Influence of training paradigm on specificity of drug mixture discriminations.

Generalization to different drugs and drug mixtures has been examined in rats trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed-ratio 10 schedule of food reinforcement. There was partial generalization to nicotine and midazolam and no generalization to cocaine, caffeine, or ethanol under AND-discrimination conditions and no generalization to any of these drugs in the AND-OR discrimination. Nicotine or midazolam coadministered with the training doses of pentobarbitone and amphetamine, respectively, produced full generalization in the AND discrimination and partial generalization under AND-OR conditions. Cocaine coadministered with pentobarbitone generalized fully under both procedures, but at larger doses in the AND-OR than in the AND discrimination. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. The results consistently supported the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures.     

AND and AND-OR drug mixture discriminations in rats: generalization to single drugs and drug mixtures

Rationale: Studies of the discriminative stimulus effects of drug mixtures provide an approach to polydrug abuse and studies on single drugs with multiple effects. Objective: This study was designed to investigate whether the use of the AND-OR procedure increases the specificity of drug mixture discriminations. Methods: Rats were trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND-discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND–OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed ratio 10 schedule of food reinforcement. Results: Under AND-discrimination conditions, there was partial generalization to nicotine and midazolam when each drug was administered singly, and there was no generalization to cocaine, caffeine or ethanol. With the AND-OR discrimination, there was no generalization to any of the preceding drugs administered singly. In “single substitution” tests, nicotine or midazolam was co-administered with the training doses of pentobarbitone and amphetamine, respectively; there was full generalization in the AND-discrimination and partial generalization under AND-OR conditions. Cocaine co-administered with pentobarbitone generalized fully under both procedures, but the dose of cocaine needed was much larger in the AND-OR than in the AND-discrimination. In “dual substitution” tests, mixtures of two novel substances were tested. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. Throughout the studies, in every instance where comparisons were made, generalization was greater or occurred at lower doses under AND- than under the AND-OR discrimination. Conclusions: The study yielded extensive evidence supporting the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures. Received: 6 May 1998/Final version: 4 October 1998     

Antagonism of AND and AND-OR drug mixture discriminations in rats

It has been suggested that use of the AND-OR training method may be associated with an enhancement of the pharmacological specificity of discriminations based on mixture of drugs. Rats were trained to discriminate a mixture of nicotine (0.4 mg/kg s.c.) plus midazolam (0.2 mg/kg s.c.) from saline (AND-discrimination, n = 8) or to discriminate the mixture from either drug alone (AND-OR discrimination, n = 6). The studies used two-lever operant procedures with food reinforcers presented on a tandem schedule. After discriminations were acquired to 80% accuracy, the nicotine antagonist mecamylamine (0.03–1.0 mg/kg s.c.) and the benzodiazepine antagonist flumazenil (0.32–10 mg/kg i.p.) were tested on the response to the mixture of nicotine plus midazolam. The antagonist effects of either mecamylamine or flumazenil given alone were more marked in rats trained under the AND-OR procedure than in rats trained on the AND-discrimination. Similarly, the antagonist effects of mixtures of mecamylamine plus flumazenil were much more potent under the AND-OR than under the AND-discrimination procedure. The AND-OR method reduced the dose of the antagonist mixture needed to produce complete block by a factor of about 10, as compared with the AND-discrimination. These striking differences in sensitivity to antagonists support the view that AND-OR or related procedures may enhance the pharmacological specificity of complex drug discriminations.     

