Cholinergic drugs reverse AF64A-induced impairment of passive avoidance learning in rats

The cholinergic neurotoxin AF64A was administered to rats in order to produce learning impairment to test the effect of cholinergic drugs. Seven days after receiving an intracerebroventricular injection of AF64A (2.5–7.5 nmol), rats were subjected to one-trial passive avoidance acquisition and tested 24 h later. Learning was significantly impaired at 3.75 nmol AF64A, a dose at which significant reduction in acetylcholine level and choline acetyltransferase and acetylcholinesterase activity in the hippocampus was observed but changes in monoamine levels in the hippocampus, general behavior, or sensory sensitivity were not observed. Arecoline (4 mg/kg, IP) and physostigmine (0.1 mg/kg, IP) significantly decreased the learning impairment produced by AF64A (3.75 nmol) when given before the acquisition of passive avoidance learning but not when given after the acquisition or before the 24 h retention test. These drugs and oxotremorine (0.1 mg/kg, IP) given immediately after the acquisition, however, improved passive avoidance retention when the interval between the acquisition and the test was shortened to 1 h. These results indicate that the impairment of learning in AF64A-treated rats is caused by a memory retention deficit and suggest that such impairment can be effectively ameliorated by cholinergic drugs.     

Assessment of drug effects on memory by delayed discrimination responses in rats

Delayed discrimination experiments were conducted to examine drug effects on memory in rats. Three kinds of experimental situations: a Y-maze, an operant chamber with two retractable levers, and an operant chamber with two fixed levers were used. A discriminative stimulus light either on the left or the right side of a stimulus panel was presented for a brief period in each situation. After a certain delay time following extinguishment of the light, a choice response to the previously lighted side was termed as a correct choice. Scopolamine at 0.015-0.06 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0 sec in the Y-maze situation and in trials with longer delay times in the operant chamber situations. Nicotine at 0.06-1 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0-4 sec in the Y-maze situation, a delay time of 4 sec in the retractable-lever operant chamber situation, and a delay time of 0.1 sec in the fixed-lever operant chamber situation. Using this delayed discrimination procedure, drug effects on the relationship between delay time and correct choice ratio were observed. From these results, the present procedure was found to be useful for the evaluation of drug effects on memory in rats.     

Effects of nicotinic agonists and antagonists on spatial working memory in normal adult and aged rats

The present study had two goals (1) to examine the effects of treatments with nicotinic agonist (nicotine) and antagonist (mecamylamine) on working memory in normal adult rats (14 months of age), and (2) to determine if treating aged (36 to 42 months of age), memory-impaired rats with nicotine could improve their memory function. Memory testing was carried out using a delayed non-matching to position paradigm in a T-maze. Rats were trained to run down one arm of the maze (e.g., right) on an information run and then, after a variable memory delay period of 10, 90, or 180 sec, run down the other arm (e.g., left). In normal adult rats after water injection, memory accuracy was inversely related to memory delay (> 90, 75, and 67% accuracy at the 10, 90, and 180 sec delays, respectively). Administration of nicotine (0.1 or 0.4 mg/kg), or mecamylamine (2.5 or 5 mg/kg), or combinations of these drugs had no significant effects on memory in these rats. However, mecamylamine alone or in combination with nicotine reduced running speed in the T-maze in normal adults, indicating that the drugs did produce some behavioral effects. In aged rats, memory accuracy after water injection was much lower than that of younger adults, averaging 64, 57, and 50% at 10, 90, and 180 sec delays. Interestingly, nicotine injections of 0.1 or 0.4 mg/kg resulted in highly significantly improved accuracy in the memory task. The deficit in memory accuracy in aged rats, evident even at the shortest delay period (10 sec), suggests that the rats may have had impairments in attention or visual discriminatory ability. If this is so, then the beneficial effects of nicotine observed in this study may be more related to its effects on attention rather than memory directly. © 1994 Wiley-Liss, Inc.     

