Associative factors in drug pretreatment effects on gustatory conditioning: Cross-drug effects

The pretreatment effect (PE) in gustatory avoidance conditioning refers to the fact that pretreatment with a variety of pharmacological agents subsequently reduces the ability of the same agents to induce gustatory aversion. Explanations of this phenomenon emphasize either tolerance or associative interference. Any explanation of the phenomenon must also account for the present findings which demonstrate the PE when agents of pretreatment and conditioning were pharmacologically dissimilar. Rats were pretreated with d-amphetamine and tested for acquisition of an aversion to saccharin conditioned by amphetamine or morphine. The PE was obtained regardless of the drug used in conditioning. An associative manipulation involving nonreinforced presentation of the drug administration cues (i.e., injections followed by saline instead of drug), that attenuated the PE when pretreatment and conditioning were with amphetamine, was also effective when the pretreatment agent was amphetamine and the conditioning agent was morphine. The findings were interpreted within a framework of compensatory conditioning of a general physiological mechanism common to all gustatory avoidance.     

Parametric investigations of the effects of prior exposure to amphetamine and morphine on conditioned gustatory aversion

Pretreatment by a psychoactive drug can greatly attenuate the conditioning of gustatory avoidance by that drug. Although such findings have been interpreted in terms of tolerance, alternative explantions are possible. In a series of experiments, it was found that pretreatments with morphine or amphetamine massed at 24-h intervals were no more effective in attenuating conditioning than pretreatments spaced at 120-h intervals, but pretreatment with morphine provided more persistent protection against subsequent conditioning by itself than did amphetamine in a comparable previous experiment. The similarity of massed and spaced pretreatment effects can be interpreted without appealing to tolerance as a factor, but the greater persistence of morphine pretreatment implicates tolerance as a mechanism.     

Latent inhibition is not affected by acute or chronic administration of 6 mg/kg dl-amphetamine

Latent inhibition (LI) is a behavioral paradigm in which animals learn to ignore a repeatedly presented stimulus not followed by meaningful consequences. We previously reported that LI was disrupted following the administration of 1.5 mg/kg dl-amphetamine. The present experiments investigated the effects of 6 mg/kg dl-amphetamine administration on LI in a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, the drug was administered in a 2×2 design, i.e. drug-no drug in pre-exposure and drug-no drug in conditioning. LI was obtained in all conditions. In Experiment 2, animals were given either 5 days of 6 mg/kg amphetamine pretreatment and amphetamine in pre-exposure and conditioning or 7 days of saline. LI was not obtained under amphetamine, but this outcome reflected a state-dependency effect. In Experiment 3, animals received either 5 days of amphetamine pretreatment and amphetamine in pre-exposure, conditioning and test or 8 days of saline. LI was obtained in both the placebo and amphetamine conditions. Experiments 4a and 4b compared the effects of two drug doses, 1.5 (4a) and 6 mg/kg (4b), administered in pre-exposure and conditioning. LI was abolished with the 1.5 mg/kg dose but not with the 6 mg/kg dose.     

Development of both conditioning and sensitization of the behavioral activating effects of amphetamine is blocked by the non-competitive NMDA receptor antagonist,MK-801

The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, has been shown to block the development of sensitization of the behavioral activating effects of amphetamine. Three experiments were designed to determine in rats whether MK-801 had its effects through interference with long-term changes underlying sensitization, per se, or through interference with the development of conditioning of the drug effect to the environment where the drug was given. In experiment 1, conditioning was promoted by explicitly pairing amphetamine (1.5 mg/kg, IP) with the testing environment. In experiment 2, a random-pairing procedure was used to eliminate the possibility of association between the drug and a specific context. Experiment 3 was carried out to assess the duration of the blockade of sensitization by MK-801. The effect of MK-801 (0.25 mg/kg, IP) during amphetamine pre-exposure was studied in tests for conditioning (following saline injections, experiment 1) and in tests for sensitization (following 0.75 mg/kg amphetamine, experiments 1, 2 and 3). It was found in experiment 1 that MK-801 given with amphetamine during the amphetamine pre-exposure phase blocked the development of both conditioning activity and environment-specific sensitization to amphetamine. The results of experiment 2, showing that sensitization to amphetamine was blocked by MK-801 even when conditioning was prevented, suggest that the two effects of MK-801 are independent, and may implicate different sites of action. Experiment 3 showed that the blockade of sensitization by MK-801 was evident in tests made 10 days after pre-exposure to amphetamine, supporting the view that MK-801 interferes with long-term changes underlying sensitization to amphetamine.     

