Ethanol induces impulsive-like responding in a delay-of-reward operant choice procedure: impulsivity predicts autoshaping

 Autoshaping conditioned responses (CRs) are reflexive and targeted motor responses expressed as a result of experience with reward. To evaluate the hypothesis that autoshaping may be a form of impulsive responding, within-subjects correlations between performance on autoshaping and impulsivity tasks were assessed in 15 Long-Evans hooded rats. Autoshaping procedures [insertion of retractable lever conditioned stimulus (CS) followed by the response-independent delivery of food (US)] were followed by testing for impulsive-like responding in a two-choice lever-press operant delay-of-reward procedure (immediate small food reward versus delayed large food reward). Delay-of-reward functions revealed two distinct subject populations. Subjects in the Sensitive group (n=7) were more impulsive-like, increasing immediate reward choices at longer delays for large reward, while those in the Insensitive group (n=8) responded predominantly on only one lever. During the prior autoshaping phase, the Sensitive group had performed more autoshaping CRs, and correlations revealed that impulsive subjects acquired the autoshaping CR in fewer trials. In the Sensitive group, acute injections of ethanol (0, 0.25, 0.50, 1.00, 1.50 g/kg) given immediately before delay-of-reward sessions yielded an inverted U-shaped dose-response curve with increased impulsivity induced by the 0.25, 0.50, and 1.00 g/kg doses of ethanol, while choice strategy of the Insensitive group was not influenced by ethanol dose. Ethanol induced impulsive-like responding only in rats that were flexible in their response strategy (Sensitive group), and this group also performed more autoshaping CRs. Data support the hypothesis that autoshaping and impulsivity are linked. Received: 30 September 1997 / Final version: 20 February 1998     

Pavlovian autoshaping procedures increase plasma corticosterone levels in rats

Pavlovian autoshaping conditioned responses (CRs) are complex sequences of conditioned stimulus (CS)-directed skeletal-motor responses that are elicited by CS objects predictive of food unconditioned stimulus (US). Autoshaping CRs are observed under conditions known to be conducive to elevations in plasma corticosterone levels, as, for example, in response to the eating of food as well as in response to signals predictive of food. Two experiments investigated the relationships between Pavlovian autoshaping procedures, the performance of Pavlovian autoshaping CRs, and plasma corticosterone levels in male Long-Evans rats. In Experiment 1, rats in the CS-US paired group (n=30) were given 20 daily sessions of Pavlovian autoshaping training wherein the insertion of a retractable lever CS was followed by the response-independent presentation of the food US. Tail blood samples obtained after the 20th autoshaping session revealed higher plasma corticosterone levels in the CS-US paired group than in the CS-US random control group (n=10). In Experiment 2, rats (n=35) were assessed for basal plasma corticosterone levels 2 weeks prior to autoshaping training. Plasma samples obtained immediately following the first autoshaping session, and prior to the acquisition of lever-press autoshaping CR performance, revealed higher plasma corticosterone levels in the CS-US paired group (n=24) relative to basal levels. This effect was not observed in the CS-US random control group (n=11). Data suggest that corticosterone release is a physiological endocrine Pavlovian CR induced by lever CS-food US pairings during Pavlovian autoshaping procedures, rather than a by-product of autoshaping CR performance. Implications of the link between autoshaping procedures and corticosterone release are discussed.     

Individual differences in pavlovian autoshaping of lever pressing in rats predict stress-induced corticosterone release and mesolimbic levels of monoamines

