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PubMed2005

Attitudes towards change and treatment outcome in eating disorders.

OBJECTIVE: To investigate the influence of the stage of change on treatment outcome among patients suffering from eating disorders. METHOD: Sixty-seven women receiving free outpatient treatment for eating disorders initially participated in this study. Their demographic, lifetime and clinical characteristics, eating disorder symptoms and general distress were assesssed at baseline and after one year, together with the results of self-report questionnaire on Attitudes towards Change in Eating Disorders (ACTA). RESULTS: High scores on the Maintenance subscale were protective for eating psychopathology as measured by the Eating Attitudes Test (EAT-40), Eating Disorders Inventory (EDI-2) and the frequency of purging. Action was predictive of weight changes. Precontemplation and Relapse respectively predicted little change in EAT and the Bulimic Inventory Test Edinburgh (BITE). High Preparation scores were predictive of the level of EDI-2 Interoceptive Awareness, Maturity Fears, and Ascetism. DISCUSSION: Our results suggest considering the stage of change as a useful outcome predictor.

Adolescent↗

PubMed2000

The Eating Disorder Inventory in evaluation of impaired eating behaviour in subjects requesting nutritional consultation.

The present study evaluated impaired eating behaviour in women seeking participation in a diet-based programme of weight reduction or achievement of ideal body weight. Forty-seven obese, 42 overweight and 14 normal-weight subjects, attending an Italian university outpatient clinic completed the Eating Disorder Inventory (EDI). Forty-eight mothers of primary school children (25 normal-weight and 23 overweight) were used as controls. The EDI consists of 8 subscales, 3 evaluating psychopathology related to eating disorders (drive for thinness, bulimia, body dissatisfaction) and 5 evaluating general psychopathology (intereoceptive awareness, ineffectiveness, maturity fears, perfectionism, interpersonal distrust). Significantly altered scores in the first three subscales were observed both in normal-weight and overweight outpatients compared to the controls. The overweight outpatients scored higher than the obese patients in terms of drive for thinness and bulimia and higher than the normal-weight women for terms of bulimia, body dissatisfaction and drive for thinness. The overweight controls scored significantly higher than the normal-weight controls in the first three subscales in the remaining subscales, mean values were also higher in the overweight group, though significance was only reached in the interpersonal distrust and interoceptive awareness subscales. Impaired eating behaviour is frequent in subjects seeking participation in weight reduction or ideal body weight achievement programmes.

Adult↗

PubMed2003

Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey.

RATIONALE: The discriminative stimulus effects of a combination of acute morphine followed by naltrexone have been described in rats. OBJECTIVE. The purpose of this study was to extend observations to a non-human primate. METHODS: Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discriminate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR-->NTX) versus saline (1.0 ml/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (SAL-->NTX). RESULTS: Seven subjects acquired the discrimination in an average of 108+/-14 sessions. MOR-->NTX-appropriate responding increased as an orderly function of increasing dose of morphine (0.56-1.7 mg/kg) and of naltrexone (0.01-10 mg/kg). The discrimination was also dependent upon interval between morphine and naltrexone administration. The MOR-->NTX cue was fully generalized to the combination of levorphanol (0.3 mg/kg) followed by naltrexone, but not to the non-opioid stereoisomer of levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/kg) followed by naltrexone. Naltrexone administered 15 min before morphine dose-dependently blocked MOR-->NTX-appropriate responding. CONCLUSIONS: This is the first non-rodent study of the discriminative effects of MOR-->NTX. MOR-->NTX produces a unique interoceptive stimulus that is pharmacologically selective, requires occupation of opioid receptors, presumably mu, for some minimum period of time, and is reversible. This discrimination procedure might provide new insights into the early drug-receptor interactions that underlie the development of physical dependence upon morphine-like drugs.

Animals↗

PubMed2005

Hallucinogen-like actions of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats.

