Acquisition of cocaine self-administration in male Sprague–Dawley rats: effects of cocaine dose but not initial locomotor response to cocaine

Rationale  

We have previously described a model in which adult outbred male Sprague–Dawley rats are classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced open-field activation. This model revealed important individual differences in cocaine's effects, including that LCRs exhibited greater responding than HCRs on a progressive ratio schedule of cocaine reinforcement. However, no LCR/HCR differences in acquisition of cocaine self-administration (0.25 mg/kg/12 s infusion) were observed under these conditions.     

Patterns of cocaine and opioid co-use and polyroutes of administration among street-based cocaine users in Montréal,Canada

BackgroundEffective public health programs aimed at problematic cocaine users are challenged by the fact that they can have complex patterns of drug use with respect to polysubstance use and routes of drug administration. This study was carried out to explore the presence of subgroups of cocaine users on the basis of their concurrent use of opioids and their routes of cocaine and opioid administration, and to determine if subgroups could be differentiated in terms of sociodemographic factors and risk behaviours.MethodsRegular cocaine users (≥1 per week) were recruited in low-threshold services located in the Montréal downtown area. The following variables were examined: demographic characteristics, types of drug used, routes of drug administration, and condom use with occasional or commercial sexual partners. Latent class analysis and multinomial logistic regression modeling were carried out.Results886 cocaine users were recruited (83.5% male: mean age 35.38 years). A 5-class model was identified: (1) “cocaine smokers” (CSs) (n = 161; membership probability (MP) = 0.183); (2) “cocaine smokers/sniffers” (CSSs) (n = 201; MP = 0.218); (3) “cocaine injectors” (CIs) (n = 207; MP = 0.231); (4) “cocaine-opioid injectors” (COIs) (n = 277; MP = 0.291); (5) “cocaine-opioid polyroute users” (COPs) (n = 40; MP = 0.077). Compared with COIs, other subtypes were significantly different in terms of either age, duration of cocaine use, ethnic background, homelessness, polydrug use or condom use.ConclusionThe heterogeneity of consumption patterns supports the importance of offering an array of interventions aimed at problematic cocaine users. These should include the provision of clean injecting and smoking material, the promotion of safe sexual behaviours and the prevention of initiation to drug injection. In the absence of specific treatment, cocaine users should have access to primary health care services and addiction treatment based on innovative behavioural and pharmacological approaches.     

Opioid modulation of the discriminative stimulus effects of cocaine: comparison of µ, kappa and delta agonists in squirrel monkeys discriminating low doses of cocaine

Modulation of the discriminative stimulus effects of cocaine by the μ agonist morphine, the kappa agonist U 50, 488, and the delta agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3- to 5.6-fold lower dose of cocaine (0.1 or 0.18mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED(50) values were reduced 2- to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03-1.0mg/kg), U 50,488 (0.1-3.0mg/kg) and BW 373U86 (0.001-0.1mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED(50) values were reduced 3- to 7-fold. Pretreatment with U 50,488 (0.3mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED(50) values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the μ and kappa agonists, pretreatment with BW 373U86 (0.01 or 0.03mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.     

Lack of involvement ofδ-opioid receptors in mediating the rewarding effects of cocaine

The non-selective opioid antagonist naltrexone and the partial agonist buprenorphine have been reported to reduce cocaine self-administration (SA) and relapse in both humans and rhesus monkeys. Data suggesting an involvement of-opioid receptors in modulating the conditioned rewarding effects of cocaine were also recently presented. In view of such findings, the present SA and place conditioning studies were conducted to examine the influence of the selective-opioid receptor antagonist naltrindole upon the rewarding effects of cocaine. Sprague-Dawley rats were trained to self-administer cocaine (1.0 mg/kg per infusion) on an FR2 schedule of reinforcement. Dose-response and antagonist testing commenced once stable rates of cocaine SA were achieved. For antagonist testing, rats received naltrindole (0.03–10.0 mg/kg, IP) 30 min prior to the start of 2-h SA sessions. SA behavior in response to cocaine delivery (0.25 and 1.0 mg/kg per infusion) was then determined. Naltrindole in doses of 0.03–3.0 mg/kg did not alter the number of cocaine infusions taken by the rats. A higher dose of naltrindole (10.0 mg/kg), which markedly depressed locomotor activity, resulted in a 16% reduction of cocaine (0.25 mg/kg per infusion) SA behavior. When SA sessions were terminated and naltrindole (1.0 mg/kg) was administered repeatedly for 3 days, no alterations in the re-acquisition of cocaine SA were seen. Place conditioning studies also failed to find an effect of naltrindole (0.1–3.0 mg/kg) on cocaine (10 mg/kg) — induced conditioned place preferences. Naltrindole, by itself, did not induce significant place conditioning. These data fail to indicate a role of-opioid receptors in modulating either the positive reinforcing or conditioned rewarding effects of cocaine. Furthermore, they suggest that the therapeutic actions of naloxone, naltrexone and buprenorphine on cocaine SA behavior may not result from the specific blockade of-opioid receptors.     

