT cholinergic agonists to prevent the hypotensive effect of IT bupivacaine (BUP) (430 nmol) in rats instrumented with IT and arterial catheters. The mean arterial pressure (MAP) decreased 35 +/- 4 mm Hg (n = 10) after IT-BUP alone. In contrast, MAP did not significantly change after IT-BUP + IT-NEO (12.5 and 25 nmol; n = 5 for each dose). Intramuscular (IM) NEO was not effective, and MAP decreased 38 +/- 4 mm Hg after IT-BUP + IM-NEO (25 nmol; n = 5). Three additional cholinesterase inhibitors, physostigmine, edrophonium, and ambenonium, as well as the direct-acting cholinergic agonists carbachol, oxotremorine, and arecoline, each lessened the hypotension seen after IT-BUP. Furthermore, the nonselective muscarinic antagonist, atropine, as well as the M2 receptor selective antagonist, methoctramine, prevented the vasopressor effect of IT-NEO in our model. Finally, the nicotinic antagonist, mecamylamine, and the M1 selective antagonist, pirenzepine, did not affect the pressor effects of NEO in our model. In conclusion, IT cholinergic agonists lessen BUP spinal-block-induced hypotension in rats by a muscarinic dependent pathway.

Nitric Oxide Synthesis Inhibitors Induce Airway Hyperresponsiveness in the Guinea PigIn VivoandIn Vitro: Role of the Epithelium

The administration by aerosol of the nitric oxide (NO) synthesis inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME) or Ng-monomethyl-L-arginine (L-NMMA), to spontaneously breathing anesthetized guinea pigs resulted in a significant enhancement of lung resistance (RL) after increasing intravenous doses of histamine. The maximal response was increased (p < 0.01) by 126% (L-NAME) and 282% (L-NMMA) compared with the control groups. This effect was inhibited by giving an aerosol of the NO precursor L-arginine (L-Arg) but not by its inactive enantiomer D-arginine (D-Arg). Perfusion through the lumen of guinea pig tracheal tubes in vitro with nitric oxide synthesis inhibitors (120 microM) resulted in a significant increase in basal tone, suggesting a role for NO in the maintenance of basal tone. In addition, the histamine concentration-response curve was significantly shifted upward: the maximal response was increased (p < 0.01) by 335% (L-NAME) and 250% (L-NMMA) compared with the control group. This effect was concentration dependently inhibited by coincubation with L-Arg (120, 200, and 400 microM), but not with D-Arg (200 microM). Furthermore, removal of the epithelium resulted in an upward shift in the histamine concentration-response curve: the maximal response was increased by 185%. However, incubation with L-NAME did not further increase tracheal responsiveness to histamine, but addition of L-Arg (360 microM), when a plateau was reached, relaxed the tissues to control values. Nitric oxide synthesis inhibition did not change the responsiveness of intact tissues in vitro after intraluminal stimulation with leukotriene D4, serotonin, or the cholinergic agonist arecoline.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute infusion of the muscarinic cholinergic agonist arecoline on verbal memory and visuo-spatial function in dementia of the alzheimer type

Raffaele, Kathleen C., Annamaria Berardi, P. Pearse Morris, Sanjay Asthana, James V. Haxby, Stanley I. Rapoport, and Timothy T. Soncrant: Effects of Acute Infusion of the Muscarinic Cholinergic Agonist Arecoline on Verbal Memory and Visuo-spatial Function in Dementia of the Alzheimer Type. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1991, 15 (5) : 643–648. 1. 1. Treatment of patients with dementia of the Alzheimer type (DAT) with arecoline, a muscarinic cholinergic receptor agonist, reportedly improves performance on a picture recognition memory task, but not on other memory measures. To examine further possible performance improvements following arecoline treatment, patients with DAT were treated with a 30 min intravenous infusion of arecoline (5 mg). 2. 2. Psychometric testing was done at five time points (two before and three following the infusion). Patients were tested on a memory task (Buschke selective reminding) and a test of visuo-spatial performance (figure copying). 3. 3. No net change from baseline was seen in mean scores following arecoline infusion. However, the changes in performance on the two tasks were correlated (p<0.02) over subjects at 10 min but not at 1.5 or 5.5 hr following the infusion. 4. 4. This result suggests that although individual patients vary in their response to a given dose of arecoline, their responses are consistent across types of tasks. Thus the lack of a mean drug effect may be due to individual differences in response rather than to a lack of response.