Pavlovian autoshaping CRs are directed and reflexive consummatory responses targeted at objects repeatedly paired with rewarding substances. To evaluate the hypothesis that autoshaping may provide an animal learning model of vulnerability to drug abuse, this study relates individual differences in lever-press autoshaping CR performance in rats to stress-induced corticosterone release and tissue monoamine levels in the mesolimbic dopamine tract. Long-Evans rats (n = 14) were given 20 sessions of Pavlovian autoshaping training wherein the insertion of a retractable lever CS was followed by the response-independent presentation of food US. Large between-subjects differences in lever-press autoshaping CR performance were observed, with group high CR frequency (n = 5) performing many more lever press CRs than group low CR frequency (n = 9). Tail-blood samples were obtained before and after the 20th autoshaping session, then 24 h later the rats were sacrificed and dissection yielded tissue samples of nucleus accumbens (NAC), prefrontal cortex (PFC), caudate putamen (CP), and ventral tegmental area (VTA). Serum levels of postsession corticosterone were elevated in group high CR frequency. HPLC revealed that group high CR frequency had higher tissue levels of dopamine and DOPAC in NAC, lower levels of DOPAC/DA turnover in CP, and lower levels of 5-HIAA and lower 5-HIAA/5-HT turnover in VTA. The neurochemical profile of rats that perform more autoshaping CRs share some features of vulnerability to drug abuse.     

Dietary additives and the acquisition of cocaine self-administration in rats

 The effects of dietary caffeine and the amount and palatability of food on the acquisition of cocaine (0.2 mg/kg) self-administration were examined. Using an autoshaping procedure, seven groups of 13 rats each were trained to press a lever resulting in a cocaine (0.2 mg/kg infusion under a fixed-ratio 1 (FR 1) schedule. One group had ad libitum access to caffeine- (0.2% w/w) admixed food. Three groups had access to 10 g, 20 g or ad lib food each day. Another three groups had the same three amounts of ground food with powdered saccharin (0.2% w/w) added. During daily 6-h autoshaping sessions, ten infusions were delivered each hour under a random-time 90-s schedule after a brief (15 s) extension of a retractable lever. These were followed by 6-h self-administration sessions, when the lever remained extended and cocaine infusions were available under an FR 1 schedule. The acquisition criterion was self-administration of a mean of 100 infusions over 5 days. Cocaine self-administration was accelerated in the caffeine group compared to the regular chow group. However, by 30 days nearly the same percentage of rats in the caffeine and regular food groups met the acquisition criterion. In the other six groups, as the amount of food increased, the rate of acquisition and percentage of rats per group meeting the acquisition criterion decreased. In the ad lib group, acquisition was further reduced when saccharin was added to food. In summary, dietary caffeine accelerated acquisition and a greater amount and increased palatability of food independently interfered with acquisition of cocaine self-administration in rats. Received: 9 August 1997 / Final version: 14 November 1997     

Acquisition of lever pressing for cocaine in C57BL/6J mice: effects of prior Pavlovian conditioning

The purpose of this study was to determine (1) if C57BL/6J (C57) mice would lever-press for intravenous cocaine infusions in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers and (2) if prior Pavlovian conditioning of cocaine to the response contingent stimulus complex used in the cocaine self-administration sessions would facilitate acquisition of lever responding for cocaine. After implanting jugular catheters, some mice received Pavlovian conditioning during which 12 passive cocaine infusions (0.1 or 1 mg/kg unit doses) were paired with the tone/light/pump sound stimulus complex used in the self-administration sessions. The remaining mice simply began the cocaine self-administration sessions for 0.1 or 1 mg/kg unit doses of cocaine. Twenty-seven of the 33 mice with patent catheters acquired stable lever responding within an average of 5 to 6 days without previously establishing the instrumental response with natural rewards. Prior Pavlovian pairing of cocaine with the response contingent stimulus complex used in the self-administration sessions did not influence the acquisition of cocaine self-administration at the highest cocaine dose (1 mg/kg). This conditioning procedure using the low cocaine dose (0.1 mg/kg/infusion) reduced the number of mice acquiring cocaine self-administration to 50%, and the number of mice developing stable response patterns was only 25%. The results establish that C57 mice can acquire cocaine self-administration over several unit doses in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers. Furthermore, prior pairing of response contingent cues with cocaine via Pavlovian conditioning did not facilitate the acquisition of cocaine self-administration.     