Euphorigenic doses of cocaine reduce [123I]β-CIT SPECT measures of dopamine transporter availability in human cocaine addicts

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [¹²³I]-CIT ([¹²³I]2-carbomethoxy-3-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n=6) were injected with [¹²³I]-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28±0.03 and 0.56±0.07 mg/kg) produced significant (P<0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V₃ (6±6 and 17±3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED₅₀) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.     

Perceived risk of cocaine use and experience with cocaine: do they cluster within US neighborhoods and cities?

This study investigates whether experience with cocaine and the perception of risk associated with cocaine use might tend to cluster within neighborhoods and cities in the US. Population-based data from six years of the National Household Surveys on Drug Abuse public use files are employed. The alternating logistic regressions model is used to quantify the extent of geographic concentration. Perceptions of the harm associated with cocaine use and actual experience with cocaine tend to cluster within neighborhoods; once within-neighborhood concentration is taken into account, there is little evidence of residual concentration within cities.     

Postnatal consequences of prenatal cocaine exposure and myocardial apoptosis: does cocaine in utero imperil the adult heart?

Cocaine use is common among pregnant women with a history of substance abuse, and has been shown to cause abnormalities in the heart during fetal and postnatal development. However, mechanisms underlying the detrimental effects of cocaine on the developing heart are not fully understood. In this issue, Bae and Zhang show that prenatal cocaine exposure increases the susceptibility of the postnatal heart to ischemia and reperfusion injury. Their results suggest that myocardial apoptosis induced by cocaine during fetal development may represent one of the mechanisms by which prenatal cocaine exposure exerts its long-term, deleterious consequences on postnatal cardiac function.     

Rewarding effects of ethanol and cocaine in µ opioid receptor-deficient mice

To investigate the role of mu opioid receptors in the reinforcing effects of psychotropic drugs, the voluntary ethanol intake and ethanol- and cocaine-induced conditioned place preference in mu opioid receptor-deficient mice and their wild-type counterpartners was tested. Moreover, dopamine D1 and D2 receptor binding was measured. It was found that ethanol intake was significantly lower in deficient mice. Conditioned place preference in wild-type animals was induced with 5.0 mg/kg cocaine and this dose was ineffective in the knockouts. In this group conditioned place preference occurred after injection of 10.0 mg/kg cocaine. Cocaine induced a similar increase in locomotor activity in both groups of mice. There was no difference in dopamine D1 receptor binding, whereas dopamine D2 receptor binding was significantly lower in the hippocampus of deficient animals. This suggests that interaction between opioid systems and dopaminergic systems may account for the differences in responding to the drugs.     

Self-administration of cocaine–remifentanil mixtures by monkeys: an isobolographic analysis

RATIONALE: Abuse of mixtures of stimulants and opioids ("speedball") is common. Although this combination has been studied in the laboratory, conclusions about the nature of the cocaine/opioid interaction have been mixed. OBJECTIVES: The objectives of the present experiment were to allow monkeys to self-administer mixtures of cocaine and the mu opioid agonist remifentanil and to quantify the interaction using the isobolographic approach. Our hypothesis was that the drugs would be super-additive in their reinforcing effects. MATERIALS AND METHODS: Rhesus monkeys (n = 5) prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule. When responding was stable, doses of cocaine or remifentanil were made available in test sessions. Next, mixtures of doses of the drugs were tested over a range of doses in 1:1, 1:2, and 2:1 ratios of their ED(50)s. Results were analyzed using isobolographic techniques. RESULTS: Both drugs alone and all drug mixtures functioned as positive reinforcers in a dose-related manner. Cocaine maintained more responding at maximum than did remifentanil, i.e., was a stronger reinforcer. The experimentally determined equi-effective dose for the 1:1 and 1:2 cocaine/remifentanil mixtures tended toward super-additivity, but the difference from additivity did not achieve statistical significance. The 2:1 mixture was super-additive. Maximum responding maintained by the mixtures was higher than that maintained by remifentanil but not different from cocaine. CONCLUSIONS: Combinations of cocaine and remifentanil can be additive or super-additive as positive reinforcers, depending on proportions of each. Interactions between stimulants and opioids may contribute to the abuse of these mixtures.     

What aspects of treatment matter to the patient in the treatment of cocaine dependence?