Selective strengthening of conditioned behaviors that occur during periods of amphetamine exposure.

Exposure to psychomotor stimulants, during conditioning sessions, can lead to a persistent increase in the strength of conditioned behaviors and the effects of conditioned stimuli, which can be detected in subsequent drug-free periods. It is possible that the effects are selective for the behaviors and stimuli conditioned during drug exposure. The present study was designed to test this prediction. Animals were trained to discriminate two sets of stimuli. For each set, lever pressing during the presentation of one stimulus (S+) was reinforced and responding during the presentation of the other stimulus (S-) had no programmed consequences. Following an initial acquisition phase, training with one set of stimuli continued during sessions of amphetamine exposure, whereas training with the second set continued during saline exposure (20 intermixed sessions). The findings of subsequent drug-free choice tests showed that the drug history selectively enhanced the propensity of animals to engage in the drug-assigned behavior relative to the saline-assigned behavior. This change in behavior was evident in S+, but not S- trials and was potentially mediated by an acute effect of amphetamine on stimulus conditioning. The findings provide novel evidence that the facilitative effects of coincident conditioning and acute psychomotor stimulant exposure can be selective for the stimuli and behaviors conditioned during the drug exposure. These findings are relevant to hypotheses regarding the etiology of drug addiction.     

Effects of central and peripheral pretreatment with fluoxetine in gustatory conditioning

The administration of fluoxetine, a relatively specific serotonin uptake inhibitor, an hour prior to a taste-drug pairing was shown to attenuate the acquisition of taste aversions in a dose-dependent manner. Desipramine which is less effective than fluoxetine in blocking the reuptake of serotonin was also less potent in reducing the magnitude of taste aversions. Depletion of forebrain serotonin by lesions of the dorsal and median raphe nuclei or of norepinephrine by lesions of the dorsal noradrenergic bundle failed to prevent the pretreatment effect produced by either fluoxetine or desipramine. Rats with raphe lesions consistently consumed less of the taste paired with lithium than did control animals; however, this decreased intake occurred under both drug and saline pretreatment conditions, suggesting an increased sensitivity to the taste-lithium pairing rather than a diminution of the pretreatment effect. Rats with dorsal bundle lesions failed to differentiate between drug and saline pretreatment, consuming similar amounts under both conditions. These findings as well as the observation that intraventricular administration of fluoxetine did not produce a pretreatment effect suggest that forebrain serotonergic systems are not the critical site of action for the production of pretreatment effects by monoamine uptake inhibitors. Instead, the hypothesis that the peripheral effects of fluoxetine have a stimulus value that acts by way of an associative mechanism to attenuate gustatory conditioning must be considered.     

Learned taste aversion to saccharin following intraventricular or intraperitoneal administration of d,1-amphetamine

The effects of intracerebroventricular (ICV—160, 250, 500 μg) and intraperitoneal (IP—3,5 mg/kg) administration of d,1-amphetamine were compared using a multiple-bottle CTA procedure. After one conditioning trial animals receiving IP amphetamine exhibited a marked aversion to saccharin. This effect was dose-dependent. With cannulated animals receiving ICV saline the effectiveness of amphetamine at 5 mg/kg IP was equivalent to that of 3 mg/kg IP with unoperated rats. After one conditioning trial amphetamine at 160 μg ICV was ineffective in inducing an aversion to saccharin. Animals receiving 250 or 500 μg ICV exhibited a marked aversion to saccharin after one trial. The 160 μg ICV dose was effective after two conditioning trials. This differential potency of centrally and peripherally administered amphetamine after one conditioning trial indicates that the aversive stimulus properties of amphetamine may not simply be centrally mediated. It is proposed that both central and peripheral amphetamine effects may be necessary for the induction of a CTA with this drug.     

