Drug Discriminative Stimuli Research Articles

Opioid-environment interaction: Contrasting effects of morphine administered in a novel versus familiar environment on acute and repeated morphine induced behavioral effects and on acute morphine ERK activation in reward associated brain areas

We report that environmental context can have a major impact on morphine locomotor behavior and ERK effects. We manipulated environmental context in terms of an environmental novelty/ familiarity dimension and measured morphine behavioral effects in both acute and chronic morphine treatment protocols. Wistar rats (n=7 per group) were injected with morphine 10 mg/kg or vehicle (s.c.), and immediately placed into an arena for 5 min, and locomotor activity was measured after one or 5 days. The morphine treatments were initiated either when the environment was novel or began after the rats had been familiarized with the arena by being given 5 daily nondrug tests in the arena. The results showed that acute and chronic morphine effects were strongly modified by whether the environment was novel or familiar. Acute morphine administered in a novel environment increased ERK activity more substantially in several brain areas, particularly in reward-associated areas such as the VTA in comparison to when morphine was given in a familiar environment. Repeated morphine treatments initiated in a novel environment induced a strong locomotor sensitization, whereas repeated morphine treatments initiated in a familiar environment did not induce a locomotor stimulant effect but rather a drug discriminative stimulus dis-habituation effect. The marked differential effects of environmental novelty/familiarity and ongoing dopamine activity on acute and chronic morphine treatments may be of potential clinical relevance for opioid drug addiction.

Pavlovian-Instrumental Transfer of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats

To date, only 1 study has evaluated the impact of a Pavlovian drug conditional stimulus (CS) on operant responding. A within-subject operant 1-lever go/no-go (across sessions) design was used to evaluate the impact of Pavlovian contingencies on the discriminative stimulus effects of nicotine (0.4 mg/kg) and ethanol (800 mg/kg) in male Sprague Dawley rats. Drugs were administered 10 min before each acquisition and test session. One drug predicted sessions of food reinforcement and the other drug predicted sessions of non reinforcement; stimulus roles were counterbalanced. In Experiment 1 (n = 7), operant lever pressing was initially maintained on a VI-30 s schedule of food reinforcement. This phase was followed by 20 (CS+ vs. CS-) Pavlovian drug discrimination training sessions without the levers present. Two extinction tests revealed significantly more operant lever pressing under the CS+ drug conditions compared to the CS- drug conditions, suggesting evidence for Pavlovian-instrumental transfer. Operant training significantly strengthened stimulus control. In Experiment 2 (n = 7), the drugs functioned as operant drug discriminative stimuli first. Next, the predictive roles of the drug S D s and S Δ S were reversed under Pavlovian CS- and CS+ contingencies, respectively. The original stimulus control was significantly undermined but was not reversed. These studies suggest that Pavlovian drug-reinforcer contingencies embedded within the operant 3-term contingency may play a partial role in mediating the discriminative stimulus effects of drugs.

Relationship of Components of an Alcohol Interoceptive Stimulus to Induction of Desire for Alcohol in Social Drinkers

The ability of a low (0.2 g/kg) oral dose of ethanol to provide a drug discriminative stimulus was studied in young healthy human volunteers, who were social drinkers. Seventeen of 24 subjects acquired the discrimination following 10 trials in which they received aliquots of ethanol or of placebo drink (tonic water mixed with Tabasco sauce). In generalization studies, in which the dose of ethanol was varied, discrimination performance was dose dependent; doses greater than 0.05 g/kg gave rise to significant ethanol-appropriate responding. Concurrent estimates of the subjective effects of doses administered as discriminative stimuli revealed that two factors—taste and light-headedness—were associated with discrimination; at the training dose, 0.2 g/kg, although both the factors taste and light-headedness were significantly increased, only taste predicted discrimination performance. At lower doses, taste did not contribute to discrimination, but the subjective rating light-headedness correlated significantly with discrimination accuracy. Post hoc analyses of the influence of the amount of alcohol regularly drunk by the volunteers, on discrimination performance suggested light-headedness correlated with discriminative performance only in social drinkers drinking more than 20 units per week. In a second experiment, groups of “high” (mean 40 units per week) and “low” (mean 10 units per week) social drinkers were prospectively identified. Discrimination performance of 0.2 g/kg ethanol in orange juice vs. orange juice vehicle indicated that both groups were able to perform the discrimination following a single training trial, and that generalization curves over the range 0.05–0.2 g/kg were dose dependent, and not different between the groups. At the lowest dose, discrimination performance was predicted by taste, stimulation, and light-headedness in the “high” group, but not in the “low” group. The ability of these ethanol doses to induce feelings of craving for ethanol were assessed in parallel, using the Desire for Alcohol Questionnaire (DAQ). “High” drinkers showed higher desire for ethanol on all factors of the DAQ except the “positive negative reinforcement” factor, and sampling ethanol tended to increase desire in these measures. However, at each dose, the induction of feelings of desire for ethanol showed a negative correlation with discrimination performance. These findings are discussed in the context of the ability of animals and humans to use several components of drug-induced stimuli in the performance of drug discrimination, and the role of such discriminative stimuli in priming of ethanol drinking.