Effects of intracerebroventricular injection of AF64A on learning behaviors in rats

The effects of intracerebroventricular (ICV) injection of ethylcholine aziridinium ion (AF64A) (3 nmole/2 microliter, each lateral ventricule), a putative selective cholinotoxin, on learning behaviors and choline acetyltransferase (ChAT) activity were studied in rats. AF64A-treated rats (AF64A-rat) exhibited deficient performance in a passive avoidance task and a delayed alternation task in the T-maze, but demonstrated superior avoidance response in a two-way shuttle avoidance task. These changes in learning behaviors were associated with the selective decrease of hippocampal ChAT activity. Physostigmine (0.1 mg/kg, i.p.) significantly improved the retention latency of AF64A-rats in the passive avoidance task. AF64A-rats receiving physostigmine (0.2 mg/kg, i.p.) exhibited a slight but not significant improvement of performance in the delayed alternation task in the T-maze. These findings suggested that ICV injection of AF64A may be useful for producing an experimental amnesia model with hippocampal cholinergic hypofunction like Senile dementia of the Alzheimer type (SDAT), if appropriate learning tests are selected.     

Protective effect of WEB 1881 FU on AF64A (ethylcholine aziridinium ion)-induced impairment of hippocampal cholinergic neurons and learning acquisition.

The effect of continuous administration of 4-aminomethyl-1-benzylpyrrolidin-2-one-hemifumarate (WEB 1881 FU) on cerebral cholinergic neurons was studied using rats treated with ethylcholine aziridinium ion (AF64A), a neurotoxic choline analog. AF64A (2.0 nmol, administered i.c.v.) caused a significant decrease in the hippocampal acetylcholine (ACh) content. This decrease in hippocampal ACh content was accompanied by a reduction of choline acetyltransferase (CAT) activity. Under these experimental conditions, the latency of the passive avoidance response of rats, determined with a step-through method, was strongly decreased as compared with that of sham-operated rats. Although treatment with WEB 1881 FU (50 mg/kg per day, administered orally for 7 days) from immediately after the administration of AF64A did not affect the AF64A-induced decrease of ACh in the hippocampus, 100 mg/kg per day of WEB 1881 FU (orally for 7 days) significantly suppressed the AF64A-induced declines in hippocampal ACh content and CAT activity. The AF64A-induced reduction in latency of the passive avoidance response was also significantly antagonized by the treatment with 100 mg/kg per day of WEB 1881 FU (administered orally for 7 days) from immediately after the administration of AF64A. Continuous administration of WEB 1881 FU (100 mg/kg per day, orally for 7 days) from 7 days after the treatment with AF64A also had a significant inhibitory effect on the AF64A-induced decrease in ACh content in the hippocampus. These results suggest that WEB 1881 FU may have protective actions on the destruction of hippocampal cholingergic neurons as well as memory impairment induced by AF64A administration.     

Alteration of Cholinergic Pressor and Antinociceptive Responses in Rats Pretreated with the Cholinergic Toxin AF64A

• 1.In the present study, the pressor and antinociceptive effects of physostigmine and oxotremorine were investigated in rats injected with AF64A intracerebroventricularly.
• 2.Physostigmine (50–100 μg/kg, IV)-induced pressor responses were significantly lower in AF64A-injected rats compared with saline-injected animals, whereas oxotremorine (20–80 μg/kg, IV)-induced responses were found to be similar to those seen in the saline group.
• 3.The physostigmine (100 μg/kg, SC)-induced antinociceptive effect was totally abolished by AF64A treatment, but that of oxotremorine (30 μg/kg, SC) remained unchanged at the tail-flick test.
• 4.The results of this study present functional evidence for AF64A-produced substantial loss of cholinergic neurons involved in the regulation of blood pressure and nociception but not in postsynaptic muscarinic receptors.

     

Comparative effects of dextromethorphan and dextrorphan on morphine, methamphetamine, and nicotine self-administration in rats.