Patient views of the helpful aspects of treatment were examined in the NIDA Collaborative Cocaine Treatment Study, a multi-site trial comparing four psychosocial treatments: individual cognitive therapy (CT), individual supportive expressive dynamic therapy (SE), individual drug counseling, and group drug counseling only, for the treatment of cocaine dependence. Factor analysis of the items of Helpful Aspects of Treatment measure suggested a general therapy factor, a group treatment/education factor, and a treatment structure factor. No differences were found among the four treatments on the ratings of helpfulness of these three factors, common factors, or drug intervention components. However, treatment specific cognitive therapy items (e.g. use of the cognitive model) and treatment structure differentiated individual CT from individual SE, and to a lesser extent from individual drug counseling. Ratings of helpfulness were significantly related to retention and alliance but were largely unrelated to changes in drug use or psychiatric outcomes.     

Alzheimer—like phosphorylation of tau and neurofilament induced by cocaine in vivo

目的:研究可卡因导致细胞环素依赖激酶5(CDK5)过度表达与细胞骨架蛋白阿尔采末病样过度磷酸化的关系。方法:大鼠腹腔注射可卡因(20mg·kg(?)·d~_(-1)),采用免疫印迹技术检测tau蛋白和神经细丝的过度磷酸化。结果:腹腔注射可卡因8天和16天后,大鼠海马、皮质和尾壳核的tau蛋白在PHF-1位点的磷酸化和神经细丝磷酸化水平显著增加。在4天未见细胞骨架蛋白磷酸程度的改变。另外,在同样的脑区和相同的时相点,tau蛋白在Tau-1位点的非磷酸化和神经细丝的非磷酸化水平显著降低。然而,未在实验中发现CDK5和p35的过度表达。结论:腹腔注射可卡因可导致大鼠大脑tau和神经细丝的阿尔采末病样过度磷酸化,但这种变化可能与CDK5的过度激活和表达无关。     

Effects of (−)-Phenylephrine on force of contraction in the presence of cocaine and hydrocortisone in cat papillary muscle

Summary The positive inotropic effect of (–)-phenylephrine, in the presence of propranolol, was studied after inhibition of neuronal and extraneuronal uptake in isolated papillary muscles from reserpine-pretreated cats. An inhibition of extraneuronal uptake with hydrocortisone influenced the effect of (–)-phenylephrine neither when present alone nor in the presence of cocaine (additional inhibition of neuronal uptake). An inhibition of neuronal uptake with cocaine caused a small but significant increase in the potency of (–)-phenylephrine. We conclude that in cat ventricular cardiac muscle the extraneuronal compartment is apparently neither a site of loss nor a site of gain for (–)-phenylephrine with respect to force of contraction.     

Differences in perimenstrual symptoms between cocaine‐abusing and non‐cocaine‐abusing women

Cocaine abuse among women has become a major health problem in the United States, yet there is little information in the literature concerning the effects of this form of substance abuse on a woman's reproductive system. This study of 65 women in residential treatment for cocaine abuse and 65 non‐cocaine‐abusing women was undertaken to determine if there are differences in frequency or severity of perimenstrual symptoms between these two groups of women. Data were collected by questionnaire and included demographics, a substance use history, and the Menstrual Distress Questionnaire developed by Moos. Findings suggested that there are statistically significant differences in frequency and severity of perimenstrual symptoms between the two groups of women.     

Interaction of tyrosine 151 in norepinephrine transporter with the 2β group of cocaine analog RTI-113

Cocaine binds and inhibits dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter. The residues forming cocaine binding sites are unknown. RTI-113, a cocaine analog, is 100× more potent at inhibiting DAT than inhibiting NET. Here we show that removing the hydroxyl group from residue Tyr151 in NET by replacing it with Phe, the corresponding residue in DAT, increased the sensitivity of NET to RTI-113, while the reverse mutation in DAT decreased the sensitivity of DAT to RTI-113. In contrast, RTI-31, another cocaine analog having the same structure as RTI-113 but with the phenyl group at the 2β position replaced by a methyl group, inhibits the transporter mutants equally well whether a hydroxyl group is present at the residue or not. The data suggest that this residue contributes to cocaine binding site and is close to the 2β position of cocaine analogs. These results are consistent with our previously proposed cocaine-DAT binding model where cocaine initially binds to a site that does not overlap with, but is close to, the dopamine-binding site. Computational modeling and molecular docking yielded a binding model that explains the observed changes in RTI-113 inhibition potencies.     

Effect of food restriction on cocaine locomotor sensitization in Sprague–Dawley rats

Rationale

The interaction between repeated cocaine exposure and food restriction on sensitization to the stimulatory effects of cocaine has not been characterized.