RATIONALE: Few studies have examined the effects of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in vivo. OBJECTIVES: 2C-T-7 was tested in a drug-elicited head twitch assay in mice and in several drug discrimination assays in rats; 2C-T-7 was compared to the phenylisopropylamine hallucinogen R(-)-1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane (DOM) in both assays, with or without pretreatment with the selective 5-HT2A antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907). Finally, the affinity of 2C-T-7 for three distinct 5-HT receptors was determined in rat brain. METHODS: Drug-elicited head twitches were quantified for 10 min following administration of various doses of either 2C-T-7 or R(-)-DOM, with and without pretreatments of 0.01 mg/kg M100907. In rats trained to discriminate lysergic acid diethylamide (LSD), 2C-T-7 and R(-)-DOM were tested for generalization. In further studies, rats were trained to discriminate 2C-T-7 from saline, then challenged with 0.05 mg/kg M100907. In competition binding studies, the affinity of 2C-T-7 was assessed at 5-HT2A receptors, 5-HT1A receptors, and 5-HT2C receptors. RESULTS: 2C-T-7 and R(-)-DOM induced similar head twitch responses in the mouse that were antagonized by M100907. In the rat, 2C-T-7 produced an intermediate degree of generalization (75%) to the LSD cue and served as a discriminative stimulus; these interoceptive effects were attenuated by M100907. Finally, 2C-T-7 had nanomolar affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors. CONCLUSIONS: 2C-T-7 is effective in two rodent models of 5-HT2 agonist activity and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of 2C-T-7 strongly suggests that the 5-HT2A receptor is an important site of action for this compound.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed2006

Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant.

RATIONALE: Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. OBJECTIVES: To investigate the effects of ayahuasca administration on regional cerebral blood flow. METHODS: Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100-110 min after drug administration by means of single photon emission tomography (SPECT). RESULTS: Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. CONCLUSIONS: The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.

Adult↗

PubMed2006

Ligands selective for alpha4beta2 but not alpha3beta4 or alpha7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat.

RATIONALE: Nicotine produces behavioural effects that are potentially related to its interaction with diverse nicotinic acetylcholine receptor populations. Evidence from gene deletion studies suggests that the interoceptive stimulus properties of nicotine are mediated by heteromeric high-affinity receptors containing alpha4beta2 subunits. Mice lacking beta2 subunits do not discriminate nicotine (Shoaib et al., Neuropharmacology, 42:530-539, 2002), and nicotine does not elicit dopamine release in these animals (Grady et al., J Neurochem, 76:258-268, 2001). The stimulus properties of nicotine can be detected in rats using a two-lever operant drug discrimination paradigm, allowing them to be classified pharmacologically using ligands with selectivity for receptors containing alpha4beta2, alpha3beta4 or alpha7 subunits. MATERIALS AND METHODS: Rats trained to discriminate 0.4 mg/kg nicotine from vehicle were given the nicotinic receptor agonists, cytisine, varenicline, TC2559, ABT-594, A-85380 (all having high affinity but varying selectivity for alpha4beta2-containing receptors), and WO 03/062224 and WO 01/60821A1 (selective for beta4- and alpha7-containing receptors, respectively). In separate studies, WO 03/062224 was used as the training stimulus. RESULTS: Nicotine, TC-2559, A-85380 and ABT-594 showed dose-dependent and complete stimulus substitution, whilst WO 03/062224 and WO 01/60821A1 were completely without effect. Cytisine and varenicline showed partial generalisation, consistent with their partial agonist activity at nicotinic receptors eliciting dopamine release in rat striatal slices. After almost 50 training sessions with WO 03/062224, there was no clear evidence that an alpha3beta4 receptor agonist could sustain a discriminable stimulus. CONCLUSION: Substitution to the nicotine discriminative stimulus required high-affinity and high intrinsic activity at beta2 but not at beta4- or at alpha7-containing nicotinic receptors.

Animals↗

PubMed2001

Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats.

RATIONALE: The discriminative stimulus (DS) properties of the selective serotonin (5-HT) uptake inhibitor (SSRI), citalopram, are mediated by 5-HT2C receptors. Interestingly, the "atypical" antidepressants, mianserin and mirtazapine, behave as antagonists at 5-HT2C receptors. OBJECTIVE: Herein, we evaluated the influence of mianserin and mirtazapine upon the DS effects of citalopram. METHODS: In a two-lever drug discrimination procedure, rats initially trained to discriminate citalopram (2.5 mg/kg, i.p.) from saline were retrained with a lower dose of citalopram (0.63 mg/kg, i.p.). Subsequently, generalization and antagonist studies were conducted with mianserin and mirtazapine. RESULTS: Both dose-dependently blocked, but did not generalize to, the DS properties of citalopram without markedly disrupting response rates. Their effective dose50s were 0.1 and 1.4 mg/kg, s.c., respectively. CONCLUSION: These observations are consistent with a role of 5-HT2C receptors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" properties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.

