Floor Cues Research Articles

Drug-free and context-dependent locomotor hyperactivity in DBA/2 J mice previously treated with repeated cocaine: Relationship with behavioral sensitization and role of noradrenergic receptors

Drug-associated contexts and discrete cues can trigger motivational states responsible for drug-seeking behavior and relapse. In preclinical research, drug-free conditioned hyperactivity has been used to investigate the expression of memories associated with psychostimulant drug effects. Addictive drugs can produce long-lasting sensitization to their psychomotor actions, a phenomenon known as behavioral sensitization. The neuroplasticity underlying behavioral sensitization appears to be involved in pathological drug pursuit and abuse. In the present study we evaluated drug-free, context-dependent hyperactivity in DBA/2 J mice previously treated with cocaine and we explored whether this conditioned effect was related to behavioral sensitization. Given the role of noradrenergic (NA) neurotransmission in memory retrieval, consolidation and reconsolidation processes, we also investigated whether conditioned hyperactivity in a drug-free state was mediated by NA receptors. Animals underwent a sensitization protocol with six cocaine injections (0, 5, 10 or 20 mg/kg) paired to a particular floor cue. Three days after this sensitization phase, all animals were exposed to the same familiar floor environment without drug treatment. A second test with an unfamiliar floor was conducted 24 h later. Conditioned hyperactivity was also explored after one or three cocaine pairings and was evaluated for its duration (with repeated familiar vs. unfamiliar floor tests). In a series of pharmacological experiments, we evaluated the effects propranolol (a non-selective antagonist of β1- and β2-receptors) and prazosin (α1-receptor antagonist) on conditioned hyperactivity. Cocaine treatment produced both robust sensitization and drug-free conditioned hyperactivity, an effect that lasted up to 17 days (with cocaine 20 mg/kg). A significant correlation between the magnitude of cocaine sensitization and the level of conditioned hyperactivity was found. Propranolol, but not prazosin, blocked context-dependent hyperlocomotion in a drug-free state. Our data, together with a vast body of literature, indicate that the NA system plays a key role in the retrieval and behavioral expression of drug-associated memories.

Objects and landmarks: hippocampal place cells respond differently to manipulations of visual cues depending on size, perspective, and experience.

Human navigation studies show that landmarks are used for orientation, whereas objects contribute to the contextual representation of an environment. What constitutes a landmark? Classic rodent studies show that hippocampal place fields are controlled by distal, polarizing cues. Place fields, however, are also influenced by local cues. One difficulty in examining mechanisms by which distal and local cues influence the activity of hippocampal cells is that distant cues are necessarily processed visually, whereas local cues are generally multimodal. Here, we compared the effects of 90° rotations under different cue conditions in which cues were restricted to the visual modality. Three two-dimensional visual cue conditions were presented in a square open field: a large vertical cue on one wall, a large floor cue in a corner abutting two walls, and a smaller complex floor cue in a corner adjacent to two walls. We show that rotations of large distal cues, whether on the wall or floor, were equally effective in controlling place fields. Rotations of the smaller floor cues were significantly more likely to result in remapping, whether or not animals were also exposed to the distal polarizing cues. Responses of distal and local cues were affected differently by extended experience. Our data provide evidence that hippocampal place cell responses to visual cues are influenced by perspective, salience of the cue, and prior experience. The hippocampus processes visual cues either as stable landmarks useful for orientation and navigation or as nonstationary objects or features of the local environment available for associative learning or binding items in context.

The role of the laterodorsal tegmental nucleus in methamphetamine conditioned place preference and locomotor activity

Methamphetamine (METH) indirectly stimulates the laterodorsal tegmental nucleus (LDT) acetylcholine (ACh) neurons to increase ACh within the ventral tegmental area (VTA). LDT ACh inhibition attenuates METH and saline locomotor activity. The aim of these experiments was to determine whether LDT ACh contributes to METH conditioned place preference (CPP). C57BL/6J mice received a bilateral electrolytic or sham lesion of the LDT. After recovery, mice received alternating pairings of METH (0.5 mg/kg) and saline with distinct tactile floor cues over 8 days. During preference tests, mice were given access to both floor types and time spent on each was recorded. Mice were tested again after exposure to both extinction and reconditioning trials. Brains were then processed for choline acetyltransferase immunohistochemistry to label LDT ACh neurons. Lesioned mice had significantly fewer LDT ACh neurons and showed increased saline and METH locomotor activity during the first conditioning trial compared to sham mice. Locomotor activity (saline and METH) was negatively correlated with the number of LDT ACh neurons. Lesioned and sham mice showed similar METH CPP following conditioning, extinction and reconditioning trials. LDT ACh neurons are not necessary for METH reward as indexed by CPP, but may be important for basal and METH-induced locomotor activity.