Effects of amphetamine on the plus-maze discriminative avoidance task in mice

RATIONALE: The contradictory amphetamine effects on memory could be due to different protocols of amphetamine administration or the well-known anxiogenic effect of the drug. OBJECTIVE: The effects of different protocols of administration of amphetamine were investigated on mice tested in the plus-maze discriminative avoidance task (DAT), which provides simultaneous information about memory and anxiety. METHODS: Acutely pre- or post-training, 0.3, 1.0, or 3.0 mg/kg amphetamine-treated, 10-day chronically 3.0 mg/kg amphetamine-treated, 0.3 mg/kg amphetamine plus 0.25 mg/kg scopolamine and 3.0 mg/kg amphetamine plus 3.0 mg/kg tacrine-treated mice were conditioned to choose between two enclosed arms (one of which was aversive) while avoiding two open arms. Learning/memory was evaluated by the percentage time in the aversive enclosed arm (PTAV), and anxiety by the percentage time in the open arms (PTO). RESULTS: Given acutely before conditioning, amphetamine significantly decreased PTO in training, suggesting an anxiogenic effect, and significantly increased PTAV in the test, suggesting an amnestic action. Given acutely after the conditioning, no action of this drug on memory was found. After repeated treatment, the anxiogenic effect disappeared, while the amnestic effect remained. While no effects of subeffective doses of amphetamine and scopolamine co-administration were detected, tacrine attenuated the amnestic effect of amphetamine. CONCLUSIONS: Amphetamine has different effects on DAT when given pre- or post-training. While acute pre-training amnestic action is temporally correlated with an anxiogenic effect, there is tolerance to the anxiogenic but not to the amnestic effect after repeated administration. Because this acute amnestic effect of amphetamine is attenuated by tacrine, a possible relationship with cholinergic system cannot be discarded as a mechanism to amphetamine-induced amnesia in DAT.     

Effect of the kappa-opioid receptor agonist, U69593, on reinstatement of extinguished amphetamine self-administration behavior

Previous research has indicated that pretreatment with the kappa-opioid receptor agonist, U69593, decreased the ability of experimenter-administered cocaine to reinstate extinguished cocaine self-administration behavior. This effect was specific to cocaine-produced drug seeking since U69593 failed to attenuate the ability of experimenter-administered amphetamine to reinstate extinguished cocaine self-administration behavior. One possibility is that U69593 selectively attenuates the behavioral effects of the drug that was originally self-administered. In order to test this hypothesis, the present study examined the effect of U69593 (0.0 or 0.32 mg/kg) on the reinstatement of extinguished amphetamine self-administration behavior produced by experimenter-administered injections of cocaine and amphetamine. Following extinction of amphetamine self-administration (0.04 mg/kg/infusion) the ability of cocaine (0.0, 5.0, 10.0 or 20.0 mg/kg) or amphetamine (0.0, 0.3, 1.0 or 3.0 mg/kg) to reinstate extinguished self-administration behavior was measured. Both drugs reinstated extinguished responding and the reinstatement was attenuated by pretreatment with U69593. The data indicate that the ability of U69593 to decrease drug seeking is not restricted to subjects experienced with cocaine self-administration. Self-administration history does, however, determine the effect of U69593 on amphetamine-produced drug seeking.     

Extinction procedures abolish conditioned stimulus control but spare sensitized responding to amphetamine

The effect of extinction on previously established environment-specific sensitization of the locomotor activating effects of 1.0mg/kg d-amphetamine sulfate was studied in an attempt to investigate the relation between sensitization and conditioning of the drug effect. During the conditioning phase, groups of eight rats each were administered drug, i.p., prior to being placed in activity boxes and saline in their home cages (paired group), drug in the home cages and saline in the activity boxes (unpaired group), or saline in both environments. Evidence for conditioning and environment-specific sensitization was found following the conditioning phase in tests during which animals were administered saline or amphetamine, respectively. On a final test for environment-specific sensitization that followed the extinction phase (during which all animals received saline injections in both the activity boxes and the home cages), sensitized responding to amphetamine was found in both the paired and unpaired groups, suggesting that prior to extinction the expression of sensitization in the unpaired group had been under inhibitory control.     

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release

RATIONALE: Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. OBJECTIVES: To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. METHODS: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. RESULTS: The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. CONCLUSIONS: Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.     

The effects of haloperidol on amphetamine-and methylphenidate-induced conditioned place preferences and locomotor activity

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S–) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.     