The Muscarinic Cholinergic Agonist Arecoline Stimulates the Rat Hypothalamic-Pituitary-Adrenal Axis Through a Centrally-Mediated Corticotropin-Releasing Hormone-Dependent Mechanism

Several lines of experimental evidence suggest that acetylcholine and other cholinergic agonists are excitatory to the hypothalamic-pituitary-adrenal (HPA) axis. To examine the site on the HPA axis that is stimulated by cholinergic agents, we evaluated the in vivo and in vitro effects of the muscarinic cholinergic agonist arecoline in intact and pituitary stalk-transected rats as well as on isolated rat hypothalami, dispersed anterior pituicytes, and adrenocortical cells in culture. Arecoline, injected iv to catheterized, freely moving male Sprague-Dawley rats, stimulated plasma ACTH and corticosterone release in a dose-dependent fashion. The muscarinic cholinergic antagonist atropine significantly blunted the ACTH response to arecoline. Pituitary stalk transection led to diminished plasma ACTH and corticosterone responses to arecoline. Similarly, previous administration of anti-CRH serum significantly blunted these responses. These findings suggest that arecoline stimulates the HPA axis centrally, mainly via secretion of CRH. This hypothesis was confirmed by the dose-dependent ability of arecoline to cause hypothalamic CRH secretion in vitro, an effect antagonized by atropine, and its failure to elicit ACTH and corticosterone secretion by dispersed anterior pituicytes and adrenocortical cells in culture, respectively. These data suggest that the muscarinic cholinergic agonist arecoline stimulates the HPA axis in the rat and that this effect is mediated mainly by the release of endogenous CRH. Arecoline, therefore, appears to be a compound suitable to selectively evaluate the responsiveness of the central component of the HPA axis.

Regional brain metabolic responsivity to the muscarinic cholinergic agonist arecoline is similar in young and aged Fischer-344 rats

In order to determine whether a functional deficit in brain cholinoception accompanies the reported loss of muscarinic receptors with age, local cerebral glucose utilization (LCGU) was measured in awake 3- and 24-month-old rats after the administration of the muscarinic cholinergic agonist arecoline. Awake, male Fischer-344 rats received isotonic saline or arecoline (0.05–50 mg/kg), i.p., and LCGU was measured in 95 regions with the [ 14C]2-deoxy- d-glucose technique. Plasma and brain pharmacokinetics of arecoline in rats of both ages were measured in a separate experiment and were found not to differ between the two age groups. Peak cerebral cortex arecoline concentrations, at 3 min after the administration of 5 mg/kg, i.p., were 1558 ± 588and1830 ± 317ng/g in 3- and 24-month-old rats, respectively. LCGU effects were dose-dependent, with fewer regions activated by smaller doses. In 24-month-old rats, arecoline in one or more doses elevated LCGU significantly in 94% of the regions examined; no declines in LCGU were found. Increases in whole brain glucose utilization produced by all doses of arecoline, compared to control values, were similar in 3- and 24-month-old rats. After one or more doses, the rise in LCGU in 24-month-old animals, compared to that in 3-month rats, was not significantly different in 75 brain regions, greater in 13 and smaller in 7. These findings demonstrate that the functional responsivity of brain regions to a cholinergic agonist is, for the most part, age-invariant in the rat, implying that the function of muscarinic receptor and postreceptor mechanisms remains intact despite reported age-related losses of muscarinic receptors.