Effects of acute withdrawal on ethanol-induced conditioned place preference in DBA/2J mice

Reexposure to ethanol during acute withdrawal might facilitate the transition to alcoholism by enhancing the rewarding effect of ethanol. The conditioned place preference (CPP) procedure was used to test whether ethanol reward is enhanced during acute withdrawal. DBA/2J mice were exposed to an unbiased one-compartment CPP procedure. Ethanol (0.75, 1.0, or 1.5 g/kg IP) was paired with a distinctive floor cue (CS+), whereas saline was paired with a different floor cue (CS-). The withdrawal (W) group received CS+ trials during acute withdrawal produced by a large dose of ethanol (4 g/kg) given 8 h before each trial. The no-withdrawal (NW) group did not experience acute withdrawal during conditioning trials but was matched for acute withdrawal experience. Floor preference was tested in the absence of ethanol or acute withdrawal. All groups eventually showed a dose-dependent preference for the ethanol-paired cue, but development of CPP was generally more rapid and stable in the W groups than in the NW groups. Acute withdrawal suppressed the normal activating effect of ethanol during CS+ trials, but there were no group differences in test activity. Acute withdrawal enhanced ethanol's rewarding effect as indexed by CPP. Since this effect depended on ethanol exposure during acute withdrawal, the enhancement of ethanol reward was likely mediated by the alleviation of acute withdrawal, i.e., negative reinforcement. Enhancement of ethanol reward during acute withdrawal may be a key component in the shift from episodic to chronic ethanol consumption that characterizes alcoholism.

FAAH inhibitor, URB-597, promotes extinction and CB 1 antagonist, SR141716, inhibits extinction of conditioned aversion produced by naloxone-precipitated morphine withdrawal, but not extinction of conditioned preference produced by morphine in rats

Converging evidence suggests that the endogenous cannabinoid (eCB) system is involved in extinction of learned behaviours. Using operant and classical conditioning procedures, the potential of the fatty acid amide (FAAH) inhibitor, URB-597, and the CB 1 antagonist/inverse agonist, SR141716, to promote and inhibit (respectively) extinction of learned responses previously motivated by either rewarding or aversive stimuli was investigated. In the operant conditioning procedure (Expt. 1), rats previously trained to lever press for sucrose reward were administered URB-597 (0.3 mg/kg) or the CB 1 antagonist/inverse agonist SR141716 (2.5 mg/kg) prior to each of three extinction trials. In the conditioned floor preference procedure (Expts 2a–d), rats trained to associate morphine with one of two distinctive floors were administered one of several doses of the CB 1 antagonist/inverse agonist, AM-251 (Expt 2a) or URB-597 (Expt 2b and 2d) prior to each extinction/test trial wherein a choice of both floors was presented and prior to forced exposure to each floor (Expt 2c). In the conditioned floor aversion procedure (Expt. 3), rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered URB-597 or SR141716 prior to each of 24 extinction/testing trials. URB-597 did not promote and SR141716 did not reduce extinction rates for sucrose reward-induced operant responding (Expt. 1) or morphine-induced conditioned floor preference (Expts. 2a–d). In contrast, URB-597 facilitated, whereas SR141716 impaired, extinction of the conditioned floor aversion (Expt. 3). These data support previous reports that the eCB system selectively facilitates extinction of aversive memories. URB-597 may prove useful in targeting extinction of aversively motivated behaviours.