The effects of dextromethorphan and its metabolite dextrorphan on morphine, methamphetamine and nicotine self-administration and on responding for a nondrug reinforcer (water) were assessed in rats. Both dextromethorphan and dextrorphan decreased morphine self-administration at 10-30 mg/kg, s.c., decreased methamphetamine self-administration at 20 and 30 mg/kg, s.c., and decreased nicotine self-administration at 5-30 mg/kg, s.c.; doses of both drugs less than 40 mg/kg, s.c. did not affect responding for water. The equal potencies of dextromethorphan and dextrorphan suggest mediation of these effects by a non-NMDA receptor mechanism, possibly involving blockade of alpha3beta4 nicotinic receptors. The results also suggest that dextromethorphan should be tested extensively as a potential treatment for diverse populations of drug-abusing patients.     

Role of the cholinergic system in the rat basolateral amygdala on morphine-induced conditioned place preference

The effects of intra-basolateral amygdala (intra-BLA) injections of physostigmine, atropine, nicotine and/or mecamylamine on morphine-induced conditioned place preference (CPP) in rats was investigated by using an unbiased 3-day schedule of place conditioning design. Animals that received 3 daily injections of morphine (0.5-10 mg/kg) subcutaneously (s.c.) or saline (1.0 ml/kg, s.c.) showed a significant preference for compartment paired with morphine. The maximum response was observed with 7.5 mg/kg of the opioid. Administration of the anticholinesterase drug, physostigmine (1, 3 and 5 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. Injections of antimuscarinic receptor agent, atropine (1, 4 and 7 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. The injections of nicotine (0.75, 1 and 2 microg/rat) potentiated the morphine (0.5 mg/kg)-induced place preference, while the nicotinic receptor antagonist, mecamylamine (1, 3 and 6 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. Furthermore, administration of atropine (7 microg/rat) but not mecamylamine (6 microg/rat) reduced the response induced by different doses of physostigmine plus morphine. Moreover, mecamylamine (6 microg/rat) but not atropine (7 microg/rat) reduced the response induced by different doses of nicotine plus morphine. It is concluded that the muscarinic and nicotinic receptor mechanisms in the BLA may be involved in the acquisition of morphine-induced place preference.     

Coptidis Rhizoma attenuates repeated nicotine-induced behavioural sensitization in the rat

Repeated injections of nicotine can produce an increase in locomotor activity and the expression of immediate-early gene, c-fos, in the central dopaminergic areas. Many studies have shown that Coptidis Rhizoma (CR) and its main alkaloid compound, berberine (BER), have a suppressive effect on the central nervous system. We examined the influence of CR or BER on repeated nicotine-induced locomotor activity in rats and the change of c-Fos expression in the brain by using immunohistochemistry. Male Sprague-Dawley rats were given CR and BER before repeated injections of nicotine hydrochloride (0.4 mg kg(-1), s.c.) twice daily for 7 days. After 3 days withdrawal, rats received a challenge injection of nicotine. Pretreatment with CR (100 mg kg(-1), i.p.) and BER (100 mg kg(-1), i.p.) significantly inhibited the nicotine-induced locomotor activity and expression of c-Fos in the striatum and the nucleus accumbens. These results suggest that CR and BER may produce inhibitory effects of nicotine on behavioural sensitization by possibly reducing postsynaptic neuronal activation in the central dopaminergic systems.     

Cholinergic drug effects on antidepressant-induced behaviour in the forced swimming test

The contribution of anticholinergic effects to the action of desipramine and nomifensine was investigated in the forced swimming test in rats. The immobility time was reduced by high doses of atropine (10-25 mg/kg i.p.) and scopolamine (1.5 mg/kg i.p., 1 and 0.5 h before the test, respectively) and was unaffected by physostigmine (0.25-0.5 mg/kg i.p., 1 h before the test). Unlike atropine (25 mg/kg), scopolamine (1.5 mg/kg) increased motor activity (open-field). The anti-immobility effect of i.p. desipramine (20 or 30 mg/kg) and nomifensine (2.5 or 5 mg/kg), administered 24, 5 and 1 h before the test, was potentiated by scopolamine (0.5-1.0 mg/kg) and antagonized by physostigmine (0.25-0.5 mg/kg). The brain levels of desipramine and nomifensine were unaffected by scopolamine or physostigmine. Motor performance was impaired in rats treated with physostigmine and desipramine whereas hypermotility was observed in rats treated with scopolamine and nomifensine. The anti-immobility effect of atropine (25 mg/kg) and scopolamine (1.5 mg/kg) was not antagonized by physostigmine (0.5 mg/kg). These results indicate that anticholinergic mechanisms alone are not sufficient to influence immobility time and suggest that the cholinergic system may control, the neural circuitry upon which desipramine and nomifensine act to reduce immobility time.     

