Characterization of a dose-response curve for nicotine-induced conditioned taste aversion in rats: relationship to elevation of plasma beta-endorphin concentration

In the first experiment a conditioned taste aversion paradigm was used to characterize a dose-response curve for the aversive properties of nicotine in male Sprague-Dawley rats. Doses of nicotine ranging from 0.01 to 0.46 mg/kg, 2.0 ml of 0.47 M lithium chloride, or saline were injected, ip, 10 min after exposure to a novel saccharin solution. Amount of saccharin consumed in a two-bottle test was assessed 72 h later. Nicotine doses of 0.046 mg/kg and above produced a significant degree of conditioned taste aversion. In a second experiment, four groups of 10 rats each were injected with saline, 0.022 mg/kg nicotine, 0.46 mg/kg nicotine, or 2.0 ml 0.47 of M LiCl. Doses of 0.46 mg/kg nicotine and 0.47 M LiCl elevated plasma beta-endorphin concentrations significantly above saline control values. The 0.022 mg/kg dose, the highest dose that did not produce conditioned taste aversion in Experiment 1, did not significantly increase plasma beta-endorphin concentrations. This finding suggests that doses of nicotine that produce conditioned taste aversion also promote the release of pituitary stress hormones. Taken together these data suggest that some of the pharmacological and behavioral effects attributed to nicotine, including the release of endogenous neuromodulators, may be dose-dependent concomitants of the aversive effects of nicotine in nicotine-naive animals.     

Effects of schedule of reinforcement on a pentobarbital discrimination in rats.

The purpose of this study was to determine the effects of the schedule of reinforcement on a pentobarbital discrimination in rats. Five rats were trained to discriminate 10 mg/kg pentobarbital from saline under a multiple fixed-interval 180-s fixed-ratio 20 schedule of reinforcement. During both saline and pentobarbital training sessions, subjects emitted a higher percentage of correct responses under the fixed-ratio component as compared to the fixed-interval component of the multiple schedule. Determination of the pentobarbital dose-response curve under the fixed-ratio component resulted in a steep curve characterized by responding on the saline lever at low doses and on the drug lever at higher doses. Under the fixed-interval component, a graded dose-effect curve was produced, with considerable responding on both levers after intermediate doses of pentobarbital. The administration of phencyclidine and MK-801 resulted in an intermediate level of drug-lever responding for some subjects. Administration of d-amphetamine resulted in saline (nondrug) appropriate responding. The results of this study demonstrate that the schedule of reinforcement is a determinant of drug stimulus control, just as it is a determinant of other drug effects.     

Effects of amphetamine-CNS depressant combinations and of other CNS stimulants in four-choice drug discriminations

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine-pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs at these doses, and saline (methamphetamine-morphine group). After 10 to 13 months of training, the pigeons averaged more than 90% of their responses on the appropriate key during training sessions. In subsequent testing, dose-response curves were determined for the individual drugs, for a wide range of dose combinations of the training drugs, and for two drugs to which the pigeons had not been exposed previously (pseudoephedrine and nicotine). After low test doses of the training drugs, pigeons responded on the saline key. As the dose increased, responding on the key associated with that drug during training sessions increased. When training drugs were combined at doses that were not discriminable when given alone, responding occurred on the saline key. When a discriminable dose of one training drug was combined with a nondiscriminable dose of the other training drug, responding occurred on the key associated with the discriminable dose. When both drugs were given at discriminable doses, responding almost always occurred on the drug-combination key. The response-rate decreasing effects of pentobarbital and amphetamine were mutually antagonized when the drugs were combined, but the rate-decreasing effects of morphine and methamphetamine were not. After low doses of pseudoephedrine and nicotine, pigeons in both groups responded on the saline key. After higher doses of pseudoephedrine and nicotine, responding in the amphetamine-pentobarbital group occurred primarily on the amphetamine key. In the methamphetamine-morphine group, higher doses of pseudoephedrine and especially nicotine engendered more responding on the combination key than had occurred in the other group. The four-choice procedure can reveal subtle effects in the discrimination of individual drugs and drug combinations that are not apparent with procedures offering fewer response alternatives.     