Effects of d‐Cycloserine on Extinction and Reconditioning of Ethanol‐Seeking Behavior in Mice

D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist, has been shown to enhance the extinction of both cocaine and amphetamine-induced conditioned place preference (CPP). However, there have been no reports of the effects of DCS on the extinction of ethanol-conditioned behaviors in mice. Thus, the current experiments examined the effects of DCS on the extinction and subsequent reconditioning of ethanol-induced CPP in mice. Male DBA/2J mice received either 2 or 4 pairings of ethanol (2 g/kg) with a conditioned stimulus (CS+) floor cue (and an equal number of saline pairings with a CS- floor cue on alternate days) resulting in either a weak or strong ethanol CPP, respectively. Following conditioning of a strong ethanol CPP mice received saline or 30 mg/kg DCS prior to each of the twelve 30-minute choice extinction trials administered at 48-hour intervals. Mice that had received conditioning of a weak ethanol CPP received saline, 30 or 60 mg/kg DCS immediately before each of the six 30-minute choice extinction trials. Following successful ethanol CPP extinction, mice received reconditioning trials similar to the initial conditioning trials. A final experiment examined the effects 12 DCS pre-exposures (15, 30, and 60 mg/kg) on initial conditioning of ethanol CPP. First, we showed that 2 doses of DCS (30 and 60 mg/kg) did not have aversive properties that could confound the effects on extinction of CPP (Experiment 1). Second, we showed that DCS (30 and 60 mg/kg) had no effect on the rate of extinction of either strong (Experiment 2) or weak (Experiment 3) ethanol-induced CPP. Interestingly, DCS administered during extinction interfered with reconditioning of ethanol-induced CPP--an effect specific to reconditioning, as DCS pre-exposure did not influence initial ethanol CPP conditioning (Experiment 4). These experiments show that although DCS showed no effect on extinction behavior, when given during extinction it interfered with subsequent reconditioning of ethanol CPP. The mechanisms of this effect were not, however, due to nonspecific interference with learning because repeated DCS pre-exposures did not impair initial conditioning of ethanol CPP.

Reference-dose place conditioning with ethanol in mice: empirical and theoretical analysis

A frequently expressed criticism of the conditioned place preference (CPP) procedure is that it sometimes lacks a graded dose-response curve for many drugs. We used a combination of standard and reference-dose CPP procedures to examine the dose-response curve for ethanol-induced CPP in DBA/2J mice. In the standard procedure, ethanol (0.5, 1.5, 2, and 4 g/kg) was paired with a distinctive floor cue, whereas saline was paired with a different floor cue. In the reference-dose procedure, each cue was paired with a different dose of ethanol. All mice received four 5-min trials of each type in both procedures. Standard procedures yielded similar levels of CPP at doses of 1.5, 2, and 4 g/kg, whereas 0.5 g/kg did not produce significant CPP. However, in the reference-dose procedure, exposure to the 0.5-g/kg dose interfered with CPP normally produced by 1.5 or 2 g/kg. Moreover, mice showed significant preference for the 4-g/kg-paired cue over the 1.5-g/kg-paired cue. These studies show that a reference-dose procedure can reveal effects of low doses that are sometimes difficult to detect in a standard procedure. The reference-dose procedure may also uncover differences between higher doses that normally produce similar preference. Efficacy of the reference-dose procedure may be explained by a theoretical analysis that assumes the procedure places behavior between the extremes of the performance range, offering a more sensitive method for detecting effects of manipulations that produce small changes and/or differences in the rewarding effects of ethanol.

Alcohol place preference conditioning in high- and low-alcohol preferring selected lines of mice

High- and low-alcohol preferring (HAP and LAP) selected lines of mice diverge greatly in free-choice alcohol consumption. This study investigated whether the lines differ in a measure of alcohol reward not dependent on drinking, specifically place conditioning. Mice were subjected to a differential conditioning procedure in which four alcohol-paired CS+ trials on one floor cue (0, 1.5, 3, or 4 g/kg; ns=20–24) alternated with four saline-paired CS− trials on a different floor cue. Testing was on a split floor, half CS+ and half CS−. HAP and LAP mice showed no preference at 0 g/kg, and equivalent, moderate preference at 1.5 and 3 g/kg alcohol. At 4 g/kg, LAP, but not HAP mice showed an increase in preference. The present findings imply greater efficacy of alcohol preference conditioning in LAP mice, but do not speak for line differences in sensitivity. Results do not support the hypothesis that selection for high drinking yields greater efficacy of alcohol as a reinforcer when reward is measured using a technique that does not rely on drinking. Low drinking in LAP mice may emerge from innate taste avoidance of alcohol as a result of selective breeding for low preference, which prevents them from encountering alcohol's rewarding, pharmacological effects.