Adrenergic alpha-Antagonists↗

PubMed1996

Initiation, maintenance and extinction of cocaine self-administration with and without conditioned reward.

Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS+ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n = 6) and a group responding on a second-order (SO) schedule (n = 5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n = 7) responses during extinction were counted with and without the CS+. Responding was greater in the presence of the CS+ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli.

Animals↗

PubMed1997

Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data.

Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.

Amphetamine↗

PubMed1997

Discriminative-stimulus effects of clozapine in squirrel monkeys: comparison with conventional and novel antipsychotic drugs.

The effects of conventional and novel atypical antipsychotic drugs were compared to clozapine in squirrel monkeys that discriminated I.M. injections of clozapine (1.0 mg/kg) from saline in a two-lever drug discrimination procedure. Clozapine (0.03-3.0 mg/kg) produced dose-related increases in responding on the clozapine-associated lever with full substitution at the training dose in all monkeys. Dose-related increases in responding on the clozapine-associated lever and full substitution also were observed with structural analogues of clozapine including perlapine and fluperlapine (0.1-3.0 mg/kg), seroquel (0.1-5.6 mg/kg), and JL 5, JL 8 and JL 18 (0.1-3.0 mg/kg). Other clozapine analogues, including olanzapine, amoxapine, loxapine and clothiapine, and conventional antipsychotic drugs, including phenothiazines such as chlorpromazine and thioridazine, produced some clozapine-associated responding up to the highest doses that could be studied, but did not substitute for clozapine. Olanzapine did produce full clozapine-lever responding following pretreatment with the dopamine D2-receptor agonist (+)-PHNO (0.003-0.01 mg/kg). Putatively atypical antipsychotics that are structurally unrelated to clozapine including risperidone (0.003-0.1 mg/kg), sertindole (0.03-1.0 mg/kg) and remoxipride (0.1-5.6 mg/kg) similarly failed to substitute for clozapine up to the highest doses. The present results indicate that some, but not all, structural analogs of clozapine have clozapine-like discriminative-stimulus effects and that novel antipsychotic drugs which purportedly have clozapine-like clinical efficacy may not produce its interoceptive stimulus effects.

Animals↗

PubMed1998

Generalization of a restraint-induced discriminative stimulus to cocaine in rats.

The ability of the interoceptive cues produced following exposure to restraint stress to generalize to the discriminative stimulus effects of cocaine was investigated. Rats were trained to discriminate cocaine (10 mg/kg, IP, n=10; or 20 mg/kg, IP, n=6) from saline using a two-choice, food-reinforced, drug discrimination design. Substitution for the 10 mg/kg training dose of cocaine was observed subsequent to exposure to 15 min of restraint when administered immediately following an injection of saline. Restraint-induced generalization in the 20 mg/kg training group was substantial, but not statistically significant. These data suggest that a component of the subjective effects of cocaine may be associated with "anxiety".

Animals↗

PubMed1998

Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat.

The potential of centrally (ICV) or systemically (SC) administered M6G to substitute for morphine in a drug discrimination task was characterized in the present study. Rats with a cannula in the lateral cerebral ventricle were trained to discriminate between injections of morphine (3 mg/kg, SC) and saline using a discrete-trial avoidance/escape procedure. Substitution tests were conducted with SC or ICV morphine, morphine-3-beta-D-glucuronide (M3G), or morphine-6-beta-D-glucuronide (M6G) and response latency in a tail-flick test was measured before each session began. The stimulus effects of morphine (ED50=1.02 mg/kg SC or 2.1 microg/kg ICV) were fully shared by M6G, with potency dependent on route of administration (ED50=3.12 mg/kg SC or 0.34 microg/kg ICV). The stimulus effects of M6G were highly correlated with its antinociceptive activity (r=0.84 SC or 0.46 ICV) and, at equipotent systemic doses, they lasted longer (t1/2=391 min) than those of morphine (t1/2=185 min). M3G was inactive in both procedures by both routes of administration. Naltrexone SC, given 30 min prior to testing, completely attenuated the stimulus effects of ICV M6G (AD50=0.011 mg/kg), indicating that they are mediated by opioid receptors. The results of this study suggest that M6G might contribute to the interoceptive effects of morphine that underlie its potential for abuse.