Conditioning tastant and the acquisition of conditioned taste avoidance to drugs of abuse in DBA/2J mice

RATIONALE: Conditioned taste aversion (CTA) produced by drugs of abuse such as morphine and cocaine has been interpreted as representing the rewarding actions of these drugs. Evidence for this interpretation is based, in part, on findings in rats indicating saccharin is a more effective conditioning flavor compared to salt (NaCl). However, our studies with ethanol have found salt to be a highly effective conditioning flavor in mice. OBJECTIVES: The present series of studies examined the acquisition of CTA to morphine, ethanol, lithium chloride, and cocaine. Further, saccharin and salt were utilized in each experiment in order to determine effectiveness of each flavor to serve as a conditioning stimulus. METHODS: In four separate experiments, adult male DBA/2J mice were acclimated to a 2 h/day water restriction regimen. Subsequently they received four conditioning trials consisting of 1 h access to either 0.15% w/v saccharin or 0.1 M salt followed by 0, 10 or 20 mg/kg morphine (experiment 1), 0, 2, or 4 g/kg ethanol (experiment 2), 0, 1.5 or 3.0 milliequivalents/kg lithium chloride (experiment 3) or 0, 10 or 20 mg/kg cocaine (experiment 4). A fifth flavor access period (trial 5) was not followed by drug exposure. Following trial 5, each subject received 24-h access to the conditioning flavor and water (two-bottle test 1). Control subjects (0 dose groups from each experiment) received a second two-bottle test with 24-h access to both saccharin and salt flavors. RESULTS: Reduced flavor intake and reduced flavor preference was noted in all drug-paired groups in each experiment. However, more rapid development of CTA was seen with the saccharin flavor in morphine- or cocaine-paired groups. In contrast, ethanol-induced CTA appeared more rapidly with the salt flavor. Lithium-induced CTA was modest, and emerged equally with either flavor. CONCLUSIONS: CTA induced by morphine or cocaine in mice occurs in a similar pattern to that seen in rats, and these findings agree with an interpretation based on drug reward. In contrast, ethanol-induced CTA is more likely attributable to aversive effects.     

5-HT(6) receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine.

The localization of serotonin 5-HT(6) receptors in limbic and motor brain regions, and the high affinity of these receptors for several antipsychotic agents, suggest that they may be involved in motor activity, reward-related behaviors, and psychotic disorders. The present study characterized the effects of a novel 5-HT(6) receptor antagonist, SB 258510A, on psychostimulant-induced motor activity, self-administration, and increases in extracellular dopamine in the nucleus accumbens and frontal cortex of male Wistar rats. The locomotor-activating effects of amphetamine (1mg/kg) were dose-dependently enhanced by pretreatment with SB 258510A (3, 10mg/kg). Similarly, amphetamine self-administration was dose-dependently altered by SB 258510A in a manner indicative of enhanced reinforcing effects of amphetamine on both fixed and progressive ratio schedules of reinforcement. SB 258510A treatment had no effect on either cocaine-induced locomotor activity or cocaine self-administration. Dual-probe in vivo microdialysis revealed that pretreatment with 3mg/kg SB 258510A potentiated an amphetamine-induced increase in extracellular dopamine more robustly in the frontal cortex than in the nucleus accumbens. These data indicate that activation of 5-HT(6) receptors may regulate behaviors related to amphetamine but not cocaine, and point to the frontal cortex as a possible site of action for these effects.     

Pharmacological modification of shock potentiated amphetamine lethality

The ability of the acute application of inescapable footshock to potentiate d- and d,l-amphetamine in rodents has previously been ascertained. The present study confirmed these results and demonstrated a similar interaction with l-amphetamine. Aggregation further enhanced this potentiation. Prior subacute exposure to shock did not prevent the potentiated lethality. Shock potentiated amphetamine lethality was antagonized by pretreatment with agents which indirectly reduce catecholamine release (6-hydroxydopamine, α-methyl-p-tyrosine) and by bilateral adrenalectomy. However antagonism did not result from pretreatment with the adrenergic blocking agents propanolol and phenoxybenzamine. Pretreatment with methoxamine and hydrocortisone likewise did not afford protection. However pretreatment with haloperidol and pentobarbital completely antagonized the potentiated lethality whereas morphine and fenfluramine pretreatment did not provide protection. Shock potentiated amphetamine lethality was enhanced by pretreatment with physostigmine and neostigmine but was antagonized by pretreatment with methylatropine. However atropine pretreatment enhanced lethality. It would appear that the release of norepinephrine from the brain and/or the adrenal medulla either is directly involved in mediating amphetamine lethality or in mediating the effects of acute stress on emphetamine's lethal actions.     

The behavioral effects of a new psychoactive drug (d-Carbine) on a passive avoidance response and locomotion and its interaction with amphetamine

The relationship between amphetamine and a new psychotropic drug, carbidin (in comparison with imipramine and chlorpromazine) was studied on a test of activity and the passiv avoidance conditioned response.Carbidin and imipramine woud appear to differ from chlorpromazine in their mode of action on conditioned response. Looking at the interactions between amphetamine and the other drugs in the two tests differences in the mode of action of carbidin and imipramine becomes apparent. Whereas in the passive avoidance conditioning situation both drugs had similar effects alone and in combination with amphetamine in the activity test, though both are without effect when given alone, in combination with amphetamine the interactions are in opposite directions. Imipramine has a synergistic effect, whereas carbidin has marked antagonistic affect completely reversing the amphetamine induced increase in activity.     

Selective blockade of drug-induced place preference conditioning by ACPC, a functional NDMA-receptor antagonist.

ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some clinical utility in the treatment of addiction, without affecting responses to natural rewards.     

Differential involvement of central cholinergic mechanisms in the aversive stimulus properties of morphine and amphetamine

Previously, it was reported that pretreatment with the centrally-acting cholinergic antagonist atropine, but not the peripherally-acting antagonist, methyl-atropine, may serve to attenuate the positive reinforcing properties of morphine and conversely, to enhance those of amphetamine as evidenced within a drug self-administration paradigm in rats. In parallel, evidence from several sources would suggest that there may be a functional relationship between the neurochemical mechanisms mediating these drugs' positive reinforcing properties and their seemingly paradoxical capacity to act as aversive stimuli, as evidenced within a conditioned taste aversion (CTA) paradigm. Accordingly, the present study undertook to examine whether a similar differential involvement of central cholinergic mechanisms established for these drugs' positive reinforcing effects may be obtained for morphine and amphetamine-induced CTA. Using a conventional CTA paradigm, animals were pretreated with either intraperitoneal (IP) atropine or methyl-atropine (0.6 mg/kg) 40 minutes prior to consuming a novel 0.1% saccharin solution. This taste stimulus was paired with IP injection of 15 mg/kg morphine or vehicle. Results showed that atropine (but not methyl-atropine) pretreatment served to attenuate the morphine CTA. In a second experiment, atropine-pretreatment failed to attenuate, and may have slightly potentiated, a CTA induced by 1 mg/kg amphetamine. Atropine pretreatment did not affect a CTA induced by the emetic agent, lithium chloride. Pretreatment with the peripherally-acting methyl-atropine had no effect on the amphetamine CTA and served, if anything, to slightly attenuate the lithium chloride CTA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amphetamine increases aversive conditioning to diffuse contextual stimuli and to a discrete trace stimulus when conditioned at higher footshock intensity

Amphetamine can increase conditioning to poor predictors of reinforcement in selective learning tasks (e.g. latent inhibition, LI). In the present study, a noise stimulus was contiguous with footshock or presented at a trace interval. A flashing light background stimulus was used to measure contextual conditioning. Experiment 1 used 1.5 mg/kg and 6 mg/kg dl-amphetamine. Experiments 2 and 3 used 0.5 mg/kg and 1.5 mg/kg d-amphetamine. Unconditioned stimuli parameters (intensity, number, duration) were also manipulated from one experiment to the next. Amphetamine consistently increased conditioning to the background stimulus, and increased conditioning to the trace stimulus at higher footshock intensity (Experiment 3). Thus, amphetamine increased conditioning only to relatively uninformative predictors. The effect on conditioning to trace conditioned stimuli depended on the level of reinforcer but increased conditioning to background did not. Throughout, there was no effect of amphetamine on conditioning of the contiguous stimulus. Thus, the results did not simply arise because amphetamine increased conditioning under any condition in which conditioning without amphetamine was poor. The results are discussed in terms of amphetamine effects on breadth of attention and LI to context.