Training dose as a decisive factor for discrimination of a drug mixture in rats

The impact of training dose on the characteristics of a discrimination maintained by a mixture of two dissimilar drugs has been investigated in order to refine this approach to the study of drug interactions. Three groups of rats (n = 10) were trained to discriminate mixtures of (+)-amphetamine (0.2-0.8mg/kg) plus pentobarbitone (5-20mg/kg) from saline, in a two-lever operant procedure with food reinforcement, with the ratio of the doses held constant (amphetamine: pentobarbitone, 1:25). Discriminations were acquired to an accuracy of 90-97%. There was full generalisation to amphetamine alone, but only in rats trained with mixtures of the smaller doses of the single drugs. There was partial generalisation when either apomorphine (50%) or nicotine (63%) was administered alone, and the magnitude of these responses was inversely related to the dose of mixture used for training. Doses of pentobarbitone half of those used for training produced little discriminative response when administered alone to rats trained with the two smallest doses of the mixture; the same doses of pentobarbitone increased responses to amphetamine or apomorphine in a more than additive manner. Strikingly, some doses of apomorphine and pentobarbitone that did not generalise when administered separately, produced full generalisation when administered together, but only in rats trained with the smaller doses of the mixture. In contrast, pentobarbitone did not enhance generalisation to nicotine in any group. It was concluded that, on the one hand, patterns of generalisation to single drugs followed an orderly pattern resembling those for discriminations established with single drugs. On the other hand, there was a complex pattern of generalization from one mixture to another; thus, altering the doses of drugs used for training markedly influenced discriminations of an abused drug mixture, but no simple rules to predict the influence of training dose have been ascertained.     

Drug mixtures and ethanol as compound internal stimuli.

Drug discrimination methods that entail training with mixtures of drugs may shed light on polydrug abuse and on the actions of single drugs that interact with more than one receptor. In AND-discrimination procedures (drug A + drug B vs. vehicle), mixtures are discriminated primarily on the basis of their component drugs: these discriminations may be useful for testing interactions between component drugs in mixtures. The role of training dose, overshadowing and associative blocking in AND-discriminations have been investigated. For example, after prior training with midazolam, it was possible to demonstrate associative blocking of the nicotine element of the mixture stimulus, and vice versa. Using the AND-OR discriminations (drug A + drug B vs. drug A or drug B) increased pharmacological specificity considerably, and these procedures may be valuable for determining whether the effects of a novel mixture are similar to the combined effects of the training drugs. Ethanol is an example of a single drug that may produce a compound cue; rats trained to discriminate ethanol from water generalize (asymmetrically) to GABA(A) enhancers such as chlordiazepoxide (CDP) or pentobarbitone, to NMDA antagonists such as dizocilpine (MK-801), and to some serotonin agonists, such as trifluoromethylphenylpiperazine (5-HT(1B/2C)). In addition, rats trained to discriminate mixtures of either CDP or pentobarbitone plus MK-801 generalize to ethanol. A previous history of training with MK-801 or CDP (prior to ethanol discrimination training) enhanced the MK-801-like and CDP-like effects of ethanol respectively, but associative blocking of proposed elements in the ethanol stimulus was not seen. These studies provide some support for the multielement concept of ethanol discrimination but also suggest that rules governing three-component stimuli (such as those putatively produced by ethanol) may differ from those for the two-component mixtures of drugs studied previously.     

Discrimination of a drug mixture in rats: role of training dose, and specificity

Many drugs produce compound discriminative stimuli with at least two elements; in contrast, the present study examines discrimination of a mixture of two drugs and tests the role of training dose in, and the specificity of, such a discrimination. Rats discriminated a mixture of nicotine (0.2mg/kg s.c.) and midazolam (0.1mg/kg s.c.) from saline in a two-bar operant conditioning procedure with accuracy of at least 80%. Stimulus control was analyzed by testing each drug separately. Initially, stimulus control was mainly attributable to the midazolam. The doses of drugs used to maintain the discrimination were then altered. As the training dose of nicotine increased and that of midazolam decreased, the magnitudes of responses to the separate drugs were progressively reversed, until stimulus control was mainly attributable to nicotine. Thus, responses to the components of the compound stimulus were systematically related to the amounts of drugs in the mixtures used to maintain the discrimination, and there was some evidence that a strong stimulus produced by one drug may have overshadowed a weaker stimulus produced by a different agent. To test specificity, generalization to other drugs was examined. There was no generalization to amphetamine, morphine or quipazine, up to doses that reduced overall rates of responding. It follows that cues produced by mixtures of drugs may be as specific as those produced by single agents.     