Multiple-Dose Arecoline Infusions in Alzheimer's Disease

Twelve patients with dementia of the Alzheimer type received two-hour infusions of placebo and the muscarinic cholinergic agonist arecoline hydrobromide at rates of 1, 2, and 4 mg/h in a double-blind, randomized fashion. These infusions resulted in dose-dependent physiologic and neuroendocrine effects consistent with central cholinergic stimulation. Infusions were generally well tolerated. No statistically significant improvement in performance on most cognitive tasks assessing knowledge memory and episodic learning and memory was observed at any dose, although marginal improvement in picture recognition ability and in ratings of word-finding were observed at the lower doses. Psychomotor activation and slightly improved affect were reliably observed at the lower doses, whereas increasing psychomotor retardation was observed at the highest dose. The data support a role for central cholinergic modulation of some aspects of cognition, behavior, and affect in this population. The apparent greater behavioral sensitivity of patients with Alzheimer's disease in comparison with subject populations previously studied, as well as the altered dose responsiveness, merit further study in relationship to normal aging.

Pharmacogenetics of psychoactive drugs

Response to psychoactive drugs is subject to genetic variation. Heritable differences in metabolism of antidepressants have been demonstrated and appear to be clinically relevant. More complex genetic variations in drug response are important in alcoholism and possibly other forms of substance abuse. Pharmacologic challenge studies in volunteer twins have shown familial variation in responses to the cholinergic agonist arecoline and to the monoaminergic aginist amphetamine. Arecoline responses also differentiate well-state bipolar patients from controls; this is consistent with a hypothesis of muscarinic supersensitivity in affective disorder. Genetically characterized animal models may be useful in futher analyzing such neurochemical differences.

Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: Modification by cholinergic drugs

Five common marmosets ( Callithrix jacchus) received unilateral ibotenic acid lesions of the basal nucleus of Meynert (nBM). Seven days later, choline acetyltransferase activity was significantly reduced by 50% in the frontal and temporal neocortex, 40% in the amygdala, and ∼ 30% in the motor, parietal and occipital cortex in the ipsilateral hemisphere. Four marmosets receiving equivalent bilateral ibotenic acid lesions were severely impaired on new visual object discrimination learning and on relearning an object discrimination learnt prior to surgery when compared with operated controls. New learning in lesioned animals was substantially improved by i.m. administration of the cholinergic agonist arecoline. Lesioned animals' learning ability improved with time but these animals were then differentially sensitive to the disruptive effect of scopolamine on discrimination learning. These results show that lesions of the nBM which destroy the rising cholinergic pathways impair learning ability but that this ability can be substantially restored by administration of a cholinergic agonist.

Enhanced elevation of corticosterone following arecoline administration to rats selectively bred for increased cholinergic function.

Serum corticosterone levels were determined following administration of the cholinergic agonist arecoline (4 mg/kg) to rats selectively bred for differences in cholinergic function. The Flinders Sensitive Line (FSL) of rats exhibited both greater suppression of behavioural activity and enhanced elevation fo serum corticosterone than the Flinders Resistant Line of rats. These enhanced responses to arecoline in the FSL rats parallel those reported in depressed humans, suggesting that these rats may provide a new animal model of affective disorders.

Behavioral, physiological, and neuroendocrine responses to arecoline in normal twins and “well state” bipolar patients

Cholinergic supersensitivity has been postulated to be an etiologic factor in affective disorder. After several pilot dose-response studies, we administered 8 mg of the cholinergic agonist arecoline subcutaneously to eight pairs of normal volunteer identical twins and eight bipolar patients currently euthymic and unmedicated. During the hour following arecoline administration, the Profile of Mood States (POMS) showed an increase in total mood disturbance in both patient and control groups. Mean systolic blood pressure, pulse, plasma cortisol, prolactin, and growth hormone also increased. Anger and elation scores on the POMS showed significant concordance in identical twins, as did change in prolactin, implying that these are the components of drug response possibly influenced by genetic factors. None of these responses differentiated well state patients from controls. Thus, mood, behavioral, and neurochemical responses to arecoline, which appears to have nonspecific neurochemical effects at the dose employed, are not markers of vulnerability to affective illness.