Are memories for stimulus–stimulus associations or stimulus–response associations responsible for serial-pattern learning in rats?

Previous research has provided convincing evidence that rats can learn to anticipate the individual elements of a stimulus series consisting of differing amounts of food reinforcement. Rats prepared with lesions of the dorsal striatum or hippocampus were initially trained to acquire a three-element series consisting of 21 sucrose pellets, followed by 0- and 7-pellets (Noyes standard), respectively. During the initial 30 days of training, the animals were run in two adjacent runways; the runways included either of a white, rough runway or a black, smooth runway as additional series cues. Thus, training included both floor (S–R) cues and the series (inter-item memory) cues. Anticipation was defined as faster running on the 21- than on the 7-pellet element and 7- than on the 0-pellet element. While anticipation developed more slowly in the lesion groups than in the control group, all animals eventually demonstrated the ability to track the elements of the series. Reversal of the floor cues disrupted tracking in the hippocampus-lesioned and control animals; dorsal striatum-lesioned rats were also affected but did continue tracking. As a final test, shifting the order of the series produced a marked disruption in performance in the dorsal striatum-lesioned rats but not in the hippocampus-lesioned or control rats. The results are consistent with the proposal that integrated neural mediation is required for anticipation, with a system that includes the dorsal striatum necessary for the promotion of a reinforced approach response and a system that includes the hippocampus necessary for associating and temporarily maintaining an internal record of the different elements of the stimulus series.

DBA/2J mice develop stronger lithium chloride-induced conditioned taste and place aversions than C57BL/6J mice

Genetic differences in lithium-induced conditioned aversion were examined using both place- and taste-conditioning procedures. In the place-conditioning procedure, adult male C57BL/6J (B6) and DBA/2J (D2) mice were exposed to a differential conditioning procedure in which each mouse received four 30-min pairings of a distinctive floor cue immediately after IP injections of either 0.75, 1.5, or 3.0 mEq/kg LiCl. A different floor cue was paired with saline injections. A separate group of control mice received saline injections paired with both floor types. Subsequent floor preference testing revealed greater conditioned aversion in D2 mice compared to B6 mice in groups receiving 3.0 mEq/kg LiCl. Lower LiCl doses did not produce conditioning in either strain. In a conditioned taste-aversion procedure, fluid-restricted mice received four trials in which access to 0.2 M NaCl solution was followed by IP injection of either 0.75, 1.5, 3.0, or 6.0 mEq/kg LiCl. D2 mice showed stronger conditioned taste aversion than B6 mice at all doses, suggesting that taste conditioning may be a more sensitive index of aversive drug sensitivity than place conditioning. These findings are not well explained by strain differences in general learning ability or by strain differences in stimulus salience or innate preference. Rather, these data appear more consistent with previous studies showing strain differences in lithium pharmacokinetics and in general sensitivity to aversive events.

Ordinal Position Learning and Remote Anticipation

Rats were runway trained on each of two 3-trial series of reward outcomes. The series are labeled XNY and ZNN, for which X represents a trial that was rewarded with Noyes pellets and N represents a trial that ended with no reward. Units of distinctively flavored breakfast cereals served as reward on trials labeled Y and Z. One group (Floor) had each series occur with a correlated runway floor, either smooth and black or rough and white. For a second group (Memory), the floor cue was uncorrelated with series. Animals in both groups learned to approach the goal rapidly on the 1st trials of the 2 series and slowly on the 2nd trials, but only Group Floor learned to differentiate the 3rd trials of the series. These results recommend a view of serial learning that emphasizes the role played by information about the ordinal position of series items.