Reversal of overshadowing in a drug mixture discrimination in rats

Previous studies have suggested that in some circumstances, learning processes such as overshadowing may determine the effects that one drug has upon the response to another. The experiments described here examined overshadowing in rats trained to discriminate mixtures of nicotine plus midazolam in two-lever operant procedures with food reinforcement. After training for 60 sessions, midazolam (0.32 mg/kg SC) overshadowed nicotine (0.32 mg/kg SC) so that the discriminative stimulus effect of nicotine seen in control rats trained with nicotine alone was abolished (n=8–10). In the next phase of the study, the discriminative response to midazolam in one group of mixture-trained rats was devalued by means of an extinction procedure which weakened the relationship between administration of midazolam and the response that was reinforced. Dose-response determinations then showed that the devaluation procedure had indeed attenuated the response to midazolam, whereas the previously overshadowed response to nicotine was restored. Post-session injections of drugs were used to equate the pharmacological histories of the groups and the effects seen were therefore attributable to training with the drugs and not simply to repeated exposure to them. Additionally, in the control rats trained with nicotine only (with midazolam given post-session), midazolam markedly reduced response rates, whereas in the three groups of rats trained with the mixture, midazolam had little response rate-depressant effect; this observation suggests that behaviourally contingent tolerance had developed to the response rate-reducing effect of midazolam. Application of devaluation procedures in studies of the discriminative stimulus effects of single drugs with multiple effects may provide a means for manipulating the characteristics of the discriminations obtained and for identifying individual elements of the drug-produced stimulus complex.     

Discrimination of an amphetamine-pentobarbitone mixture by rats in an AND-OR paradigm

Rats were trained to discriminate a mixture of amphetamine plus pentobarbitone from either drug separately in a two-bar procedure with food reinforcement. Discrimination was 86% accurate after 48 sessions, and no dose of amphetamine or pentobarbitone alone produced mixture-appropriate responding. Some mixtures increased response rates whereas the same doses of each drug separately had little effect. The same rats were then trained to discriminate a mixture from saline. There was a continuing lack of discriminative response to amphetamine and only a partial response to pentobarbitone, and under these conditions mixtures did not increase overall response rates. Thus, the way rats are trained, and their previous history, can determine the characteristics of the cue obtained.     

Four-choice drug discrimination in pigeons

(+)Amphetamine was added as a training stimulus for pigeons previously trained to discriminate among pentobarbital, morphine and saline using a three-choice procedure. Pigeons quickly learned the four-choice drug discrimination. Generalization from the training drugs was similar to that established with simpler drug discriminations; pentobarbital generalized to chlordiazepoxide, morphine generalized to methadone, and (+)amphetamine generalized to cocaine and methamphetamine. Low doses of phencyclidine generalized to saline, while higher doses partially generalized to pentobarbital and (+)amphetamine. When dose-response curves were redetermined with a cumulative-dosing procedure, the same pattern of generalization occurred as under single-dose procedures. Dose-response curves were quantal under both the single-dose and the cumulative-dosing procedures. The four-choice procedure offers some important advantages for studying the discriminative stimulus effects of drugs that interact with multiple receptor subtypes and for studying drug mixtures.     

Impact of training history on discrimination of a drug mixture by rats

The impact of training sequence on discrimination of a mixture of two drugs was investigated with five groups of rats (n = 10). In phase I, two groups were trained according to conventional two-lever, operant drug discrimination protocols with food reinforcement; one of these groups was trained with nicotine (0.4mg/kg) and the other group was trained with midazolam (0.15mg/kg). The three remaining groups served as controls and were subjected to 'sham' training in which administrations of saline, nicotine or midazolam were unrelated to contingencies of reinforcement. After completion of phase I (40 sessions), all five groups were trained to discriminate a mixture of nicotine (0.4mg/kg) plus midazolam (0.15mg/kg) from saline (phase II). Any differences between the groups in their performance during phase II could, therefore, be attributed to their different histories in phase I. During phase II, all groups discriminated the mixture from saline with similar accuracy (89-94% drug-appropriate responding after mixture as compared with 2-7% after saline). In the three groups of rats subjected to 'sham' training in phase I, there was partial generalization to both nicotine (45-53%) and midazolam (39-40%), each of which therefore contributed about equally to stimulus control by the mixture. In rats that were initially trained to discriminate nicotine, midazolam had acquired little stimulus control over behaviour (9%) and discrimination of the mixture was attributable largely to the nicotine (87%). Conversely, in rats that were initially trained to discriminate midazolam, nicotine contributed 3% and midazolam 76% to stimulus control by the mixture. These powerful, persistent effects of training sequence were interpreted as examples of associative blocking demonstrated with the interoceptive stimuli produced by psychoactive drugs.     