Biphasic effects of 7-OH-DPAT on the acquisition of responding for conditioned reward in rats.

Previous studies have shown that dopamine (DA) receptor subtype-specific agonists differentially affect responding for conditioned reward D1-like agonists impair, whereas D2-like agonists enhance responding. The present study compared the effects of the D2-like agonists bromocriptine and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT). Food-deprived rats (N=159) were preexposed to a chamber with two levers, one producing a tone (3 s) and the other turning the house lights off (3 s), for five 40-min sessions. In four subsequent 65-min conditioning sessions with the levers removed, the lights-off stimulus was paired with food (80 presentations per session). During two 40-min test sessions, the lights-off (CR) and tone (NCR) levers were replaced and responses at each lever were recorded. Confirming previous results, bromocriptine (0.50-5.0 mg/kg) dose-dependently enhanced responding on the lever producing conditioned reward. In contrast, 7-OH-DPAT had a biphasic effect on responding for conditioned reward. Low doses (0.10-0.25 mg/kg) reduced CR lever responding, whereas a higher dose of 1.0 mg/kg enhanced such responding. An intermediate dose of 0.50 mg/kg neither impaired nor enhanced CR lever responding. The biphasic profile of 7-OH-DPAT may arise through differential actions at D3 vs. D2 receptors or presynaptic vs. postsynaptic DA receptors at low and high doses, respectively.     

Effects of removing food on maintenance of drinking initiated by pairings of sipper and food

Two experiments evaluated the effects of removing food presentations on the maintenance of drinking induced by experience with sipper — food pairings. In Exp 1, ethanol drinking was induced in non-deprived Long-Evans rats by Pavlovian conditioning procedures employing an ethanol sipper as conditioned stimulus (CS) and food pellet as unconditioned stimulus (US). The Paired/Ethanol group received presentations of the ethanol sipper CS followed immediately by the response-independent presentation of the food pellet US. The Random/Ethanol group received the ethanol sipper CS and food US randomly with respect to one another. For both groups, the concentration of ethanol in the sipper CS [(3%, 4%, 6%, 8% (vol./vol.)] was increased across sessions, and, as in previous studies employing low concentrations of ethanol in non-deprived rats (i.e., maintained with free access to food in their home cages), the two procedures induced comparable levels of sipper CS-directed ethanol drinking. Removing food US presentations had no effect on sipper CS-directed ethanol drinking in either group. In Exp 2, groups of non-deprived Long-Evans rats were trained either with water or ethanol in the sipper CS paired with food US. Removing food US presentations had no effect on ethanol drinking in the Paired/Ethanol group, but water drinking in the Paired/Water group declined systematically across sessions. Results indicate that food US presentations contribute to the maintenance of water drinking but not to the maintenance of ethanol drinking. Implications for accounts of ethanol drinking based on Pavlovian sign-tracking, behavioral economics and intermittent sipper procedures are considered.     

Autoshaping i.v. cocaine self-administration in rats: effects of nondrug alternative reinforcers on acquisition

