Discriminative Stimulus Properties Of Cocaine Research Articles

Responsiveness to cocaine challenge in adult rats following prenatal exposure to cocaine

Adult rats that were gestationally exposed to cocaine and control offspring were examined for their sensitivity to challenge doses of cocaine. Offspring were derived from Sprague-Dawley dams that had received subcutaneous injections of 40 mg/kg per 3 cc cocaine hydrochloride daily on gestational days 8-20, pair-fed dams that were injected with saline, and nontreated control dams. In order to investigate the sensitivity to challenge doses of cocaine, offspring were assessed in adulthood for locomotor activity, cocaine drug discrimination, and the time course of cocaine in brain tissue following acute cocaine challenge. Adult offspring prenatally exposed to cocaine were observed to exhibit a reduced sensitivity to the discriminative stimulus effects of cocaine as evidenced by a significant shift to the right in the dose-response curve of cocaine discrimination. No prenatal treatment effects were observed in terms of the temporal patterns of cocaine discrimination or with regard to brain levels of cocaine. In addition, baseline locomotor activity and locomotor responses to challenge doses of cocaine were comparable across the prenatal treatment groups. Thus, prenatal cocaine exposure reduced sensitivity of offspring to the discriminative stimulus properties of cocaine without altering either the distribution of cocaine to the brain or the sensitivity of the offspring to the locomotor stimulant effects of cocaine.

Discriminative stimulus properties of cocaine: modulation by dopamine D1 receptors in the nucleus accumbens.

Dopamine (DA) D1 and D2 receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accumbens DA D1 receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625-20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5-40 micrograms) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 microliter/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D1 antagonist SCH 23390 (3-12 micrograms/kg) completely antagonized (< 20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025-0.4 microgram) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D1 receptors in modulating this behavior.

P-125 - Studies on drug dependence (Rept.240): Attenuation of the discriminative stimulus properties of cocaine by opioid receptor antagonists.

P-125 - Studies on drug dependence (Rept.240): Attenuation of the discriminative stimulus properties of cocaine by opioid receptor antagonists.

Discriminative stimulus properties of cocaine in the rat using a two-choice discrete-trial avoidance paradigm

The discriminative stimulus effects of cocaine were studied in rats trained to discriminate 10.0 mg/kg cocaine from vehicle in a shock avoidance paradigm. Rats used could discriminate 10.0 mg/kg cocaine from vehicle within an average of 20 sessions after the start of discrimination training. Cocaine produced dose-dependent stimulus effects at 1.0- to 10.0-mg/kg doses. Cocaine (10.0 mg/kg) generalized to the dopamine reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine 2HCl (GBR 12909) (30.0 mg/kg), methamphetamine (0.3 mg/kg), apomorphine (0.3 mg/kg), and the D 2 dopamine agonist quinpirole (0.1 mg/kg), but not to the D 1 dopamine agonist SK&F38393 (3.0–30.0 mg/kg). 1-Phenyl-2,3,4,5-tetrahydro-[ 1H]-3-benzazepine-7,8-diol HCl (SK&F38393) (10.0 mg/kg) combined with several doses (1.0–10.0 mg/kg) of cocaine shifted the stimulus generalization curve for cocaine to the left. Haloperidol (0.1 and 0.3 mg/kg), the D 1 dopamine antagonist 7-chloro-2,3,4,5-tetrahydro-3-methyl- phenyl-1- H-benzazepine-7- ol maleate (SCH23390) (0.01–0.03mg/kg), and the D 2 dopamine antagonist S(−)-sulpiride (20.0 and 40.0 mg/kg) only partially blocked the stimulus effects of cocaine. Haloperidol (0.3 mg/kg) combined with SCH23390 (0.03 mg/kg) completely blocked the stimulus effects of cocaine. In addition, haloperidol (0.3 mg/kg) blocked the stimulus effects of quinpirole (0.1 mg/kg), in common with cocaine. These data suggest that both D 1 and D 2 dopamine receptors contribute to the discriminative stimulus effects of cocaine.