Analgesics, Opioid↗

PubMed1999

Effects of central and peripheral nicotinic blockade on human nicotine discrimination.

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

Adult↗

PubMed1999

Characterizing withdrawal in rats following repeated drug administration using an amphetamine-vehicle-haloperidol drug discrimination.

RATIONALE: Previous research using an amphetamine (AM)-haloperidol (HA) drug- drug discrimination task has shown that predominant responding on the HA-appropriate lever occurs 24 h after a single or multiple administrations of 10 mg/kg AM. Conversely, rebound responding on the AM-appropriate lever occurs following single or multiple administrations of 1 mg/kg HA. HA-appropriate responding was also observed 24 h following a single injection of AM using a three-lever, AM-vehicle-HA discrimination task. However, a single administration of HA did not produce robust rebound responding on the AM-appropriate lever. The present studies seek to clarify the discrepancy between responding following HA in the two- and three-choice tasks. OBJECTIVE: Experiment 1 examined the extent of rebound responding that could be achieved following ten daily administrations of either 10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences between the two- and three-choice tasks in characterizing the post-HA cue. METHODS: Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033 mg/kg HA. In experiment 1, animals received ten daily injections of 10 mg/kg AM, vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again 8, 15, and 22 days post-treatment. In experiment 2, animals were retrained and then treated daily with either vehicle or 1.0 mg/kg HA for 10 days, and then tested 24 h after the final injection, and again 5 and 11 days post-treatment, with either all three levers or with only the AM- and HA-appropriate levers available. RESULTS: In experiment 1, multiple injections of AM produced robust HA lever responding, which is consistent with results from previous studies that used the two-choice, AM-HA discrimination task. However, multiple injections of HA did not produce predominant responding on the AM-appropriate lever. In experiment 2, animals treated with either vehicle or HA responded predominantly on the vehicle-appropriate lever when tested with all three levers present. When tested with the vehicle lever removed, however, animals treated with vehicle responded predominantly on the HA-appropriate lever, whereas those treated with HA responded predominantly on the AM-appropriate lever. CONCLUSIONS: These results suggest that the two-choice and three-choice task used here differ in how the post-HA withdrawal cue is characterized. This finding emphasizes the importance of knowing the relative locations of the agonist-, vehicle-, and antagonist-produced cues on the interoceptive stimulus continuum established by discrimination training.

Amphetamine↗

PubMed1999

Effects of training dose and two- versus three-choice testing procedure on nicotine discrimination responding in humans.

RATIONALE: Discrimination of a drug's interoceptive stimulus effects often depends substantially on training and testing conditions. OBJECTIVES: We examined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing procedure. METHODS: Smokers and never-smokers (n=10 each) were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of doses from 0 to 20 microg/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her threshold dose for discrimination was identified (mean=2.7 microg/kg). A repeat testing of generalization responding across 0-20 microg/kg was then conducted, using placebo and the subject's threshold dose as training doses. Generalization testing involved both two-choice and three-choice (novel response option) quantitative procedures. RESULTS: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when the nicotine training dose was lowered (i.e. from the first to the second test of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-appropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effects of "head rush" and, in never-smokers only, "jittery" also showed a shift to the left in their relationship with nicotine generalization dose when the training dose was lowered. CONCLUSIONS: These results confirm the importance of training and testing conditions on discrimination behavior and subjective drug responses within subjects and demonstrate the utility of the novel-response, three-choice procedure for assessing qualitatively different stimulus effects of novel drug doses.

Adult↗

PubMed1999

The discriminative stimulus properties of LY233708, a selective serotonin reuptake inhibitor, in the pigeon.