Response suppression by visual stimuli paired with postsession d-amphetamine injections in the pigeon

Responding of pigeons, maintained under a fixed-interval 3-minute schedule of food presentation, was decreased on days that the color of the lights illuminating the food magazine was changed and d-amphetamine (1.0 mg/kg, i.m.) was injected after the session. Responding was not decreased by keylight color changes paired with postsession d-amphetamine or by postsession injections of saline. Administration of pentobarbital (3.0 to 5.6 mg/kg), but not d-amphetamine (.3 to 3.0 mg/kg), before the session increased rates of responding suppressed by drug-paired magazine lights. Responding maintained under a fixed-ratio 30-response schedule was not decreased when differently colored magazine lights were paired with a low (.3 mg/kg) postsession dose of d-amphetamine; with high (3.0 mg/kg) postsession doses, however, responding was completely suppressed after two pairings. The effects of pairing magazine stimuli with an intermediate (1.0 mg/kg) postsession dose of d-amphetamine depended upon the magnitude of prior postsession doses. After being paired with a low dose, stimuli paired with 1.0 mg/kg did not suppress responding. After being paired with a high dose, stimuli paired with 1.0 mg/kg completely suppressed responding. The suppression of food-maintained responding by stimuli paired with postsession drug administration depends upon both behavioral and pharmacological variables.     

Further evaluation of morphine aversion: maintenance of a taste aversion using a low, nonaversive morphine dose

Previously, in an investigation of morphine-conditioned taste aversion (CTA), we found that limited preexposure to a low, nonaversive (non-CTA-inducing) dose of morphine (2.5 mg/kg) was as effective as preexposure to a higher, CTA-inducing dose (15 mg/kg) in blocking the formation of a subsequent morphine CTA. In the present study, we examined the capacity of this low, 2.5-mg/kg morphine dose to maintain a CTA initially induced by the 15-mg/kg dose. A standard CTA procedure was used. Results indicated that rats given three initial taste-drug pairings with 15 mg/kg morphine followed on subsequent pairing days by treatment with the low, non-CTA-inducing, 2.5-mg/kg dose continued to exhibit a strong CTA over 8 pairing days. A similar pattern was observed for animals continuing to receive taste-drug pairings with the 15-mg/kg dose. Animals receiving only one taste-drug pairing with the 15-mg/kg dose, followed on subsequent pairing days by 2.5-mg/kg conditioning, failed to show such a pattern of CTA. An intermediate CTA pattern was seen with animals conditioned with 15, 10, 5, and repeated 2.5-mg/kg doses over consecutive pairing days. These data suggest that exposure to a low dose of morphine, with no apparent CTA-inducing properties, is sufficient to maintain a previously established morphine taste aversion. Potential implications for understanding the apparent discriminative complexity of morphine's motivational properties are discussed.     

Long-delay associations between drug states produced in rats by injecting two drugs in sequence

Injection of pentobarbital after a rat has consumed saccharin solution usually produces a mild aversion to the saccharin. However, the pentobarbital-produced aversion is eliminated or attenuated by prior pairings of pentobarbital injections with lithium injections. This is called the Avfail (aversion failure) effect. The present experiments dealt with the effect of the temporal relation of the pentobarbital injection to the lithium injection. After forward pairings (pentobarbital before lithium) with delays between the two injections varying among groups from 2.5 min to 320 min, Avfail was invariably obtained. There was little effect of the length of the forward delay, although the Avfail effect appeared to be slightly stronger at 30-40 min or so. When the two drugs were injected simultaneously or in a backward sequence, there was a weakening of the flavor aversion produced by pentobarbital, but this is attributable to habituation to the drugs, not to Avfail.     

Conditioned taste aversions support drug discrimination learning at low dosages of morphine.