Cocaine discrimination is attenuated by isradipine and CGS 10746B

The discriminative stimulus properties of cocaine are thought to be mediated by dopaminergic mechanisms that may be modulated by calcium ion influx and/or interact with 5-hydroxytryptamine 3 (5-HT 3) receptors. To test these possibilities, rats were trained to discriminate between the stimulus properties of 10.0 mg/kg cocaine and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance when tested with lower cocaine doses. An analysis of the dose-response curve indicated an ED 50 value of 3.04 mg/kg. Pretreatment with the presynaptic dopamine release-inhibiting agent CGS 10746B (20–40 mg/kg) resulted in a dose-related decrease in cocaine discrimination with the highest dose significantly attenuating cocaine discrimination. Pretreatment with 10–30 mg/kg isradipine, a calcium channel blocker, also resulted in a dose-related decrease in cocaine discriminative performance. In contrast to these positive results, pretreatment with the 5-HT 3 receptor antagonist MDL 72222 (3.5–7.0 mg/kg), or the same doses of ibogaine, did not significantly affect cocaine discrimination. The results suggest that cocaine controls differential responding in a discriminative stimulus task by mechanisms that involve presynaptic release of dopamine, which may be regulated by neuronal calcium influx through L-type calcium channels.

The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds1

The involvement of monoamine neurotransmitter uptake in the discriminative stimulus effects of cocaine was examined in rats (n = 48) trained to discriminate 10mg/kg of this substance from saline in a two-level, water-reinforced (FR 20), drug discrimination situation. Compounds that act primarily by inhibiting dopamine (DA) uptake substituted for the cocaine cue; the order of potency was mazindol > nomifensine > GBR 12909 > bupropion, although efficacy was lowest with GBR 12909. Desipramine, which inhibits norepinephrine (NE) uptake, substituted partially for cocaine while two drugs that inhibit serotonin (5-HT) uptake, citalopram and fluoxetine, did not mimic cocaine. When given in combination with cocaine, cis flupenthixol and SCH 23390 reduced responding on the cocaine-appropriate lever significantly and to a greater extent than either haloperidol, (+/-) sulpiride or (-) sulpiride; neither (+) sulpiride nor metergoline had significant effects. Cocaine substitutions with DA uptake inhibitors were also attenuated to varying extents by cis-flupenthixol, SCH 23390 and haloperidol, but not by metergoline. These data, in conjunction with results reported previously, suggest that inhibition of DA uptake is involved to a greater extent than either NE or 5-HT uptake in the discriminative stimulus properties of cocaine and related compounds. Since both the cocaine cue and its substitution by DA uptake inhibitors appear to be blocked most effectively, reliably and potently by compounds that act either non-selectively at DA receptors (cis-flupenthixol) or primarily at D1 receptors (SCH 23390), D1 mechanisms may play a particularly important role in the neuronal substrates of these behavioral effects.

O-296 - Effects of centrally administered neuropeptides on the discriminative stimulus properties of cocaine.

O-296 - Effects of centrally administered neuropeptides on the discriminative stimulus properties of cocaine.

Rats bred for differences in preference to cocaine: Other behavioral measurements

Cocaine has repeatedly been shown to produce conditioned place preference (CPP) in the rat. The present study employed the heterogenous N/Nih rat stock to produce a selectively bred rat line determined by individual place preference to a conditioning dose of 2.5 mg/kg cocaine. As each of three generations of rats were exposed to the CPP task, cocaine-preferring (CP) males were mated with CP females whereas cocaine-nonpreferring (CNP) male rats were paired with their female counterparts. Rats in litters of the third generation of these selectively bred rats were used in two collateral studies: one involving the discriminative stimulus properties of cocaine and the other to investigate the ability of cocaine to stimulate activity. Results indicate that the continued breeding of CP animals has resulted in rats that prefer cocaine, whereas the breeding of CNP rats is defining a line of rats that actually find cocaine aversive. In testing the discriminative stimulus performance of five male CP and five male CNP rats, the learning rates and dose-response relationship to cocaine were not significantly different between these these two groups. In contrast, administration of 5.0 and 7.5 mg/kg cocaine to male and female CP and CNP rats indicated that, although all groups were stimulated by cocaine when compared to vehicle administration, male CNP rats showed a significantly decreased reaction to these two doses of cocaine. The possibility that conditioned place preference and locomotor stimulation are subserved by the same neural substrates, that is, most probably the dopaminergic systems in the nucleus accumbens of the brain, is discussed.