Discrimination of agonist-antagonist mixtures: experiments with nicotine plus mecamylamine

Discrimination of a mixture of an agonist plus an antagonist has been analysed by training rats to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline; in different groups of rats (n = 8), nicotine was administered either alone or in combination with the non-competitive nicotine antagonist mecamylamine (0.1-0.8mg/kg s.c.). Rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. After 50 sessions, rats trained with nicotine alone had acquired the discrimination with an accuracy of about 85%. In combination, mecamylamine blocked accuracy during acquisition in a dose-related manner. In generalization tests, rats trained with nicotine alone yielded a typical dose-response curve for nicotine (ED(50) = 0.082mg/kg), without depression of response rate. In rats trained with nicotine plus 0.2mg/kg of mecamylamine, the ED(50) for the discriminative effect of nicotine was lowered (ED(50) = 0.036mg/kg), again without depression of response rate. In rats trained with nicotine plus 0.4-0.8mg/kg of mecamylamine, nicotine did not acquire stimulus control over behaviour (flat dose-response relationships), but in these animals, nicotine had a pronounced response rate-decreasing effect. These characteristics of discriminations based on nicotine plus mecamylamine differed substantially from those of previously described discriminations of nicotine plus midazolam, supporting the hypothesis that interactions between the latter drugs were based on a behavioural mechanism (overshadowing) rather than on interactions at the level of receptors.     

Discriminative stimulus effects of a nicotine-midazolam mixture in rats

Rats were trained to discriminate the effects of nicotine (0.4 mg/kg SC) plus midazolam (0.2 mg/kg SC) from those of saline in a two-bar operant conditioning procedure involving a tandem schedule of food reinforcement. After discrimination training, the component drugs of the mixture produced very considerable amounts of drug-appropriate responding when given separately. Mecamylamine and Ro 15-1788 only slightly attenuated the discriminative response to the mixture when given separately, but completely blocked the response when administered together. In different groups of rats trained to discriminate nicotine or midazolam separately from saline, neither drug appreciably altered the dose-response curve for the other, suggesting a minimal role for pharmacological interactions when effects of mixtures were assessed. The results suggest that the two components of a compound drug-produced stimulus can be perceived separately rather than being blended into a homogenous entity. Knowledge of the characteristics of compound drug-produced stimuli may aid interpretation of the discriminative effects of single drugs with wide spectra of action.     

Role of training dose in discrimination of nicotine and related compounds by rats

Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. There was partial generalization to the nicotine analogues anabasine and cytisine in rats trained to discriminate either 0.2 or 0.4 mg/kg nicotine from saline. However, generalization was complete in rats trained to discriminate 0.1 mg/kg nicotine and, in a novel procedure, any one of three doses of nicotine (0.1, 0.2, or 0.4 mg/kg). There was no generalization to the muscarinic-cholinergic agonist oxotremorine (0.0025–0.04 mg/kg). Additional experiments were carried to further characterize the response of rats trained with nicotine (0.1 mg/kg). These animals failed to generalize to compounds from a range of pharmacological classes (i.e., apomorphine, cocaine, chlordiazepoxide, picrotoxin, and quipazine), but there was partial generalization to amphetamine. Mecamylamine (0.5 mg/kg) but not hexamethonium (5.0 mg/kg) blocked the discrimination of nicotine and the generalization to cytisine. Anabasine (1.0–4.0 mg/kg) did not block the response to nicotine. The results support the view that the nicotine cue is mediated mainly through central cholinergic mechanisms. The dose of nicotine used for training has a very significant influence on the characteristics of the cue and 0.1 mg/kg of nicotine may be more suitable than 0.4 mg/kg as a training dose in future work.     