Minaprine improves impairment of working memory induced by scopolamine and cerebral ischemia in rats

Using a repeated acquisition procedure in a three-panel runway apparatus, the effects of minaprine on the impairment of working memory produced by scopolamine, ethylcholine aziridinium ion (AF64A) or cerebral ischemia were investigated in rats. Minaprine (3.2–32 mg/kg IP) as well as idebenone (10–100 mg/kg IP) and physostigmine (0.1–0.32 mg/kg IP) dose-dependently reduced the increase of errors (pushes made on the two incorrect panels located at each choice point) induced by 0.56 mg/kg IP scopolamine. Cerebral ischemia for 5 min caused a significant increase of errors in the runway task. Minaprine at 3.2 and 10 mg/kg administered IP immediately after blood recirculation and again 30 min before the runway test conducted 24 h after ischemia, significantly reduced increases in errors expected to occur after 5 min of ischemia. Physostigmine 0.1 mg/kg similarly attenuated the increase in errors in ischemic rats. However, minaprine at doses up to 32 mg/kg IP failed to reduce the increase of errors induced by AF64A 2.5 nmol injected into the dorsal hippocampus. These findings suggest that minaprine exerts an ameliorating effect on amnesia produced by scopolamine and cerebral ischemia, probably through mediation of its stimulant action on central cholinergic systems.     

Acute behavioral tolerance to nicotine in the conditioned taste aversion paradigm

Acute behavioral tolerance to nicotine is a well‐established phenomenon in animals, although previous drug discrimination studies have suggested that subpopulations of rats may exist that fail to exhibit acute tolerance to nicotine. The present study sought to determine whether these findings might extend to the conditioned taste aversion (CTA) paradigm. In experiment 1, rats were administered 0.8 mg/kg s.c. nicotine or vehicle before a pairing session with saccharin, and then administered either 0.4 mg/kg nicotine or vehicle immediately afterward. Rats treated with vehicle pre‐session and then nicotine post‐session developed a significant CTA to nicotine, whereas rats treated with 0.8 mg/kg nicotine s.c. pre‐session failed to develop a CTA to nicotine. In experiment 2, rats were identified as exhibiting or failing to exhibit acute tolerance to nicotine in a drug discrimination paradigm. Rats that produced acute nicotine tolerance failed to develop a CTA after 24 h, but did so after 48 h, while rats that did not produce nicotine tolerance exhibited CTA after 24 h, but not after 48 h. These findings indicate that acute behavioral tolerance to nicotine extends to its aversion effects. Drug Dev Res 68:522–528, 2007. © 2008 Wiley‐Liss, Inc.     

Nicotine pretreatment diminished physostigmine-induced tremor in rats

The aim of this work was evaluate the effects of acute and chronic nicotine pretreatment in the physostigmine-induced tremor in rats. Wistar male rats (3-4 months) were pretreated acutely with different nicotine doses (0, 0.1, 0.5 or 1.0 mg/kg) 10 min before physostigmine (0 and 0.5 mg/kg) treatment and then the tremor was registered by computerized system for 10 min. In another group, rats were pretreated acutely with 0.1 mg/kg of nicotine, recovered at different times (30 or 70 min), and were registered for physostigmine-induced tremor. Nicotine was also used chronically with equal doses for 8 days and recovered at 2, 7 or 21 days before registration of physostigmine-induced tremor. Tremor spectral analysis was performed for amplitude and frequency quantification. Our data show that the acute and chronic nicotine pretreatments alter physostigmine spectrum profile. Nicotine decreased physostigmine-induced tremor amplitude (p<0.05), without changing its tremor frequency. In acutely pretreated rats, recovery experiments showed return of physostigmine-induced tremor for control levels after 70 min, but after 8 days of chronic nicotine pretreatment recovery was delayed 3 weeks. The data analysis shows that acute or chronic nicotine administration can alleviate the physostigmine-induced tremor. Chronic nicotine pretreatment has a long tremor alleviation effect of physostigmine-induced tremor. Possible mechanisms involving the nicotine effects on the physostigmine-induced tremor are discussed.     