Discriminative stimulus properties of cocaine, alone and in combination with buprenorphine, morphine and naltrexone

Rats were trained to discriminate a dose of 10.0 mg/kg cocaine from saline. During substitution tests, both cocaine (5.6–10.0 mg/kg) and d-amphetamine (1.0–3.0 mg/kg) produced greater than 80% responding on the cocaine-appropriate lever. In contrast, buprenorphine (0.03–0.56 mg/kg), morphine (0.3–10.0 mg/kg) and naltrexone (1.0–10.0 mg/kg) failed to substitute for the cocaine stimulus, up to doses that substantially decreased rate of responding. When the cocaine dose-effect curve was redetermined in the presence of selected doses of buprenorphine, the amount of cocaine-appropriate responding following a low dose of cocaine (1.0 mg/kg) was increased slightly whereas cocaine-appropriate responding following higher doses of cocaine (3.0 and 5.6 mg/kg) was reduced slightly. Responding following the training dose of cocaine (10.0 mg/kg) was not changed. These results indicate that buprenorphine produced only small alterations in cocaine's discriminative stimulus effects and that the nature of these alterations differed depending on the dose of cocaine examined.

Ritanserin, a new therapeutic approach for drug abuse. Part 2: Effects on cocaine

AbstractAfter a period of forced exposure to cocaine, rats developed a preference for cocaine when given the choice to drink either a cocaine solution or water. The development of cocaine preference was dependent on the cocaine concentration given during choice but appeared to be independent of the presence of an cocaine withdrawal phase. The serotonin antagonist ritanserin reduced cocaine (0.1 mg/ml solution) preference and cocaine intake in a dose‐related manner. The activity of ritanserin started at doses ≥ 0.04 mg/kg when given subcutaneously once daily. Changes in test procedure did not affect the effectivity of ritanserin, although shifts in the lowest active dose were present. In the active dose range (i.e., between 0.04 and 10.00 mg/kg) ritanserin reduced cocaine intake by 29 to 53% and cocaine preference decreased by 19 to 32%. At any time during treatment, the decrease in cocaine consumption was compensated by an increase in water consumption. As a consequence, total fluid intake remained at a constant level. Body weight gain in ritanserin‐treated rats was not different from vehicle‐treated animals. In additional experiments it was shown that ritanserin neither directly interacted with the discriminative stimulus properties of cocaine nor induced a cocaine aversion. The activity of ritanserin against chronic exposure to cocaine is discussed in terms of a serotonin 5‐HT2 antagonism.

Serotonin 5-HT3 antagonists do not alter the discriminative stimulus properties of cocaine

The central nervous system (CNS) of the rat is known to contain serotonin (5-HT) type -3 receptors (5-HT3). Behavioral evidence suggests that 5-HT3 receptors interact with mesolimbic dopamine (DA) systems and that 5-HT3 antagonists can interfere with the hyperlocomotive effects of amphetamine and cocaine and the rewarding and stimulus effects of morphine, nicotine and ethanol. Cocaine, which blocks the reuptake of DA, norepinephrine (NE), and 5-HT in the CNS, also may be an antagonist at 5-HT3 receptors. The purpose of the present study was to determine whether systemic administration of the 5-HT3 antagonists ICS 205930 or MDL 72222 could mimic or block the discriminative stimulus properties of cocaine. Once rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline, substitution tests with various doses of cocaine (0.313-10 mg/kg), ICS 205930 (2-24 mg/kg), and MDL 72222 (2-16 mg/kg) were conducted. Cocaine produced a dose-related increase in cocaine-appropriate responding while the 5-HT3 antagonists engendered primarily saline-lever responding. Neither ICS 205930 nor MDL 72222 were able to antagonize the stimulus effects of cocaine (5 mg/kg). Response rates were not significantly reduced when the 5-HT3 antagonists were given in combination with cocaine. The results indicate that although 5-HT3 antagonists can inhibit some of the unconditioned behavioral effects of psychomotor stimulants, the discriminative stimulus effects of cocaine remain intact.

Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat

Cocaine inhibits the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). To investigate the relative role of such reuptake processes in the discriminative stimulus properties of cocaine, male rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination task and were administered neuroactive compounds during substitution or combination tests. The DA reuptake inhibitor GBR 12909 (2-16 mg/kg) completely mimicked cocaine. The reuptake inhibitors for NE (desipramine; 2-8 mg/kg) and 5-HT (fluoxetine; 0.625-5 mg/kg) did not substitute for the training drug. A low dose of either desipramine (3 mg/kg), fluoxetine (1.25 mg/kg), or GBR 12909 (2 mg/kg) coadministered with low doses of cocaine (0.625-2.5 mg/kg) enhanced the discriminative stimulus properties of this psychostimulant. The dose predicted to elicit 50% drug-lever responding is reduced (ED50) in the presence of desipramine (0.38 mg/kg), fluoxetine (0.79 mg/kg) or GBR 12909 (0.84 mg/kg) compared to the ED50 for cocaine (1.57 mg/kg) in the absence of any reuptake inhibitor. The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems. The potentiation of the stimulus effects of cocaine by monoamine reuptake inhibitors in rats suggests that these drugs could also amplify the subjective effects of cocaine in humans, a possibility that should be considered given the current use of antidepressants in the treatment of cocaine abusers.