Objectives

To compare cocaine sensitization in rats free fed and food restricted, and begin to explore the role of the stress-responsive dynorphin/kappa opioid system.

Methods

Male rats were maintained for 10 days on two feeding conditions: free fed or food restricted (85 % of free fed weight). Test 1 of locomotor reactivity to cocaine (3, 9, or 15 mg/kg, IP) was followed by a sensitizing regimen of cocaine exposure (0 or 30 mg/kg/day × 5 days, IP), by a 10-day drug-free period, and by Test 2 of reactivity to the same cocaine dose. In a second experiment, rats received an injection of norbinaltorphimine (nor-BNI; 0, 5 or 20 mg/kg, SC) 10 days prior to each locomotion test, and plasma corticosterone (CORT) was assessed after Test 2.

Results

On Test 1, it was found that food restriction enhanced locomotor responses to all doses of cocaine. On Test 2, it was found that free fed and food restricted animals displayed similar sensitized responses to cocaine. This, however, was not observed in nor-BNI-treated rats. Furthermore, 20 mg/kg nor-BNI reduced both the locomotor response to cocaine on Test 2 and the effect of cocaine and food restriction on CORT plasma levels.

Conclusions

These results indicate that the interaction between cocaine sensitization and food restriction is not synergistic, and that it involves activation of kappa-opioid receptors.     

Differential effects of self-administered cocaine in adolescent and adult rats on stimulus–reward learning

Rationale Adult cocaine addicts, abstinent at the time of testing, show a variety of neurocognitive impairments. Less clear is whether there are differences in the degree of impairment if cocaine use is initiated during adolescence rather than adulthood. Objectives Using a preclinical model, we evaluated if stimulus–reward learning was impacted differently in rats exposed to cocaine during adolescence (beginning on postnatal day 37) vs adulthood (beginning on postnatal days 74–79) and then tested after a drug-free period. Materials and methods A yoked-triad design of intravenous cocaine self-administration in adult (n = 8 triads) and adolescent (n = 8 triads) rats was used. Sets of three animals either contingently self-administered cocaine or received cocaine or saline in a noncontingent manner. Rats self-administering 1-mg/kg doses of cocaine responded under a fixed-ratio 5, timeout 20-s schedule of reinforcement. After 18 2-h drug or saline sessions, all rats (now adults) began the drug-free period in their home environments. Testing in a stimulus–reward learning task (conditioned cue preference) began 19 days later. Results Self-administration behavior was similar in adolescent and adult rats. Lever responses were not significantly different, and both age groups averaged approximately 20 infusions per session. Rats contingently self-administering cocaine or passively exposed to cocaine during adulthood showed stimulus–reward learning deficits in the conditioned cue preference task. Rats exposed to contingent or noncontingent cocaine during adolescence had normal learning, showing strong preferences for a Froot Loops-paired cue. Conclusions These findings suggest that adolescents are insensitive to cocaine-induced impairment of learning related to amygdala memory system functioning.     

Cue-induced reinstatement of cocaine seeking in the rat “conflict model”: Effect of prolonged home-cage confinement

Rationale and objectives  

Drug addiction is not just the repeated administration of drugs, but compulsive drug use maintained despite the accumulation of adverse consequences for the user. In an attempt to introduce adverse consequences of drug seeking to laboratory animals, we have developed the “conflict model,” in which the access of rats to a reinforcing lever allowing self-administration requires passing of an electrified grid floor. In this model, the current intensity leading to complete abstinence from drug seeking can be measured individually. The present study was designed to evaluated whether reinstatement of drug or natural reward seeking, despite the presence of the electrical barrier, can be achieved by presentation of discrete cues that were associated with the reward, and whether prolonged home-cage confinement can facilitate such reinstatement in this model.     

A potential vaccine for cocaine abuse prophyslaxis?

O. Bagasra, L.J. Forman, A. Howeedy, and P.A. Whittle recently conveyed the preparation of a cocaine immunogen that is a potential vaccine for cocaine abuse prophylaxis (Immunopharmacology: 1992, 23, 173–179). These investigators claim to have prepared a cocaine immunogen via reaction of cocaine with sodium metaperiodate followed by carrier protein, and to have generated anti-cocaine antibodies by using this immunogen. Periodate is used to conjugate haptens that contain a vicinal diol (or similar) group to carrier proteins and would not be expected to couple cocaine to protein. The authors of the above publication reported titres for antibodies generated by using their immunogen, but did not describe competitive inhibition of antibody binding by cocaine and did not report the specificity characteristics of their antibodies. The present author is not convinced by the claims made by Bagasra et al.