Ordinal position in the serial learning of rats

Rats were runway trained on each of two, three-trial series consisting of different varieties of reward (X, Y, and Z) and nonreward (N) serving as trial outcomes. The two series are represented as XNY and ZNN. Distinguishing the two series were different brightness and texture cues on the runway floor. Transfer tests, conducted after the rats had developed faster running for rewarded trials than for nonrewarded trials and slower running on Trial 2 of ZNN than on Trial 2 of XNY, provided evidence that trial position, rather than item memories, was controlling the discriminations. In Experiment 1, reversing the floor cues completely reversed the discriminations. In Experiment 2, transfer to NNN did not change the routine patterns of approach that had been established.

Altered Ambient Temperature and Ethanol-Induced Conditioned Place Preference in Mice

Previous studies with rats exposed to altered ambient temperature ( T a) or with mice selectively bred for their thermal response to ethanol have shown that a reduced hypothermic response is correlated with decreased place aversion and greater place preference, respectively. The present experiment was designed to test whether alterations in T a would alter ethanol’s ability to produce conditioned place preference in genetically heterogeneous mice. Three groups of mice underwent a differential conditioning procedure that paired one distinctive floor texture with ethanol (2.25 g/kg, IP) and a different floor texture with saline. During conditioning, each group was exposed to a different T a: cold (10°C), normal (21°C), or warm (34°C). Each group was further divided and subgroups were tested for preference at either the conditioning temperature or a different temperature. Consistent with previous findings, mice conditioned and tested at normal T a developed a conditioned preference for the ethanol-paired floor. In contrast, mice exposed to a warm or cold T a during conditioning or testing failed to show place conditioning. Although exposure to either warm or cold T a interfered with place conditioning, only the warm T a had an effect on hypothermia. These findings suggest that altered T a produced stimuli that may have interfered with the association between floor cues and ethanol during conditioning or interfered with expression of this association during testing.

Fluoxetine's effects on ethanol's rewarding, aversive and stimulus properties

These experiments examined the influence of fluoxetine on ethanol-induced conditioned place preference, ethanol-induced conditioned taste aversion, and ethanol discrimination. In the place conditioning experiment, male Swiss-Webster mice received 4 pairings of a distinctive floor cue with 2 g kg ethanol, 10 mg kg fluoxetine + ethanol, or fluoxetine alone. A different floor was paired with saline. During conditioning ethanol produced locomotor stimulation. Fluoxetine + ethanol resulted in greater levels of locomotor activity during conditioning trials 2–4. Fluoxetine alone also caused increases in activity. Floor preference testing revealed conditioned place preference in groups receiving ethanol. Fluoxetine did not change the magnitude of ethanol-induced conditioned place preference nor produced place conditioning alone. In the taste conditioning procedure, mice received 1-h access to 0.2 M NaCl solution followed by injections of 0, 5 or 10 mg kg fluoxetine and 0 or 2.5 mg kg ethanol. Ethanol produced reductions in NaCl intake. Fluoxetine (10 mg kg ) enhanced the development of ethanol-conditioned taste aversion but did not cause taste aversion alone. In the ethanol discrimination experiment, mice were trained to respond for 10% sucrose on an FR20 schedule following injections of either 1 g kg ethanol or saline. Following acquisition, 10 mg kg fluoxetine pretreatment enhanced ethanol-appropriate responding at a dose of ethanol (0.5 g kg ) below the training dose. These results indicate enhancement of serotonergic activity influences ethanol aversion and discrimination but not ethanol reward.

Localization of genes influencing ethanol-induced conditioned place preference and locomotor activity in BXD recombinant inbred mice.

Genetic differences in ethanol's ability to induce conditioned place preference were studied in 20 BXD Recombinant Inbred (RI) mouse strains and in the C57BL/6J and DBA/2J progenitor strains. Male mice from each strain were exposed to a Pavlovian conditioning procedure in which a distinctive floor stimulus (CS+) was paired four times with ethanol (2 g/kg). A different floor stimulus (CS-) was paired with saline. Control mice were injected only with saline. Floor preference testing without ethanol revealed significant genetic differences in conditioned place preference, with some strains spending nearly 80% time on the ethanol-paired floor while others spent only 50% (i.e., no preference). Control mice showed genetic differences in unconditioned preference for the floor cues, but unconditioned preference was not genetically correlated with conditioned preference. There were also substantial genetic differences in ethanol-stimulated activity, but contrary to psychomotor stimulant theory, ethanol-induced activity on conditioning trials was not positively correlated with strength of conditioned place preference. However, there was a significant negative genetic correlation (r = -0.42) between test session activity and preference. Quantitative trait loci (QTL) analyses showed strong associations (P < 0.01) between conditioned place preference and marker loci on chromosomes 4, 8, 9, 18 and 19. Weaker associations (0.01 < P < 0.05) were identified on several other chromosomes. Analysis also yielded several significant QTL for unconditioned preference, ethanol-stimulated activity, and sensitization. Overall, these data support the conclusion that genotype influences ethanol-induced conditioned place preference, presumably via genetic differences in sensitivity to ethanol's rewarding effects. Moreover, several chromosomal regions containing candidate genes of potential relevance to ethanol-induced conditioned place preference have been identified.