Involvement of dopamine uptake in the discriminative stimulus effects of cocaine1,2

The involvement of dopaminergic and adrenergic mechanisms in the stimulus effects of cocaine was studied in rats trained to discriminate cocaine from saline. The cocaine (10mg/kg) cue generalized to compounds that act primarily by inhibiting DA uptake with an order of potency of nomifensine (ED(50) = 0.38mg/kg) > GBR12909 (1-{2-[bis(4-fluorophenyl) methoxy]-ethyl]}-4(3-phenylpropyl) piperazine (ED(50) = 4.38mg/kg) > bupropion (ED(50) = 11.6mg/kg) but not to those that: (1) directly activate postsynaptic DA receptors (bromocriptine), (2) release DA (amantadine), (3) have antagonist actions at presynaptic DA receptors (cis-flupenthixol) or, (4) inhibit the uptake of NE (desipramine, imipramine, nisoxetine). When given in combination with cocaine, the D2 receptors antagonist (-)sulpiride had no significant effects on cocaine-lever selection. These results suggest that inhibition of DA uptake is involved in the discriminative stimulus properties of cocaine since, (1) compounds that act by inhibiting DA uptake rather than through some other mechanism mimic cocaine and, (2) the reported affinities of these drugs for the DA transport site and their order of potency in blocking cocaine are identical.

The discriminative stimulus properties of cocaine: effects of BAY K 8644 and nimodipine

Calcium channel blockers appear to reduce the cardiac toxicity of cocaine and some stimulant-induced behaviors. The present experiment was designed to test whether the internal state induced by cocaine is altered by the calcium antagonist nimodipine. Substitution tests with the calcium agonist BAY K 8644 were also conducted in rats (N = 8) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination paradigm. Cocaine (0.625–10 mg/kg) produced a dose-related increase in drug-lever responding while BAY K 8644 (0.25–2 mg/kg) and nimodipine (0.2–0.8 mg/kg) engendered primarily saline responding. In combination with cocaine (2.5–10 mg/kg), nimodipine shifted the cocaine dose-response curve to the right at doses of 0.2 and 0.4 mg/kg; this attenuation did not increase with higher doses of nimodipine (0.8 and 1.6 mg/kg). The present results suggest that nimodipine may partially block the discriminative stimulus properties of cocaine, however, this reduction is neither robust nor dose-related. Thus, nimodipine might be expected to only marginally alter the subjective cocaine state in humans.

Behavioral interaction between cocaine and caffeine: A drug discrimination analysis in rats

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 Sprague-Dawley male rats were trained to discriminate between 10 mg/kg cocaine and saline. Stimulus generalization tests with both cocaine and amphetamine resulted in a dose-related increase in cocaine-appropriate responding. A variable response rate topography was produced by cocaine. Caffeine also engendered a dose-related increase in cocaine-appropriate responding and resulted in a potency ratio of 15:1 when compared to cocaine. In contrast, increasing doses of caffeine produced a biphasic response rate function (first increases and then decreases). Response choice data suggested a potency relationship of amphetamine > cocaine > caffeine. Caffeine potentiated the discriminative stimulus properties of cocaine. Isobolographic analysis characterized this interaction as simple additivity. However, caffeine's effects upon the rate-altering effects of cocaine resulted in a biphasic interaction pattern. With low doses of cocaine in combination with various doses of caffeine, the interaction for rate reduction is best categorized as “supra-additive,” in contrast, increasing either the cocaine dose or caffeine dose could change the interaction to simple additivity and/or infra-additivity.

Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate cocaine from saline. In substitution tests, the stimulus effects of 10 mg/kg of this substance generalized to d-amphetamine (0.25-1.0 mg/kg) and the selective D2 against LY-171555 (0.05-0.25 mg/kg) but not to the D1 agonist SKF-38393 (5.0-15.0 mg/kg); in combination tests, the D1 antagonist Sch-23390 (0.0625-0.5 mg/kg) significantly blocked, and the D2 antagonist spiperone (0.25-0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D1 or D2 receptor activation; for example, the stimulus properties of this substance might involve both D1 and D2 receptor activation.