Chronic administration of haloperidol during development: Later psychopharmacological responses to apomorphine and arecoline

Offspring of pregnant rats injected with 0.25 mg/kg of haloperidol or saline throughout gestation and until weaning were psychopharmacologically tested for their responsiveness to arecoline and apomorphine. On postnatal day 50, offspring of such chronic treatments were tested in the open field after administration of 0, 0.05, 0.1, 1.0 or 3.0 mg/kg apomorphine, a dopamine agonist. The two chronic treatment groups did not differ in response to high doses of apomorphine which induced stereotyped sniffing and a depression of matrix crossing behavior. However, while control offspring exhibited a low dose (0.05 mg/kg apomorphine) suppression of matrix crossings and rearing behavior, haloperidol treated offspring did not, which may indicate a functional hyposensitivity of dopaminergic autoreceptors in these treated animals. When tested at postnatal day 65 for their cataleptic responses to the cholinergic agonist arecoline, haloperidol treated offspring were more cataleptic to 2 and 5 mg/kg arecoline than control offspring. This suggests that chronic dopamine receptor blockade during development may have long-term indirect effects on the sensitivity of the cholinergic system.

Central noradrenergic-cholinergic interaction and locomotor behavior

Depletion of forebrain noradrenaline by intracerebral injection of 4 μg of 6-hydroxydopamine into the fibres of the dorsal noradrenergic bundle was found to block the cateleptic effects of the muscarinic cholinergic agonist arecoline and to potentiate the locomotor stimulant effects of the muscarinic cholinergic blocker scopolamine. The nicotonic drugs, mecamylamine, a nicotinic blocker, and nicotine itself were unaffected in their actions by the depletion of forebrain noradrenaline. It is concluded that a noradrenergic-cholinergic interaction of the muscarinic type exists in brain and may have a function in the control of arousal, with catalepsy at one extreme and locomotor stimulation at the other.

The lack of an effect of cholinergic agonists on anterior pituitary prolactin production in vitro.

The addition of dopamine to anterior pituitary incubations resulted in a marked decrease (88% for 3H prolactin and 69% for RIA prolactin) in prolactin release. Incubation with the cholinergic agonists carbacol, arecoline and nicotine resulted in no significant change in prolactin secretion.

The influence of cholinergic, adrenergic, and serotonergic drugs on the afternoon surge of plasma prolactin in ovariectomized, estrogen-treated rats.

The effects of systemic administration of cholinergic, adrenergic, and serotonergic drugs on the afternoon surge of plasma prolactin was investigated using ovariectomized, polyestradiol phosphate (PEP)-injected rats bearing aortic catheters. Basal prolactin levels were elevated and similar after PEP administration for a period of 5 weeks, and an afternoon surge in plasma prolactin persisted for a period of 3 weeks before the magnitude of the surge diminished. The plasma estradiol levels were significantly higher for the 1100 and 1300 h samples than for the 1500 and 1700 h samples. Cornified vaginal epithelia were predominant in the vaginal smears of all animals throughout the 49-day experimental period. The cholinergic agonists arecoline, nicotine, and carbachol significantly inhibited the afternoon surge of prolactin. The muscarinic antagonist atropine resulted in a partial inhibition of the surge while the nicotinic antagonist mecamylamine did not have any inhibitory effect. The alpha-adrenergic blockers phenoxybenzamine and phentolamine and the beta-blocker propranolol inhibited the prolactin surge, with phenoxybenzamine being most effective. The administration of the serotonergic antagonist methysergide resulted in only a partial blockade of the afternoon prolactin surge. The data suggest that both the adrenergic and serotonergic systems may have a positive input in the afternoon surge of plasma prolactin. It appears that the cholinergic system does not play a significant role in the afternoon surge.