The purpose of this experiment was to examine the effects of a nondrug alternative reinforcer and feeding conditions on the acquisition of cocaine self-administration. Rats were autoshaped to press a lever that resulted in a 0.2 mg/kg IV cocaine infusion. Responses on the lever were monitored during six consecutive autoshaping sessions that occurred each day. A retractable lever was inserted into the operant chamber on a random time 60 s schedule 10 times per session for six sessions that began each hour. Each day the six autoshaping sessions were followed by a 6-h cocaine self-administration session. During self-administration the lever remained extended, and each response on the lever resulted in a cocaine infusion (0.2 mg/kg). The criterion for acquisition of cocaine-reinforced behavior was met when there were 5 consecutive days during which the mean number of infusions during the 6-h self-administration session was at least 100. This procedure was repeated daily until the criterion was met or 30 days elapsed. The rats were also trained to respond on lick-operated automatic drinking devices that delivered 0.05 ml water or a glucose and saccharin solution (G+S) contingent upon each lick response. Five groups of 12–14 rats were compared. The first four groups constituted a 2 × 2 factorial design whereby either G+S or water was available in the home cage for 3 weeks before autoshaping began and G+S or water was available in the operant chamber during autoshaping. These groups were limited to 20 g food per day and all had free access to water. A fifth group had only water available in the home cage and operant chamber, and they had unlimited access to food but no G+S. The results indicated that access to the G+S solution in the operant chamber substantially delayed autoshaping, and a large percentage of these rats did not meet the autoshaping criterion within 30 days. The data from groups that had G+S in the home cage were very similar to those that had only water in the home cage; thus, a history of access to G+S did not interfere with acquisition of cocaine self-administration. Autoshaping in the group that had free access to food was highly variable, but a high positive correlation was found between the amount of food consumed and the number of days taken to meet the acquisition criterion. When the rats from the group that consumed over 20 g were compared to the rats in another group that were limited to 20 g and had no G+S, it was found that the increased food intake markedly decreased the rate of acquisition of cocaine self-administration. These findings indicate that acquisition of cocaine-reinforced behavior is delayed or prevented in environments enriched with nondrug alternative reinforcers such as food and a preferred liquid.     

Effects of intra-amygdala R(+) 7-OH-DPAT on intra-accumbens d-amphetamine-associated learning I. Pavlovian conditioning

We have previously obtained evidence that the mesoamygdaloid dopamine projection modulates the acquisition of a conditioned response (CR) elicited by presentation of a conditioned stimulus (CS) predicting the availability of a natural (sucrose) reward. This property was found to be dependent upon D₃, but not D₁ or D₂, dopamine receptor activation. The aim of the present study was to determine whether the mesoamygdaloid dopamine projection is similarly involved in the acquisition of a drug-associated CR. Thus, two groups of rats with guide cannulae aimed at the nucleus accumbens and amygdala were trained using a Pavlovian conditioning procedure in which an initially neutral CS was paired with a computer-controlled, bilateral intra-accumbens infusion of d-amphetamine (the unconditioned stimulus; US). Conditioning sessions were conducted in standard operant chambers, with each session consisting of a single CS-US trial. For one group of rats, CS presentation was positively correlated with the drug US (Paired group), while for the second group CS and US presentations were negatively correlated (Unpaired group). During training, locomotor activity was recorded and was utilised as the measure both of the unconditioned (UR) and conditioned response (CR). A within-subjects design was utilised to investigate the effect of post-session bilateral intra-amygdala administration of R(+) 7-OH-DPAT on the development of the drug-associated CR. Hence, both Paired and Unpaired groups were exposed to two different CSs which were presented on alternate sessions. Post-session bilateral intra-amygdala administration of R(+) 7-OH-DPAT (10 nmol) followed sessions in which one CS was presented, while intra-amygdala vehicle followed sessions in which the alternate CS was presented. The development of a CR occurred only in the presence of a CS that had been positively correlated with presentation of the drug US. Post-session, intra-amygdala administration of R(+) 7-OH-DPAT enhanced the acquisition of this CR. However, R(+) 7-OH-DPAT was without effect upon the unconditioned response to intra-accumbens d-amphetamine. Our previous data indicate a comparable effect of R(+) 7-OH-DPAT on conditioning to a CS associated with a non-drug, natural reward. Therefore, taken together, these findings suggest that D₃ dopamine receptors within the amygdala modulate specifically the acquisition of Pavlovian conditioned responses, regardless of whether drug or natural rewards constitute the US. Received: 28 November 1997/Final version: 9 April 1998     