Incomplete stimulus generalization from a mixture of d-amphetamine and morphine to different doses of the component drugs

Pigeons were trained to discriminate a mixture of 1.8mg/kg morphine plus 1.0mg/kg d-amphetamine from saline, and then tested for generalization to various doses of d-amphetamine and morphine, alone and in combination. The birds discriminated the drug mixture from saline with more than 90% responding on the drug key. The training doses of morphine (1.8mg/kg) and d-amphetamine (1.0mg/kg), as well as lower doses of these drugs, did not reliably generate responding on the drug key when given in combination with saline. Higher doses of morphine and d-amphetamine did generate responding on the drug key, but not as reliably as the training dose combination. Combination of the training dose of morphine with doses of d-amphetamine higher than those in the training dose combination resulted in somewhat less responding on the drug key than that seen with the training dose combination in one bird. These data and those from other experiments where animals were trained to discriminate drug mixtures can be characterized as the net effect of stimuli produced by the component drugs and interactions between the component drugs.     

Overshadowing of nicotine discrimination in rats: a model for behavioural mechanisms of drug interactions?

Overshadowing can play an important role in conditioning with compound exteroceptive stimuli. Drug discrimination experiments have been carried out to examine overshadowing when mixtures of drugs serve as compound interoceptive stimuli. Three groups of rats were trained in a two-bar operant procedure with a tandem schedule of food reinforcement (n = 8). All rats were trained to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline, but in two groups of animals midazolam (0.1 or 0.2mg/kg s.c.) was co-administered with the nicotine to generate a compound stimulus. Dose-response curves were determined with nicotine and midazolam in each group. In rats trained with nicotine alone, there was a steep dose-response curve for the discriminative stimulus effect of nicotine. The presence of the smaller dose of midazolam in the training stimulus clearly attenuated, and the larger dose prevented, the appearance of the discriminative effect of nicotine, whereas there was a concomitant increase in the discriminative response to midazolam. These results suggest that midazolam overshadowed the response to nicotine in a dose-related manner. In rats trained with nicotine alone, the same doses of midazolam had no effect on the discriminative response established to the nicotine stimulus, indicating the absence of pharmacological antagonism. The results illustrate how conditioning factors may provide a behavioural mechanism for interactions between abused drugs.     

Midazolam cue in rats: Effects of Ro 15-1788 and picrotoxin

The discriminative stimulus effect of midazolam, a short-acting benzodiazepine, was used for testing the effects of drugs thought to act as antagonists at different sites in the proposed benzodiazepine receptor complex. Rats were trained in a standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. The benzodiazepine receptor antagonist Ro 15-1788 blocked the discriminative effect of midazolam but did not influence generalization to pentobarbitone (7.5 mg/kg). The indirect GABA antagonist picrotoxin attenuated both generalization to pentobarbitone and its response rate-reducing effect. Picrotoxin had no effect on the discriminative effect of midazolam at 0.4 mg/kg but it blocked the effect of 01 mg/kg. Even in doses which reduced overall response rates, nicotine did not block discrimination of midazolam (0.4 mg/kg). The results are consistent with models which postulate a GABA-linked ion channel which is a site of action for barbiturates and which is downstream of the benzodiazepine receptor itself.     