The present experiment shows that a conditioned taste aversion procedure can support discrimination learning at dosages of morphine comparable to those required to produce motivational effects. Sprague-Dawley rats were injected with 4.0 mg/kg morphine sulfate prior to a saccharin-lithium chloride pairing, and physiological saline prior to a saccharin-saline pairing. The rats avoided the saccharin solution following the administration of morphine and consumed significantly more saccharin following saline administration after four discrimination cycles. After this initial discrimination the subjects were trained with progressively lower doses of morphine. Discrimination learning was apparent at doses of 2.0, 1.5, 1.0, 0.75 and 0.5 mg/kg. Animals initially trained with 1.0 mg/kg morphine also learned the discrimination but required 10 training cycles. After this initial discrimination the subjects were trained with progressively lower dosages of morphine and showed a discrimination at a dosage of 0.5 mg/kg.     

Drug discrimination under a concurrent fixed-ratio fixed-ratio schedule.

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-ratio 10 fixed-ratio 40 schedule of food presentation, in which the fixed-ratio component with the lower response requirement was programmed to reinforce responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized, pigeons averaged 98% of their responses on the pentobarbital-biased key during training sessions preceded by pentobarbital, and they averaged 90% of their responses on the saline-biased key during training sessions preceded by saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, or ethanol, pigeons switched from responding on the saline-biased key at low doses to responding on the pentobarbital-biased key at higher doses (the dose-response curve was quantal). High doses of phencyclidine produced responding on both keys, whereas pigeons responded almost exclusively on the saline-biased key after all doses of methamphetamine. These and previous experiments using concurrent reinforcement schedules to study drug discrimination illustrate that the schedule of reinforcement is an important determinant of the shape of dose-effect curves in drug-discrimination experiments.     

Effects of promazine, chlorpromazine, d-amphetamine, and pentobarbital on treadle pressing by pigeons under a signalled shock-postponement schedule.

The effects of promazine on treadle pressing to postpone the presentation of electric shock were studied in three pigeons. The effects of chlorpromazine, d-amphetamine, and pentobarbital were studied in two of these pigeons. Each treadle press postponed electric shock for 20 sec and presentation of a preshock stimulus for 14 sec. Selected doses of both promazine and chlorpromazine increased the rates of treadle pressing in all birds. The response-rate increases produced by promazine and chlorpromazine were due to increased conditional probabilities of treadle pressing both before and during the preshock stimulus. d-Amphetamine (1 and 3 mg/kg) slightly increased responding in one of the birds, but not to the extent that promazine or chlorpromazine did. In the other bird, the 10 mg/kg dose of d-amphetamine increased shock rate but did not change response rate. Some doses of d-amphetamine increased the conditional probabilities of responding both in the absence of the preshock signal and during the preshock signal in both birds. Pentobarbital only decreased response rates and increased shock rates.     

Effects of flavor salience on aversion performance following relatively long-delay backward conditioning procedures

Male albino rats (n = 144) received a 0.15 M injection of lithium chloride (at 2.0% body wt), followed 10, 30, or 75 min later by a 5.0% casein CS or a 10.0% sucrose CS, casein being the more salient CS. For each CS one-third of the rats received no fluid during the toxin-CS interval. The remaining two-thirds of the rats received 2-min access to distilled water or to a novel flavor 5 min after onset of the toxin-CS interval. For sucrose CS groups, the novel flavor was casein; for casein CS groups, the novel flavor was sucrose. Groups which received no fluid during the toxin-CS interval showed reliably greater aversion effects to the casein CS than to the sucrose CS. Results of Test Trial 1 showed that aversion to casein was relatively unchanged across toxin-CS intervals, while aversion to sucrose decreased reliably from the 10-min to the 30- and 75-min intervals. However, for each toxin-CS interval, aversion to the sucrose CS was reliably enhanced when casein access occurred in the interval, relative to that for distilled water or no fluid access. For the casein CS, access to sucrose or distilled water in the toxin-CS interval altered aversion effects, relative to the no fluid condition, depending on the interval.     

Drug discrimination under a concurrent schedule.