The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food

Rationale The CB1 receptor antagonist SR141716A reduces food intake in rats. This effect is likely to depend on modulation of reward related processes.Objective To investigate the effects of SR141716A on responding for food under a second order instrumental task in which responding and consumption of food can be separated, and on Pavlovian responding for a stimulus predictive of food reward.Methods Instrumental responding and pellet consumption following administration of SR141716A (0–3 mg/kg) were recorded under an FI5 min FR5(5:S) operant schedule that incorporates both a 5 min initial appetitive phase and a 25 min consummatory phase. We compared the drug-induced change in responding to that recorded following a reduction in motivational state induced by pre-feeding. In a second experiment we assessed the effects of SR141716A (0–3 mg/kg) on Pavlovian approach behaviour for a stimulus (lever) associated with food reward (CS+) and a neutral stimulus (lever) not associated with reward (CS–).Results SR141716A reduced pellet consumption and instrumental responding during both the appetitive and consummatory phases of the second order schedule. Pre-feeding had a similar effect on responding during the appetitive phase, suggesting an effect on incentive motivation. SR141716A also blocked an enhancement of responding that occurred during the consummatory phase in pre-fed animals. SR141716A and pre-feeding had no effect on responding in the Pavlovian autoshaping paradigm.Conclusions SR141716A impacts on motivational processes in both the appetitive and consummatory phases of feeding behaviour.     

Differential effects of ondansetron and α-flupenthixol on responding for conditioned reward

Previous experiments have suggested that 5-HT₃ antagonists such as ondansetron may alter reward-related behaviour that is dependent in part upon raised mesolimbic dopamine activity. However, the evidence for this is far from conclusive. One major behavioural role of dopamine is in the control of behaviour elicited by conditioned rewarding stimuli. To date, the effects of 5-HT₃ antagonists on this function of mesolimbic dopamine have not been examined. Two experimental procedures were employed to examine the effects of ondansetron (10 and 100 μg/kg) on the acquisition of responding for conditioned reward, and on the response potentiating effect of intra-accumbens d-amphetamine (10 μg). These effects were compared to those elicited by the dopamine antagonist α-flupenthixol (0.1 mg/kg). In the first procedure, rats were trained to associate food pellet delivery with a conditioned stimulus (CS). Rats subsequently allowed to respond on a lever delivering this CS, and on an inactive lever, showed a greater preference for the lever delivering the CS, indicating that this CS functioned as a conditioned reward (CR). Ondansetron administered during the conditioning phase did not alter subsequent responding for the CR, but α-flupenthixol induced a small but significant reduction in responding on the CR lever. These results suggest that blockade of dopamine receptors, but not 5-HT₃ receptors interfere with the learning of stimulus reward relationships. In the second procedure, d-amphetamine injected into the nucleus accumbens markedly potentiated responding for CR. Ondansetron at 10 μg/kg induced a small attenuation of this effect, without altering responding in its own right. However, at a higher dose (100 μg/kg) ondansetron plus amphetamine treatment significantly enhanced responding on the inactive lever. At both doses, the net effect of ondansetron was to produce a subtle impairment in the allocation of responses such that the differential responding on the CR versus NCR lever was diminished. In contrast to these effects α-flupenthixol significantly attenuated d-amphetamine’s selective enhancement of responding for conditioned reward, as well as impairing the ability of the conditioned reward to elicit and maintain behaviour. These results confirm the role of dopamine in responding for conditioned reward, and suggest a possible modulators role for 5-HT₃ receptors in this process. However, the effects of ondansetron on the acquisition of, and responding for, conditioned reward are clearly different from those induced by blockade of dopamine receptors. Received:4 December 1996/Final version:30 April 1997     

Devazepide,a CCKA receptor antagonist,impairs the acquisition of conditioned reward and conditioned activity