Effects of lithium dose (UCS) on the acquisition and extinction of a discriminated morphine aversion

The effects of varying the lithium dose (unconditioned stimulus [UCS]; LiCl range 30-180 mg/kg) on the acquisition and extinction of stimulus control by 5.6 mg/kg of morphine in a discriminated taste aversion (DTA) procedure were examined in rats. In addition, pharmacological specificity was examined by substituting (-)-delta-9-tetrahydrocannabinol (delta9-THC) for morphine during a test phase intervening between acquisition and extinction. DTA acquisition was more rapid at higher LiCl doses. The lowest dose of LiCl, 30 mg/kg, did not robustly maintain a DTA. Two groups treated with 60 mg/kg LiCl, differing only in the type of drinking nozzle used (ball-bearing vs standard non-ball-bearing), behaved similarly. Suppression of drinking was related to the morphine dose, in an orderly manner (dose range 0.3-10 mg/kg), in rats for which morphine was followed by LiCl. No significant decline in drinking occurred for rats for which morphine was followed by saline, except perhaps at the 10 mg/kg test dose of morphine. The control of drinking was pharmacologically specific; both experimental and control animals were equally affected in tests with delta9-THC (0.3-10 mg/kg). Low doses of delta9-THC increased water consumption; this did not occur with morphine. During extinction the reinstitution of drinking was similar across groups that had been effectively conditioned, i.e. there was no apparent effect of lithium dose on extinction. After extinction, a much attenuated reaction occurred to morphine in tests with 3 and 10 mg/kg. These doses of morphine had significantly suppressed drinking before the extinction phase. Collectively, these data add to the formal similarities between sensory and drug discriminative stimuli.

Cross-generalization between drug discriminative stimuli and conditioned safety and danger cues.

Cross-generalization between drug discriminative stimuli and conditioned safety and danger cues.

Cross-generalization between drug discriminative stimuli and conditioned safety and danger cues.

Cross-generalization between drug discriminative stimuli and conditioned safety and danger cues.

Phencyclidine established as a discriminative stimulus using ethanol as a reinforcer

Long-Evans hooded rats were initially trained to lever press, in standard, operant conditioning chambers, according to a fixed-ratio 1 (FR1) reinforcement schedule using 0.06ml deliveries of 8% w/v ethanol as the reinforcer, during daily Monday-Friday, 1h experimental sessions. Next, experimental sessions were reduced to 0.5h, the FR value was increased to 5, and the rats were trained to discriminate 2.0mg/kg s.c. phencyclidine (PCP) from saline vehicle using standard, drug discrimination training procedures, with 8% ethanol as the reinforcer. Following training, dose-response tests with PCP (0.1-4.0mg/kg), ketamine (0.1-18mg/kg), dexoxadrol (1.0-5.6mg/kg) and morphine (1.0-9.0mg/kg) were conducted. More PCP-lever presses were emitted than saline-lever presses at several doses of PCP, ketamine, and dexoxadrol, indicating generalization from the 2.0mg/kg PCP stimulus. When morphine was tested, more saline-lever than PCP-lever presses were made, and percent PCP-lever pressing never exceeded an average of 12% at any dose tested. This study demonstrates that one drug of abuse, PCP, can serve as a discriminative stimulus when another drug of abuse, ethanol, serves as the reinforcing stimulus, and is the first explicit laboratory demonstration of drug discriminative stimulus control during drug self-administration.

The pentylenetetrazole-cue antagonist actions of bretazenil (Ro 16-6028) as compared to midazolam

In order to compare the potencies of bretazenil (Ro 16-6028) and midazolam (MDZ) to antagonize the pentylenetetrazole (PTZ) cue, rats were trained to discriminate between 15 mg/kg IP PTZ and saline (FR10, food reinforced). Additionally, other rats were trained to discriminate between 1.0 mg/kg IP MDZ and saline in order to investigate the degree of generalization of bretazenil to MDZ, and to test for the antagonizing effects of PTZ. Both bretazenil and MDZ were able to block the PTZ cue. Bretazenil was about 60 times more potent than MDZ in this respect. In tests for response generalization, bretazenil substituted for the MDZ cue. Bretazenil did not show MDZ-antagonist actions. PTZ did block the MDZ cue and the generalization of bretazenil in the MDZ-trained animals. Assuming that the drug discriminative stimulus functions of PTZ are closely related to its anxiogenic effects, it was concluded that bretazenil may possess powerful anxiolytic properties. Bretazenil did not suppress the response rates which is consistent with previous studies reporting a lack of sedative and muscle-relaxant effects of bretazenil.