Morphine conditioned place preference and locomotion: the effect of confinement during training.

The effect of confinement during conditioning on subsequent test levels of locomotor activity and conditioned place preference (CPP) was investigated by giving rats discrimination training with morphine and saline in the presence of different tactile floor cues in an open field. Groups of rats were trained under one of three levels of confinement (not confined, confined to 1/4, or confined to 1/16 of the open field) and tested for locomotor activity and CPP in the entire open field after receiving a saline injection. Confined rats subsequently spent less time on the morphine-paired floor cues (CS+) and were more active throughout the open field during the test than rats not confined during conditioning. Rats confined to the smallest area spent the least time on the CS+ and were the most active. It is suggested that confinement may preserve the novelty of the testing environment, which in turn may interfere with rats' usual responses to incentive drug-paired stimuli. These findings may have important implications for versions of the CPP technique in which training and testing environments differ considerably.

Concurrent counting of two and three events in a serial anticipation paradigm

Rats were runway trained with four different series of reward events for the purpose of determining if two different number cues (two and three) could be adequately employed to correctly anticipate a terminal nonreward in the series. In two of the series, two rewarded runs always occurred prior to terminal nonreward; one of these series always began with a nonrewarded run, NRRN, and the other did not, RRN. For two other series, three rewarded runs predicted terminal nonreward, NRRRN and RRRN. Each rat experienced each of the four series once a day for 26 days. The interval between runs within a series was about 20 sec, the interval between series was about 15 min, and the order in which the series were presented was randomized daily. Distinctive floor cues (smooth/black or rough/white, balanced over animals) signaled two-count and three-count series. Our animals correctly anticipated (ran slowly to) the terminal nonreward of all four series. On Day 27, an initial nonrewarded run was added to the two series that had been initiated by nonreward (NNRRN and NNRRRN). This addition produced a disruption in terminal-event anticipation that lasted for only 1 training day. In all, the results imply that the animals were concurrently counting both two and three rewarded events, and it is further suggested that counting plays a prominent role in the rat’s serial learning.

Using Environmental Design to Teach Ward Layout to Severely and Profoundly Retarded Blind Persons: A Proposal

Two behavior modification specialists moved onto a ward for severely and profoundly retarded blind men in a state institution and implemented programs to train them in basic self-care skills including toileting, bathing, dressing, teethbrushing, etc. They found that the residents’ blindness greatly inhibited their attaining independence in the various skill areas of the program. Measures taken indicated that the residents also had an extremely low incidence of movement and social interaction and depended upon staff to a great degree to lead them around the ward. A simple and inexpensive environmental design system utilizing wall and floor cues is proposed to decrease fear of the environment and to promote movement, independence, and social interaction among the residents.

Effect of Thirst Drive Conditioning on Shuttle Performance by Satiated Rats

Shuttle runs between white and black sides of a shuttle box by satiated rats previously exposed to one side of the shuttle box during the 22nd hr. of water privation were faster than runs by a control group conditioned in a distinctively different apparatus. Less stable, statistically insignificant differences occurred among groups conditioned during the 2nd hr. of privation. Experimental groups failed to run faster on trials started in the conditioned compartment (escape trials) than on trials terminating in the conditioned compartment (avoidance trials); but comparable groups showed such a difference after shuttle compartments were made discriminable by floor cues as well as by color. The escape-avoidance difference was then largest for groups conditioned during the 2nd hr. of privation.