RATIONALE: Understanding the contribution of the various serotonin (5-HT) receptor subtypes to the behavioral effects of selective serotonin reuptake inhibitors (SSRIs) may contribute to the discovery of increasingly effective drugs for the treatment of conditions such as depression, panic and obsessive-compulsive disorders. OBJECTIVES: A drug discrimination procedure was used to determine whether the administration of an SSRI was associated with a specific interoceptive stimulus cue and to what extent that cue was related to activation of the 5-HT(1A) receptor. METHOD: Pigeons were trained to discriminate 20 mg/kg of the short acting, SSRI, LY233708 dihydrochloride dihydrate [(-)-cis-1-(6-chloro-1,2,3,4- tetrahydro-1-methyl-2-naphthalenyl)piperazine] from saline. RESULTS: LY233708 induced a specific, dose-related stimulus cue. The SSRIs, fluoxetine and citalopram, induced dose-related responding on the LY233708-associated key. In contrast, nisoxetine, a selective norepinephrine uptake inhibitor, induced responding on the saline-associated key. The prototypical 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-(2-di-n-propylamino)tetralin] substituted for LY233708. This generalization was blocked by the selective 5-HT(1A) antagonist, WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide]. CONCLUSION: These data demonstrate that an SSRI can induce a specific, stable discriminative stimulus that appears to involve activation of the 5-HT(1A) receptor in the pigeon.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Similar enhancement of the discriminative stimulus effects of cocaine and GBR 12909 by heroin in squirrel monkeys.

RATIONALE AND OBJECTIVES: Heroin previously was shown to engender partial cocaine-like discriminative stimulus (DS) effects in squirrel monkeys. The present study assessed the degree to which heroin modified the DS effects of cocaine and the cocaine-like DS effects of the selective dopamine transport blocker GBR 12909. METHODS AND RESULTS: In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, cocaine and GBR 12909 dose-dependently engendered levels of responding on the cocaine-associated lever greater than or equal to 90% (full substitution). Heroin engendered full substitution for cocaine in two monkeys, partial substitution (75%) in a third monkey, and no substitution in the fourth monkey. When administered as a pretreatment, heroin shifted the dose-response function for cocaine to the left in the three monkeys for which heroin engendered cocaine-lever responding, but did not alter the DS effects of cocaine in the fourth monkey. Heroin pretreatment also shifted the dose-response function for the cocaine-like DS effects of GBR 12909 to the left in the former three monkeys, and did not alter the effects of GBR 12909 in the fourth monkey. Isobolographic analysis of the DS effects of cocaine-heroin and GBR 12909-heroin combinations in the former three monkeys revealed that the potencies of the combinations were not different from predicted values based on dose-additive effects. CONCLUSIONS: These findings show that heroin can enhance similarly the DS effects of cocaine and GBR 12909, suggesting that activation of dopaminergic systems underlies enhancement of the interoceptive effects of cocaine by heroin.

Animals↗

PubMed2001

Long-lasting rebound cue effects following single doses of nicotine and amphetamine: implications for understanding tolerance.

RATIONALE: Previous drug-discrimination studies have, with the exception of nicotine (NIC), demonstrated tolerance to the cue effects of a broad range of drugs of abuse. Barrett et al. have shown that tolerance to a drug's cue properties reflects drug-induced rebound shifts in the discrimination baseline and not a weakened or less salient cue. OBJECTIVES: The objective of the present study was to use a discrimination task sensitive to bidirectional cue changes to characterize the interoceptive cues associated with both the primary and rebound cues produced by nicotine in an attempt to understand why a recent study by Shoaib et al. failed to observe tolerance to the nicotine cue. METHODS: Since dopamine (DA) has been implicated in mediating the NIC cue, rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH), an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) following acquisition. This procedure provided a behavioral baseline to assess NIC-related changes along a presumed continuum of DA-mediated cues. Following acquisition of the discrimination: (i) NIC substitution tests were conducted, (ii) rats were tested for lever choice at intervals from 2 h to 48 h following treatment with single doses of 0.25 mg/kg and 0.50 mg/kg NIC, and (iii) rats were challenged with test doses of NIC during a period of NIC rebound. RESULTS: (i) NIC substituted for AMPH in a dose- dependent manner. (ii) At short intervals after treatment with 0.25 mg/kg and 0.50 mg/kg NIC, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-24 h post-treatment, before returning to predrug levels. (iii) No evidence was observed for acute tolerance to NIC. CONCLUSIONS: The robust and long-lasting rebound cues associated with training level doses of NIC suggest that maximal tolerance would likely develop to the NIC cue during the acquisition phase of the conventional NIC-saline discrimination study.

Amphetamine↗