Temporal factors in drug discrimination: Experiments with nicotine

The role of the presession interval (PI) in drug discrimination research has been studied in rats trained to discriminate nicotine from saline in a two-bar operant conditioning procedure. Different groups of rats were trained at different Pls, varying between 5 and 35 min, and tests were then carried out for qualitative and quantitative differences between the cues. There was complete generalization from nicotine cues trained at one time to tests carried out at other times. The sensitivity of the cues at different Pls to the nicotinic antagonist mecamylamine was very similar. Generalization to amphetamine was nearly complete when the nicotine cue was established with PI of 20-35 min and only partial when the PI for the nicotine was 5 min. Thus, there was no clear evidence for any qualitative difference between nicotine cues established with different PIs. However, the PI influenced quantitative aspects of the nicotine cue in a marked and complex manner. Increasing the PI during training produced a two- to three-fold decrease in the ED(50), whereas increasing the PI during testing produced a two- to three-fold increase in the ED(50). This shows that the effects of changing the PIs during training and testing were similar in magnitude but opposite in direction. These changes in ED(50) values can be explained by pharmacokinetic considerations in conjunction with knowledge of the role of training dose in the discrimination of nicotine. The quantitative sensitivity of the drug discrimination procedure can be substantially influenced by the choice of temporal parameters used in training and testing.     

Generalisation of ethanol with drug mixtures containing a positive modulator of the GABA(A) receptor and an NMDA antagonist

Ethanol is thought to produce its discriminative stimulus effect by actions on two or more neurotransmitter systems. To test this idea further, rats were trained to discriminate mixtures of two drugs from vehicle in two-lever procedures with food reinforcers presented on a tandem variable-interval fixed ratio schedule. After drug-appropriate responding with the training mixtures reached 85%, generalisation to ethanol was examined in extinction tests. Rats trained to discriminate a mixture of chlordiazepoxide (5.0 mg/kg, s. c.) plus dizocilpine (0.08 mg/kg, i.p.) yielded a mean of 76% drug-appropriate responding when tested with ethanol (3.0 g/kg, i.g. ). However, when rats were trained with an 8.0 mg/kg dose of pentobarbitone in a mixture with 0.08 mg/kg of dizocilpine, the same dose of ethanol produced only 33% drug-appropriate responding. After retraining with pentobarbitone (12 mg/kg) plus dizocilpine (0.04 mg/kg), ethanol (3.0 g/kg, i.g.) produced 75% drug-appropriate responding. Pentobarbitone and dizocilpine administered alone produced full, dose-related generalisation, but there was no generalisation to (+)-amphetamine (0.025-0.8 mg/kg, s.c.). Thus, ethanol substituted for mixtures in which the GABA(A)-modulatory component had equal or greater salience than the NMDA-antagonist component. Doses of ethanol that generalised with the drug mixtures always reduced overall rates of responding as compared with control rates. Nevertheless, these data provide further support for the hypothesis that ethanol produces a compound stimulus comprised of elements resembling the effects of positive modulators of GABA(A) receptors and those of NMDA antagonists.     

The discriminative stimulus properties of legal,over-the-counter stimulants administered singly and in binary and ternary combinations

Ninety-six male Sprague-Dawley rats were trained in one of seven drug versus saline (SAL) discrimination (DD) tasks under a variable-ratio 5–15 schedule of food-motivated lever press responding. Three groups of rats (n=12/group) were trained to discriminate between one of the legal over-the-counter (OTC) stimulants — caffeine (CAF), ephedrine (EPHED), phenylpropanolamine (PPA), and SAL. Three other groups (n=2/group) were trained to discriminate between one of three binary stimulant combinations — CAF + EPHED, CAF + PPA, EPHED + PPA, and SAL. The seventh group of rats (n=24) was trained to discriminate between SAL and a ternary combination of the OCT stimulants, CAF + EPHED + PPA. Generalization tests were conducted with each of the OTC stimulants and the controlled stimulants — amphetamine (AMPHET) and cocaine (COC). The data suggest: 1) there is cross-generalization between some OTC combinations and controlled stimulants; 2) full generalization between the OTC and controlled stimulants were demonstrated in rats trained to discriminate two of the binary stimulant combinations from SAL; 3) drug mixtures are not perceived as new entities distinct from their component elements; 4) training dose-ratio may influence the characteristics of mixture discriminations; 5) stimulus overshadowing may be a factor determining drug mixture cues, and 6) the DD properties of aggregate drug compounds may function within a euclidean metric space. We propose that some binary OTC stimulant combinations may effectively function as a methadone-like replacement therapy in cocaine dependence.     

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.