The classification of 5-hydroxytryptamine receptors.

1. The current classification of receptors for 5-hydroxytryptamine (5-HT) is based on functional studies, and encompasses three main receptor types. 2. 5-HT1-like receptors mediate inhibition of release of various neurotransmitters from central and peripheral sites, smooth muscle contraction and relaxation (and release of endothelium-derived relaxing factor), tachycardia, a variety of behavioural actions (for example, forepaw treading, hypothermia, hyperphagia, drug discriminative stimulus properties, nociceptive pathway modulation, and anxiolytic, anti-aggressive and prosexual effects), and central neuronal excitatory and inhibitory activity. Selective antagonists for this receptor are not yet available, but the 5-HT2 receptor antagonists methysergide and methiothepin have appreciable affinity for 5-HT1-like receptors, and 5-carboxamidotryptamine is a selective agonist. 3. 5-HT2 receptors mediate smooth muscle contraction, platelet aggregation, increased capillary permeability, some behavioural syndromes (for example, head twitch and wet-dog shakes) and drug discriminative stimulus properties, central neuroexcitatory effects, and some neuroendocrine functions. Ketanserin and cyproheptadine are selective antagonists. 4. 5-HT3 receptors mediate peripheral afferent and efferent neuroexcitatory actions, anxiogenic effects, and modulation of cytotoxic drug-induced emesis, gastric emptying, and dopamine-related mesolimbic hyperactivity. Selective antagonists include cocaine, MDL 72222 and ICS 205-930; 2-methyl-5-HT is a selective agonist.

Compound drug discrimination learning

AbstractData are summarized which indicate that drug discriminative stimuli (DDS) and exteroceptive, sensory stimuli interact in a systematic manner. Thus recent work revealed that phenomena such as overshadowing, blocking, and conditional discrimination are operable in drug discrimination learning (DDL) experiments involving exteroceptive cues and DDS. Additionally, in a reversal learning experiment, a contextual change differentially affected rate of reversal learning and subsequent generalization test data.

Tolerance to drug discriminative stimuli: A. M. Young. Wayne State University

Tolerance to drug discriminative stimuli: A. M. Young. Wayne State University

Rolipram as a discriminative stimuli: transfer to phosphodiesterase inhibitors.

Rats were trained to discriminate (+/-)-rolipram (0.32 mg/kg, i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (FR 10). (+/-)-Rolipram served as a drug discriminative stimulus, and its discrimination was readily established with a mean of 42 training sessions to achieve criterion performance (at least 80% correct response in the consecutive generalization tests with both saline and (+/-)-rolipram). Thereafter, this stimulus was stably maintained. The (-)-isomer of rolipram was generalized at about one-third of the training dose of the (+/-)-compound, but the (+)-isomer was generalized only at 10 times the dose of the (+/-)-compound. This finding suggests that the (-)-compound is more extensively involved as a stimulus than either (+/-)-rolipram or the (+)-isomer. Ro20-1724, caffeine and theophylline, which are phosphodiesterase inhibitors, were generalized to (+/-)-rolipram. This result strongly suggests that phosphodiesterase inhibition may be an important factor involved in (+/-)-rolipram discrimination.

Rolipram as a Discriminative Stimuli: Transfer to Phosphodiesterase Inhibitors

Rats were trained to discriminate (±)-rolipram (0.32 mg/kg, i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (FR 10). (±)-Rolipram served as a drug discriminative stimulus, and its discrimination was readily established with a mean of 42 training sessions to achieve criterion performance (at least 80% correct response in the consecutive generalization tests with both saline and (±)-rolipram). Thereafter, this stimulus was stably maintained. The (-)-isomer of rolipram was generalized at about one-third of the training dose of the (±)-compound, but the ( + )-isomer was generalized only at 10 times the dose of the (±)-compound. This finding suggests that the (-)-compound is more extensively involved as a stimulus than either (±)-rolipram or the ( + )-isomer. Ro20-1724, caffeine and theophylline, which are phosphodiesterase inhibitors, were generalized to (±)-rolipram. This result strongly suggests that phosphodiesterase inhibition may be an important factor involved in (±)-rolipram discrimination.

Interaction between drug discriminative stimuli and exteroceptive, sensory signals.