Cholecystokinin (CCK) is co-localized with dopamine (DA) in portions of the mesolimbic system, where it may facilitate the function of DA through the CCK_A receptor subtype. DA has been implicated in the acquisition of conditioned incentive learning, raising the possibility of a role for endogenous CCK in this learning process. This hypothesis was tested using two complementary behavioral paradigms. Experiment 1 examined the effects of systemic administration of the CCK_A receptor selective antagonist, devazepide (0, 0.001, 0.01, 0.1 mg/kg), on the acquisition of conditioned reward. Two novel levers were presented to drug-free animals in a test session; depression of the conditioned reward (CR) lever produced a light-tone stimulus previously paired with food availability while depression of the non-CR lever produced no programmed consequence. Animals receiving vehicle pretreatment in the food-CS conditioning sessions responded more frequently on the CR lever during the test session. However, pre-treatment with devazepide (0.1 mg/kg but not 0.001 or 0.01 mg/kg) in the conditioning sessions blocked the acquisition of conditioned reward. In contrast, experiment 2 showed that the development of conditioned reward was not affected by similar administration of the CCK_B selective antagonist, L-365,260 (0, 0.001, 0.01 or 0.1 mg/kg). The possibilities that devazepide (0.1 mg/kg) impaired the development of conditioned reward by decreasing the amount of food consumed or by inducing a conditioned taste aversion to the food were ruled out in experiments 3 and 4. The effects of devazepide on the acquisition of conditioned activity induced by amphetamine were assessed in experiment 5. During four conditioning sessions, rats received devazepide (0, 0.001, 0.01, 0.1 or 1.0 mg/kg) treatment prior to amphetamine-environment pairings. The conditioned activity effect was demonstrated if on the subsequent drug-free test day the environment alone elicited increased locomotion. Devazepide (0.1 or 1.0 mg/kg) attenuated the development of conditioned activity. Together, these results provide converging evidence that intact CCK_A function may be necessary for the development of conditioned incentive learning.     

Actions of nicotine on the acquisition of an autoshaped lever-touch response in rats

Experimentally naive male, Sprague-Dawley rats maintained at 85% of their original body weight were trained to touch a retractable lever that was presented on a random interval 48-s schedule. The lever retracted when touched or after 15 s had elapsed, and one 45 mg food pellet was delivered simultaneously with lever retraction or after an 8-s delay. Rats received ten daily sessions each consisting of ten lever presentations. Nicotine (0.25–0.8 mg/kg SC) administration, either 15 min prior to (pre-session) or immediately after (post-session) the daily autoshaping sessions, caused a significant dose-related impairment of acquisition with the post-session injections having the greater effect. Low doses of nicotine (0.025–0.1 mg/kg SC) had little effect on acquisition when injected pre-session or post-session. Injections of 0.45 mg/kg nicotine either immediately (t=0) or at +5 min after the daily sessions impaired acquisition of the lever-touch response. Nicotine injected at +15, +30, +60, or +120 min had no effect on acquisition. A single intraventricular injection of the ganglionic blocker chlorisondamine (5 g) 2 weeks prior to autoshaping blocked the impairment produced by 0.45 mg/kg nicotine. Post-session injections of nicotine did not alter the lever-touch behavior of well-trained animals, but suppressed responding in animals that were partially trained. Thus, nicotine-induced impairment of the autoshaped lever-touch response is dose dependent, centrally mediated, occurs within 5 min of a SC injection, and may interfere with post-training consolidation processes. Offprint requests to: E.T. Iwamoto     

Rapid induction of Pavlovian approach to an ethanol-paired visual cue in mice

Rationale Although many studies have shown Pavlovian conditioned approach to cues paired with natural reinforcers, it has been quite difficult to induce such behavior with drug reinforcers. Objectives This experiment tested a novel Pavlovian procedure for inducing approach to a conditioned stimulus (CS) paired with ethanol. Methods Mice (NZB/B1NJ, DBA/2J) received intraperitoneal injections of ethanol (2 g/kg) immediately before 10-min exposure to a rectangular chamber that contained a distinctive visual cue (star) at one end (Paired group, CS+ trials). On alternate days, saline injection preceded apparatus exposure with no distinctive cues (CS− trials). Unpaired control mice received ethanol in the home cage 60–75 min after each CS+ trial. Results NZB/B1NJ Paired group mice spent increasing amounts of time (>85% of the session) in proximity to the star, whereas Unpaired group mice did not. DBA/2J Paired group mice spent slightly more time on the star side than Unpaired group mice but did not show an acquisition curve. Postconditioning tests showed a strong preference for the star side in Paired groups from both strains after saline injection. However, only NZB/B1NJ mice showed a preference after ethanol. Conclusions This study provides the first unambiguous demonstration of Pavlovian conditioned approach to an ethanol-paired visual stimulus in the absence of any contingency between the animal’s behavior and drug exposure. This effect, which is remarkable both in terms of its magnitude and the rapidity with which it was produced (within 2–3 trials), may be related to the cue-associated craving that accompanies alcohol and drug addiction.     