Comparison of cocaine and procaine discriminative stimuli

AbstractThe discriminative stimulus, abuse potential, and locomotor‐activating properties of cocaine have all been attributed to dopaminergic activity. Unexplained are findings that the local anesthetic, procaine, with little or no documented dopamine agonist activity, has stimulus properties similar to cocaine and is also self‐administered. The purpose of the work described here was to compare the discriminative stimulus properties of cocaine and procaine and the ability of procaine and other local anesthetics to induce rotational (circling) behavior in unilaterally 6‐hydroxydopamine‐lesioned rats. Rats were trained in a two‐lever, food‐reinforced, operant task to discriminate either cocaine (10 mg/kg, i.p.) or procaine (54.6 mg/kg, i.p.) from saline. Results show that cocaine and procaine have similar stimulus properties, administration of either resulting in partial generalization to the other. Cocainetrained animals generalized perfectly to the psychomotor stimulants amphetamine and methylphenidate. Haloperidol more effectively blocked cocaine than procaine. The alphaadrenergic blocker phentolamine was ineffective against either training drug. Apomorphine, caffeine, and nisoxetine yielded partial generalization to both of the training drugs. Upon acute administration, the local anesthetics other than cocaine showed no significant ability to induce rotation in lesioned rats.

Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine.

Rats were trained to discriminate cocaine, 10.0 mg/kg, using a two-lever operant procedure. Dose-effect data were determined for the substitution of cocaine, diethylpropion, methylphenidate, phenmetrazine, phentermine, and fenfluramine for the cocaine stimulus. All of these drugs, except fenfluramine, substituted fully for the cocaine stimulus. Subsequently, training was halted and cocaine, 20 mg/kg/8 h, was administered for 9 days, and dose-effect data were redetermined for all of these drugs on days 7-9 of chronic administration. Chronic administration of cocaine produced tolerance to the stimulus properties of cocaine, and cross-tolerance to the stimulus properties of methylphenidate, phenmetrazine, and phentermine, such that doses approximately two-fold higher than those used acutely were necessary to reproduce the original effect; the potency for the substitution of diethylpropion for the cocaine stimulus was decreased greater than four-fold; and fenfluramine still failed to substitute for the cocaine stimulus. These data suggest that 1) a common mechanism may mediate tolerance to the discriminative stimulus properties of cocaine, methylphenidate, phenmetrazine, and phentermine, and 2) tolerance in the drug discrimination procedure may have potential for establishing a comprehensive evaluation of dependence liability of CNS stimulants.

Evidence of a central mechanism mediating tolerance to the discriminative stimulus properties of cocaine.

Rats were trained to detect intraperitoneal (IP) administration of cocaine, 10.0 mg/kg, using a two-lever choice discrimination procedure. Following training, cocaine was generalized to the cocaine training stimulus in a dose-dependent manner. Subsequently, bilateral cannulae were implanted in the lateral ventricles in ten animals, and intracerebroventricular (ICV) administration of cocaine was also generalized to the IP training dose in a dose-dependent manner with maximum generalization occurring with 80 micrograms cocaine. After baseline testing, training was halted and cocaine, 20 mg/kg/8-hr, was injected chronically in all rats for 6 days, and then the dose-effect curve for generalization of cocaine was redetermined. Chronic administration of cocaine significantly shifted the dose-effect curve three-fold to the right for both IP and ICV routes of administration. These data suggest that the stimulus properties of cocaine administered centrally are generalized in rats trained by peripheral administration and supports the hypothesis of central mediation of the cocaine stimulus. Also, the comparable shift of the cocaine dose-effect curve following chronic cocaine administration suggests that a central pharmacodynamic mechanism mediates tolerance to the discriminative stimulus properties of cocaine.

Evidence for dopaminergic involvement in tolerance to the discriminative stimulus properties of cocaine

Rats were trained to discriminate cocaine, 10.0 mg/kg, in a two-lever operant procedure. Dose-effect data for generalization to cocaine and substitution of apomorphine for the cocaine stimulus were determined. Subsequently, training was halted and either apomorphine, 2.5 mg/kg per 8 h, or cocaine, 20 mg/kg per 8 h, was administered for 7–9 days. During chronic administration, the efficacy of cocaine and apomorphine as discriminative stimuli was decreased. These data suggest that dopaminergic mechanisms may mediate tolerance to the discriminative stimulus properties of cocaine.