Interactions between drug discriminative stimuli (based on 5.6 mg/kg and 10 mg/kg pentobarbital) and exteroceptive stimuli (visual and auditory) were studied in a T-maze. In three groups, visual stimuli (light vs. dark) were differentially paired with drug stimuli; the fourth group discriminated combinations of tonal frequencies (1 kHz or 10 kHz) and the presence or absence of pentobarbital. (10 mg/kg). In general, visual stimuli controlled choice behavior (left or right turn) to a greater extent than did the drug training stimuli, whereas the auditory stimuli exerted no apparent control over the pentobarbital stimulus in Group 4. Tests with doses higher than the training doses indicated augmented stimulus control by the drug dimension in two groups (Group 1, 10 mg/kg pentobarbital vs. saline; Group 2, 5.6 mg/kg vs. 10 mg/kg pentobarbital) but not in the third group (5.6 mg/kg pentobarbital vs. saline) in the "conflict" situation, that is, the exteroceptive conditions signaled one response whereas the drug stimulus signaled the opposite response. Discrimination training with only one of the stimulus dimensions resulted in stimulus control in the following order: 10 mg/kg vs. saline greater than 5.6 mg/kg vs. saline greater than 1 kHz vs. 10 kHz, results indicating that the auditory stimuli were of marginal significance. In conclusion, drugs can complete with exteroceptive, visual stimuli for associative strength.

Interaction between drug discriminative stimuli and exteroceptive, sensory signals.

Interaction between drug discriminative stimuli and exteroceptive, sensory signals.

Conditioning of a discriminative drug stimulus: overshadowing and blocking like procedures.

Interactions between a drug discriminative stimulus (D, 17.5 mg/kg of pentobarbital vs. N, saline) and exteroceptive stimulus conditions (light vs. dark) were examined in a T‐maze, shock‐escape task using conditioning procedures pertaining to the phenomena of “overshadowing” and “blocking”. From an operational point of view, in the “overshadowing” procedure the stimulus compound is introduced from the outset of the training, whereas in the “blocking” procedure the stimuli components are introduced sequentially. When the compound discriminations were established, dose‐generalization tests with various doses of pentobarbital (range 5.6–17.5 mg/kg) as well as saline (1 ml/kg) were carried out under both elements (light and dark) of the exteroceptive stimulus dimension. Prior training with drug (D vs. N) neutralized the potential influence of the exteroceptive dimension (light vs. dark); conversely training with the exteroceptive stimuli prior to the drug training accentuated the control over behavior by the visual stimuli. Dose‐generalization results intermediate to those described above were observed in the group trained to discriminate the stimulus compound (D plus light vs. N plus dark) from the outset of training. It may therefore be concluded that exteroceptive stimuli can compete with interoceptive drug stimuli for associative strength in the procedure used. Thus, the formal similarities between drug discriminative stimuli and more conventionally studied exteroceptive, sensory signals are furthered by the data.

Nisoxetine and amphetamine share discriminative stimulus properties in mice

The interaction of amphetamine with noradrenergic neurons could mediate a portion of the drug's discriminative stimulus properties. To test this hypothesis, mice were trained to discriminate 1.0 or 3.2 mg/kg amphetamine, 32 mg/kg of the selective norepinephrine uptake inhibitor, nisoxetine, or 32 mg/kg nisoxetine + 1.0 mg/kg amphetamine from saline. Differential drug- or saline-appropriate responding was determined using a two photocell-beam procedure with beam interruption as the operant. Reinforcement (5-sec access to evaporated milk) was presented on a fixed-ratio 20 (FR-20) schedule. Mice trained to discriminate 1.0 mg/kg amphetamine from saline generalized to nisoxetine (32 mg/kg) alone and to doses of 0.56 mg/kg amphetamine and above but not to lower doses unless pretreated with nisoxetine (20 or 32 mg/kg). Mice trained to discriminate nisoxetine (32 mg/kg) from saline generalized to 0.56, 1.0 and 3.2 mg/kg amphetamine and generalized to all amphetamine doses when pretreated with nisoxetine (32 mg/kg). Mice trained to discriminate the drug combination from saline generalized to nisoxetine (32 mg/kg) alone, and to 3.2 mg/kg amphetamine tested alone, to 0.56 mg/kg of amphetamine or above when the lower dose of nisoxetine (20 mg/kg) was used, and to all test doses of amphetamine with nisoxetin (32 mg/kg) pretreatment. Mice trained to discriminate 3.2 mg/kg amphetamine from saline generalized to no test dose of amphetamine following either saline or nisoxetine (32 mg/kg) pretreatment. Testing with several doses of pentobarbital (1.0, 3.0, 10.0 and 18.0 mg/kg) resulted in saline-appropriate responding regardless of training group. These observations indicate that the mouse may be a useful subject for drug discrimination experiments and are consistent with the notion that the discriminative stimulus properties of a low dose of amphetamine are at least partially noradrenergically mediated.