Three pigeons were trained to discriminate a 5.0 mg/kg dose of pentobarbital from saline under a two-key concurrent schedule with responding on the key associated with the presession injection, under both stimulus conditions, producing four times as many reinforcers as responding on the other key. This concurrent schedule resulted in approximately 70% responding to the higher reinforcement key under the pentobarbital stimulus and approximately 30% responding to that key under the saline stimulus. During testing, then, the pigeons were able to dose-dependently emit higher (>70%) or lower (<30%) values than were established under the control conditions. Dose-response curves were determined for pentobarbital (twice), methamphetamine, phencyclidine, chlordiazepoxide, and the combination of pentobarbital and the barbiturate antagonist bemegride. The results obtained with pentobarbital and chlordiazepoxide showed that, as the dose increased, pentobarbital-appropriate responding also increased. Methamphetamine produced relatively flat dose--response curves, whereas phencyclidine administration produced inconsistent effects on responding. The combination of the training dose of pentobarbital with increasing doses of bemegride produced a decrease in pentobarbital-appropriate responding. The results also showed that the dose-response curves for pentobarbital and chlordiazepoxide, instead of being all or none, were graded functions of the drug dose.     

Flavor preexposures in a conditioned taste aversion situation: a dissociation of behavioral and endocrine effects in rats

A series of experiments examined the effects of flavor preexposures on pituitary-adrenal/behavior relations in a conditioned taste aversion paradigm. It was found that reexposure to a novel milk solution paired earlier with lithium chloride (LiCl) elicited conditioned activation of the pituitary-adrenal system (Experiment 1). The unconditioned response to LiCl (measured by changes in plasma levels of corticosterone) did not vary as a function of prior (2 and 5 vs. 10) exposures to the milk solution (Experiment 2). Increased familiarity with the substance (resulting from 10 prior exposures) rendered the conditioning of a taste aversion to this substance less effective. Further, reexposure to this familiar substance after its pairing with LiCl was not accompanied by the characteristic conditioned pituitary-adrenal activation (Experiment 3). By titrating the number of conditioned stimulus (CS) preexposures (Experiment 4) it was found that within the range of preexposures manipulated (5-10), subjects exhibited (a) a coupling of behavioral and pituitary-adrenocortical responses when the conditioned taste aversion to the milk solution was paralleled by elevated plasma corticosterone (5-6 preexposures), (b) a coupling of these two response systems when flavor consumption was accompanied by suppressed plasma titers of corticoids (9-10 preexposures), or (c) a dissociation of the two system when the conditioned taste aversion was not accompanied by conditioned adrenocortical activity (7-8 preexposures). These data are discussed in terms of a dissociation in the effects of CS preexposures on conditioned adrenocortical and behavioral response systems.     

The Impairment of Retention Induced by Insulin in Mice May Be Mediated by a Reduction in Central Cholinergic Activity

Immediate posttraining intraperitoneal injection of nonconvulsive doses of insulin (2-20 IU/kg) significantly impaired retention of male Swiss mice tested 24 h after training in a one-trial step-through inhibitory avoidance task. The dose-response curve showed a U-shaped form. However, of the doses tested, only 8 IU/kg was effective. Insulin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of insulin on retention performance were not due to nonspecific proactive effects on response latencies. The impairing effects of insulin (8 IU/kg) on retention were time-dependent, which suggests that insulin impaired memory storage. The simultaneous administration of glucose (10-1000 mg/kg) antagonized, in a dose-related manner, the actions of insulin (8 IU/kg) on retention, suggesting that the hormone may have produced a hypoglycemic response leading to a decrease in CNS glucose availability with a subsequent memory impairment. Low subeffective doses of atropine (0.5 mg/kg) or mecamylamine (5 mg/kg), but not methylatropine (0.5 mg/kg) or hexamethonium (5 mg/kg), given immediately after training but 10 min before an ineffective dose of insulin (4 IU/kg), interacted with and impaired retention. The central anticholinesterase physostigmine (35 or 70 μg/kg), but not its quaternary analog neostigmine (35 or 70 μg/kg), prevented the memory impairment induced by insulin (8 IU/kg). Considered together, these findings are consistent with the view that a decrease in the CNS glucose availability impairs the synthesis and/or release of acetylcholine in brain regions critically involved in memory storage.     