Alteration of response patterning by d-amphetamine on repeated acquisition in rats

The acute effects of d-amphetamine on response patterning in a repeated acquisition baseline were investigated with rats. Each session the animals acquired a different four-member response sequence on three levels. Each sequence (trial) completion produced a food pellet. Errors produced a brief timeout that was reset by responses made during the timeout. Acute doses of d-amphetamine (0.5–4.0 mg/kg) and saline were administered 30 min presession. The response patterns analyzed were perseverative responses to a single lever (runs), and a response to each lever in either a left-to-right or right-to-left direction (tranerses). The trial position, frequency, and lever location of error and timeout responses that occurred in the context of runs and traverses were studied. In contrast to control sessions, higher doses of d-amphetamine produced increases in the number of error and timeout responses emitted. The majority of these responses occurred as runs; traverse responding did not exceed control levels. Furthermore, the run error and timeout responding tended to occur early in the session and on a siingle response lever. The results are consistent with the view that d-amphetamine disrupts stimulus control and produces perseverative responding which may account for previous reports of disruption in repeated acquisition tasks following d-amphetamine administration.     

Phencyclidine retards autoshaping at a dose which does not suppress the required response

Four groups of five food-deprived hooded Long-Evans rats were injected subcutaneously with saline (vehicle) or 2, 4 or 8 mg phencyclidine (PCP) hydrochloride/kg fifteen minutes before being placed for the first time into operant chambers modified to detect exploratory behaviors. Rearing was found to be more sensitive to disruption by phencyclidine than was unconditioned lever touching (a measure of floor-level exploratory activities). In an autoshaping session immediately following, the group of animals given the low dose of PCP made as many lever-touch responses as the group given saline, but consumed fewer of the food pellets delivered. In addition, none of the animals in the low-dose group showed within-session shortening of the latency to respond which was observed in four of five control animals. The two other groups given higher doses of PCP demonstrated dose-related decrements in responding as well as a reduction in food pellet consumption during the first session of autoshaping. Over the next two daily autoshaping sessions, performance improved in those groups initially suppressed. Performance converged in all groups by the third autoshaping session.     

Ethanol state dependence involving a lever press response requirement in rats

Previous studies have found that the timely completion of an FR10 schedule of food-rewarded lever pressing in rats demonstrates state dependence in drug-to-saline state changes with benzodiazepines and NMDA antagonists, but not with ethanol. We report here that, using sweetened condensed milk rather than food pellets as a reward, ethanol nonetheless produces a symmetrical state dependence with the lever press response requirement at doses that also impair acquisition. Extensive parametric studies are needed to unravel the apparently subtle conditions that govern the occurrence and features of the state dependence produced by various CNS compounds.     

Repeated heroin in rats produces locomotor sensitization and enhances appetitive Pavlovian and instrumental learning involving food reward

We tested the hypothesis that sensitization to heroin enhances appetitive motivational processes involving food reward. In Experiment 1, sixteen rats were exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, the rats received either saline or heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. Rats were then tested in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another lever produced a tone stimulus not paired with anything. Heroin produced both significant progressive increases in locomotor activity (sensitization) and significantly enhanced conditioned reinforcement of instrumental lever pressing by the food-associated stimulus. In Experiment 2, thirty-two rats were given Pavlovian discrimination training in a conditioned magazine approach task where one stimulus was associated with food and a second unpaired with food. Rats then received repeated saline or heroin injections as in Experiment 1, before being tested under extinction conditions with the two stimuli without the drug. Chronic heroin had no effect on performance in this test, but it facilitated learning of the reversed discrimination in a subsequent phase. These data suggest that sensitization to heroin enhances appetitive motivational processes involving food reward.     