Impairments of learning and memory following intracerebroventricular administration of AF64A in rats

Three types of learning and memory tests (Morris water maze, active and passive avoidance) were performed in rats following intracerebroventricular infusion of ethylcholine aziridium (AF64A). In Morris water maze, AF64A-treated rats showed the delayed latencies to find the platform from 6th day after the infusion. In pretrained rats, AF64A caused the significant delay of latency at 7th day, but not 8th day. In the active avoidance for the pre-trained rats, the escape latency was significantly delayed in AF64A-treatment. The percentages of avoidance in AF64A-treated rats were less increased than those in the control. Especially, the percentage of no response in the AF64A-treated rats was markedly increased in the first half trials. In the passive avoidance, AF64A-treated rats shortened the latency 1.5 h after the electronic shock, but not 24 h. AF64A also caused the pretrained rats to shorten the latency 7th day after the infusion, but not 8th day. These results indicate that AF64A might impair the learning and memory. However, these results indicate that the disturbed memory by AF64A might rapidly recover after the first retrain. Furthermore, these results suggest that AF64A may be a useful agent for the animal model of learning for spatial cognition.     

Acetylcholinesterase inhibitors partially generalize to nicotine discriminative stimulus effect in rats

Acetylcholinesterase inhibitors (AChE-Is), galantamine, physostigmine and tacrine, enhance central levels of synaptic acetylcholine. Galantamine and physostigmine, but not tacrine, exhibit allosteric potentiation ligand (APL) properties on nicotinic acetylcholine receptors. The purpose of this study was to investigate whether AChE-Is with nicotinic acetylcholine receptor-positive allosteric modulator properties generalize to the discriminative stimulus effect of nicotine in rats. A two-lever operant conditioning paradigm was used in which rats were trained to discriminate nicotine (0.2 mg/kg/ml intraperitoneally) from saline. After training, generalization tests were carried out with galantamine (1, 3 or 5 mg/kg intraperitoneally), physostigmine (0.05, 0.1 or 0.2 mg/kg subcutaneously) or tacrine (0.625, 1.25 or 2.5 mg/kg subcutaneously) given as a single presession administration. Galantamine, physostigmine or tacrine produced a partial generalization of 62.2%, 55.1% or 43.6% , respectively, on the nicotine-appropriate lever compared with 100% partial generalization induced by the nicotine-training dose. High doses of galantamine, physostigmine or tacrine produced small but significant decreases in operant response rate, suggesting a possible underestimation of the degree of generalization. Our study showed that these three AChE-Is partially generalized to the nicotine stimulus without a significant distinction between AChE-Is with or without APL properties. These findings suggest that the APL property is not necessary for inducing nicotine-like effects in vivo in this behavioural paradigm.     

Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice

The present study examined the effect of a range of doses of chronic nicotine (0.75, 1.5, 3.0 and 30.0 mg kg(-1) day(-1), s.c., 14 days) upon striatal dopaminergic nerve terminal survival following 6-hydroxydopamine (6-OHDA; 10 microg intrastriatal unilaterally) in rats; and the effects of acute nicotine (1 mg kg(-1), s.c.) pretreatment upon striatal neurodegeneration induced by methamphetamine (5 mg kg(-1), i.p., three doses at 2 h intervals) in wild-type and alpha4 nicotinic receptor (nAChR) subunit knockout mice. In both models of Parkinsonian-like damage, loss of striatal dopaminergic nerve terminals was assessed by [(3)H]-mazindol autoradiography. In rats, chronic nicotine infusion delivered by osmotic minipump implanted subcutaneously 7 days prior to intrastriatal 6-OHDA injection produced significant and dose-related protection against 6-OHDA-induced neurodegeneration. Low (0.75 and 1.5 mg kg(-1) day(-1)) but not high (3.0 and 30.0 mg kg(-1) day(-1)) nicotine doses significantly inhibited 6-OHDA-induced degeneration. In wild-type mice, acute nicotine treatment produced significant inhibition of methamphetamine-induced neurodegeneration. In alpha4 nAChR subunit knockout mice, acute nicotine treatment failed to inhibit methamphetamine-induced neurodegeneration. Nicotine is capable of protecting dopaminergic neurons against Parkinsonian-like neurodegeneration in vivo. In rats, this neuroprotective effect is critically dependent upon nicotine dose and is consistent with the activation of nAChRs, as high, desensitizing doses of nicotine fail to be neuroprotective. Further, neuroprotection is absent in alpha4 nAChR subunit knockout mice. The current results therefore suggest that activation of alpha4 subunit containing nAChRs constitutes a major component of the neuroprotective effect of nicotine upon Parkinsonian-like damage in vivo.     

Social isolation modifies nicotine's effects in animal tests of anxiety

1. These experiments determined whether the housing conditions of rats influenced the effects of nicotine in two animal tests of anxiety, social interaction and elevated plus-maze tests. 2. In animals housed singly for 7 days, (-)nicotine (0.025 mg kg(-1) s.c.) was ineffective, but 0.05, 0.1 and 0.25 mg kg(-1) (s.c.) significantly increased the time spent in social interaction, without changing locomotor activity, thus indicating anxiolytic actions. (-)Nicotine (0.45 mg kg(-1) s.c.) significantly reduced social interaction, indicating an anxiogenic effect. 3. However, in group-housed animals, (-)nicotine (0.025 mg kg(-1) s.c.) had a significant anxiolytic effect in the social interaction test, but 0.01, 0.05, 0.1, 0.25 and 0.45 mg kg(-1) were ineffective. (-)Nicotine (1 mg kg(-1)) reduced motor activity and social interaction in the group-housed animals. 4. In the elevated plus-maze, the time-course and the dose-response curve to nicotine were investigated. In both singly- and group-housed rats, (-) nicotine (0.1 - 0.45 mg kg(-1) s.c.) decreased the per cent entries into, and per cent time spent on, the open arms, indicating anxiogenic effects. 5. The housing condition influenced the time course, with significant effects at 5 and 30 min after injection in group-housed rats, and significant effects at 30 and 60 min in singly-housed rats. 6. In the social interaction test there was no difference in the scores of the first and last rats removed from group cages, whereas the order of removal from the cages did affect the scores in the elevated plus-maze. 7. These results provide further evidence that the two animal tests model distinct states of anxiety, and show how social isolation powerfully modifies both anxiolytic and anxiogenic effects of nicotine.     

Nicotine and vascular endothelial dysfunction in female ovariectomized rats: role of estrogen replacement therapy

Objectives The protective effects of estrogen replacement therapy (ERT) against oxidative injury and endothelial dysfunction in the aortic tissues induced with nicotine in ovariectomized (OVX) rats were investigated. Methods Female rats were divided into a sham‐operated group (n = 8) and four groups in which OVX rats received either vehicle (0.1 ml sesame oil, i.m., n = 8), or nicotine (0.1 mg/kg, s.c., n = 8), or estradiol benzoate (0.1 mg/kg, i.m., n = 8), or both nicotine and estradiol benzoate (n = 8) starting at week 5 after the surgery and continuing for the following 6 weeks. Key findings ERT was effective in preventing the rise in plasma lipid profile, atherogenic index and the level of induced endothelin‐1 (ET‐1) in nicotine‐treated OVX rats. It also reduced aortic malondialdehyde, hydroxyproline levels, calcium content and caspase‐3 expression induced in nicotine‐treated OVX rats. ERT increased serum estradiol, high‐density lipoprotein cholesterol and nitric oxide levels in nicotine‐treated OVX rats. Furthermore, ERT was effective in restoring reduced glutathione and cyclic guanosine monophosphate contents and endothelial nitric oxide synthase expression in aortic tissues of nicotine‐treated OVX rats. Conclusions Short‐term ERT could be a promising therapeutic strategy to minimize nicotine‐induced oxidative stress and vascular endothelial dysfunction in menopausal women subjected to environmental smoke.     