Drug discrimination under concurrent variable-ratio variable-ratio schedules

Pigeons were trained to discriminate 5 mg/kg pentobarbital from saline under concurrent variable-ratio (VR) VR schedules, in which responses on the pentobarbital-biased lever were reinforced under the VR schedule with the smaller response requirements when pentobarbital was given before the session, and responses on the saline-biased key were reinforced under the VR schedule with the larger response requirements. When saline was administered before the session, the reinforcement contingencies associated with the two response keys were reversed. When responding stabilized under concurrent VR 20 VR 30, concurrent VR 10 VR 40, or concurrent VR 5 VR 50 schedules, pigeons responded almost exclusively on the key on which fewer responses were required to produce the reinforcer. When other doses of pentobarbital and other drugs were substituted for the training dose, low doses of all drugs produced responding on the saline-biased key. Higher doses of pentobarbital and chlordiazepoxide produced responding only on the pentobarbital-biased key, whereas higher doses of ethanol and phencyclidine produced responding only on this key less often. d-Amphetamine produced responding primarily on the saline-biased key. When drugs generalized to pentobarbital, the shape of the generalization curve under concurrent VR VR schedules was more often graded than quantal in shape. Thus, drug discrimination can be established under concurrent VR VR schedules, but the shapes of drug-discrimination dose-response curves under concurrent VR VR schedules more closely resemble those seen under interval schedules than those seen under fixed-ratio schedules. Graded dose-response curves under concurrent VR VR schedules may relate to probability matching and difficulty in discriminating differences in reinforcement frequency.     

Long-term memory for instrumental responses does not undergo protein synthesis-dependent reconsolidation upon retrieval

Recent evidence indicates that certain forms of memory, upon recall, may return to a labile state requiring the synthesis of new proteins in order to preserve or reconsolidate the original memory trace. While the initial consolidation of "instrumental memories" has been shown to require de novo protein synthesis in the nucleus accumbens, it is not known whether memories of this type undergo protein synthesis-dependent reconsolidation. Here we show that low doses of the protein synthesis inhibitor anisomycin (ANI; 5 or 20 mg/kg) administered systemically in rats immediately after recall of a lever-pressing task potently impaired performance on the following daily test sessions. We determined that the nature of this impairment was attributable to conditioned taste aversion (CTA) to the sugar reinforcer used in the task rather than to mnemonic or motoric impairments. However, by substituting a novel flavored reinforcer (chocolate pellets) prior to the administration of doses of ANI (150 or 210 mg/kg) previously shown to cause amnesia, a strong CTA to chocolate was induced sparing any aversion to sugar. Importantly, when sugar was reintroduced on the following session, we found that memory for the task was not significantly affected by ANI. Thus, these data suggest that memory for a well-learned instrumental response does not require protein synthesis-dependent reconsolidation as a means of long-term maintenance.     

Selective antagonism of the error-increasing effect of morphine by naloxone in a repeated-acquisition task.

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. The response chain was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When either morphine or naloxone was administered alone, the overall response rate decreased with increasing doses. The rate-decreasing effect was accompanied by an increase in percent errors with morphine but not with naloxone. Both effects of morphine were antagonized by doses of naloxone that were ineffective when given alone. The antagonism was selective in that naloxone (3 mg/kg) completely blocked the error-increasing effect but not the rate-decreasing effect of the higher doses of morphine. The view that naloxone is a specific narcotic antagonist was supported by the finding that naloxone failed to antagonize the rate-decreasing and error-increasing effects of d-amphetamine, pentobarbital, and phencyclidine.     

Electrophysiological responses to ethanol, pentobarbital, and nicotine in mice genetically selected for differential sensitivity to ethanol