Stimulus properties of nicotine, amphetamine, and chlordiazepoxide as positive features in a pavlovian appetitive discrimination task in rats.

Recent experiments from our laboratory have demonstrated that drug states can signal when environmental cues will be followed by rewarding outcomes (ie Pavlovian conditioning). However, little is known about the generality of this approach and whether it can be used for studying the pharmacological properties of drug states. Accordingly, the present experiments tested the pharmacological specificity of nicotine (0.4 mg/kg), amphetamine (1 mg/kg), and chlordiazepoxide (CDP, 5 mg/kg) in this Pavlovian drug discrimination procedure. Following drug administration, presentation of a conditional stimulus (CS) was followed by brief access to sucrose. When saline was administered, the same CS was presented but sucrose was withheld. In substitution tests, rats in each condition received varying doses of all training drugs and caffeine. Anticipatory food seeking developed during the CS on drug sessions but not on saline sessions for all drug features (ie drug state-specific conditional response (CR)). In generalization tests, this CR decreased as a function of decreases in the training dose. Median effective doses (ED50s) were calculated for nicotine (0.054 mg/kg), amphetamine (0.26 mg/kg), and CDP (2.48 mg/kg). No compound tested substituted for the CDP training drug. Partial substitution was evident between nicotine and amphetamine; CDP did not substitute for either of these drug features. Caffeine fully substituted for nicotine (ED50 = 15.45 mg/kg) and amphetamine (ED50 = 3.70 mg/kg), but not for CDP. These results are consistent with the hypothesis that drug states can occasion appetitive Pavlovian CRs in a pharmacologically specific manner.     

Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats

RATIONALE: Ketoconazole, an inhibitor of corticosterone synthesis, has been reported to decrease the self-administration of low doses of cocaine and prevent stress-induced reinstatement of cocaine-reinforced behavior in rats. OBJECTIVES: The effects of ketoconazole were extended to the acquisition of i.v. cocaine self-administration during food restriction, a form of stress. Food restriction accelerates the acquisition of cocaine self-administration, and the purpose of this experiment was to determine whether ketoconazole would block the food-restriction effect. As control conditions, the effects of ketoconazole on the acquisition of cocaine self-administration in food-satiated rats and acquisition of food-reinforced responding were also evaluated. METHODS: Six groups of rats (groups 1-6) were trained to self-administer i.v. cocaine (0.2 mg/kg; groups 1-4) or food pellets (45 mg; groups 5 and 6) under a fixed-ratio 1 (FR 1) schedule. Food availability was restricted to 20 g per day in groups 1, 2, 5, and 6, while groups 3 and 4 were fed ad libitum. Daily sessions included a 6-h autoshaping component followed by a 6-h self-administration component. During autoshaping, 10 infusions or food pellets were delivered each h under a random interval 15-s schedule after extension and retraction of a lever. During self-administration, the lever remained extended and infusions or food pellets were available under an FR 1 schedule. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions or 150 food pellets was obtained during the self-administration component. Rats were given 30 days to reach this criterion. They were pretreated with ketoconazole (25 mg/kg, i.p.; groups 1, 3, and 5) or vehicle (i.p.; groups 2, 4, and 6) 30 min prior to the autoshaping and self-administration components. RESULTS: Pretreatment with ketoconazole decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion but only under food-restricted conditions. Ketoconazole had no effect on the acquisition of food-reinforced responding. CONCLUSIONS: These results extended previous findings of the suppressant effects of ketoconazole on cocaine-reinforced responding in rats to the acquisition of cocaine self-administration using food restriction as a stressor.