Tolerance and sensitization to stimulant and depressant effects of nicotine in intracranial self-stimulation in the rat

Nicotine is thought to be an important factor in addiction to tobacco but its psychopharmacological properties are still uncertain. In the present study, rats were trained to operate a pedal to obtain threshold-current, variable-interval hypothalmic stimulation. Response rates were printed out at 10min intervals to provide a continuous record of facilitatory or depressant effects by injected nicotine. Responding was enhanced in all rats but this depended on dose, time after injection, and previous exposure to the drug. In the first 10min after injection, responding by drug-naive rats was either unaffected (40-130mg/kg s.c., as base) or strongly depressed (400μg/kg). This phase was followed by prolonged (>50min) dose-dependent facilitation. Higher doses (1.3mg/kg) caused prostration. Chronic exposure to nicotine (400μg/kg x 10 at 2-5 day intervals) reduced the initial depressant effect; it also augmented subsequent responding, but only in the early minutes after injection; the latter finding indicates that apparent sensitization to chronic nicotine may depend primarily on tolerance to its depressant effects, rather than on receptor upregulation. Stimulant and depressant effects of nicotine were prevented by pretreatment with the centrally acting antagonist, mecamylamine (2.0mg/kg s.c.), but not by the peripheral antagonist, hexamethonium (1.0mg/kg s.c.) or by the muscarinic receptor antagonist, hyoscine (scopolamine; 100-300μg/kg s.c.). Self-stimulation was unaffected by mecamylamine alone. Thus the inhibitory action of nicotine is unlikely to be due to depolarization block, peripheral activity or muscarinic activity. Its facilitatory and depressant effects appear to be narrowly time- and dose-specific, thus accounting for divergent findings in many studies.     

Inhibitory actions of mGlu4 receptor ligands on cocaine-, but not nicotine-, induced sensitizing and conditioning locomotor responses in rats

BackgroundMale Wistar rats were used to verify the hypothesis that metabotropic glutamate 4 (mGlu₄) receptor ligands may modulate the locomotor effects evoked by cocaine or nicotine.MethodsThe preferential mGlu₄ receptor orthosteric agonist (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl]butanoic acid (LSP1-2111) and the mGlu₄ receptor positive allosteric modulator (+)-cis-N¹-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) were used in the study. Rats were given repeated pairings of a test environment with cocaine (10 mg/kg), nicotine (0.4 mg/kg) or the respective vehicles for 5 days. On day 10, animals were challenged with cocaine (10 mg/kg, cocaine sensitization), nicotine (0.4 mg/kg, nicotine sensitization) or vehicle (conditioned hyperlocomotion) in experimental cages.ResultsGiven on day 10, LSP1-2111 (3 mg/kg) as well as Lu AF21934 (2.5–5 mg/kg) decreased the expression of cocaine sensitization. In another set of experiments, LSP1-2111 (3 mg/kg) and Lu AF21934 (5 mg/kg) administered on day 10 attenuated the conditioned hyperlocomotion in rats treated repeatedly with cocaine. Neither LSP1-2111 (1–3 mg/kg) nor Lu AF21934 (2.5–5 mg/kg) changed the expression of nicotine sensitization and conditioned hyperlocomotion in rats treated repeatedly with nicotine. None of the mGlu₄ receptor agonist/modulator altered the basal locomotor activity or acute hyperactivity to cocaine or nicotine.ConclusionsThe present data indicate that pharmacological stimulation of mGlu₄ receptors reduces the cocaine-induced expression of sensitization as well as conditioned hyperactivity. In contrast, mGlu₄ receptor activation seems to be devoid of any effect on the locomotor effects of nicotine.