Cortical electroencephalographic (EEG) changes induced by ethanol (4.3 and 1.4 g/kg, ip), pentobarbital (50 and 16 mg/kg), and nicotine (1.0 g/kg) were examined in long-sleep (LS) and short-sleep (SS) mice that were genetically selected for differential sleep times induced by a hypnotic dosage of ethanol. Ethanol (4.3 g/kg) caused EEG changes that paralleled the behavioral differences, whereas no differences between selected lines were observed following the activating dose (1.4 g/kg). Data support the notion that the known difference in ethanol sleep times is due not to greater SS sensitivity to ethanol activation but rather to greater LS sensitivity to ethanol hypnosis. No differences between selected lines were observed following 50 mg/kg pentobarbital, which again parallels previous behavioral data. The SS mice were more responsive to pentobarbital activation (16 mg/kg). Nicotine more severely reduced EEG power and heart rate in LS mice; a continuous iv infusion of nicotine elicited a distinct pattern of behavioral stereotypy for each selected line, with more profound motor and reflex depression in LS mice. The lines do not differ in rate of nicotine metabolism, hence they must differ in central nervous system sensitivity to nicotine. Thus, lines of mice selectively bred for differential sensitivity to ethanol also display marked differences in electrophysiological and behavioral responses to nicotine.     

Involvement of central cholinergic mechanisms in the effects of oxytocin and an oxytocin receptor antagonist on retention performance in mice

Oxytocin (OT, 0.10 microg/kg, sc) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. In contrast, the immediate post-training administration of the putative oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Thy-NH(9)(2)] OVT (AOT, 0.30 microg/kg, sc) significantly enhanced retention performance. Neither OT nor AOT affected response latencies in mice not given footshock on the training trial, and neither the impairing effects of OT nor the enhancing effects of AOT were seen when the training-treatment interval was 180 min, suggesting that both treatments influenced memory storage. The effects of OT (0.10 microg/kg, sc) on retention were prevented by AOT (0.03 microg/kg, sc) given immediately after training, but 10 min prior to OT treatment. The central acting anticholinesterase physostigmine (35, 70, or 150 microg/kg, i.p.), but not its quaternary analogue neostigmine (150 microg/kg, i.p.), reversed the impairment of retention performance induced by OT, whereas low subeffective doses of the centrally active muscarinic cholinergic antagonist atropine (0.5 mg/kg, i.p.) or the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg, i.p.), but not methylatropine (0.5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.) prevented the enhancement of retention performance caused by AOT. We suggest that oxytocin negatively modulates the activity of central cholinergic mechanisms during the posttraining period that follows an aversively motivated learning experience, leading to an impairment of retention performance of the inhibitory avoidance response.     

Effects of Posttraining Administration of Glucose on Retention of a Habituation Response in Mice: Participation of a Central Cholinergic Mechanism

Male Swiss mice were allowed to explore a novel environment, provided by an open-field activity chamber, for 10 min. The procedure was repeated twice with a 24-h interval. The difference in the exploratory activity between the first (training) and the second (testing) exposures to the chamber was taken as an index of retention of this habituation task. Posttraining intraperitoneal administration of glucose (10–300 mg/kg) enhanced retention in a dose-related manner, although only the dose of 30 mg/kg of glucose produced significant effects. Thus, the dose–response curve adopted an inverted U-shaped form. Glucose (30 mg/kg) given to untrained mice did not modify their exploratory performance when recorded 24 h later. The effects of glucose on retention were time-dependent, suggesting an action on memory storage. The memory-improving actions of glucose were prevented by the simultaneous administration of both the central acting muscarinic cholinergic antagonist atropine (0.5 mg/kg) and by the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg). In contrast, neither methylatropine (0.5 mg/kg), a peripherally acting muscarinic receptor blocker, nor hexamethonium (5 mg/kg), a peripherally acting nicotinic receptor blocker, prevented the effects of glucose on retention. Low subeffective doses of glucose (10 mg/kg) and the central anticholinesterase physostigmine (35 μg/kg), but not neostigmine (35 μg/kg), given together, act synergistically and facilitated retention. We suggest that glucose modulates memory storage of one form of learning elicited by stimuli repeatedly presented without reinforcement, probably through an enhancement of brain acetylcholine synthesis and/or its release.     

AF-DX 116, a Presynaptic Muscarinic Receptor Antagonist, Potentiates the Effects of Glucose and Reverses the Effects of Insulin on Memory

Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of -(+)-glucose (10 mg/kg, ip), but not its stereoisomer -(−)-glucose (30 mg/kg, ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg, ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose-related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice.