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PubMed2001

Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats.

RATIONALE: Ketoconazole, an inhibitor of corticosterone synthesis, has been reported to decrease the self-administration of low doses of cocaine and prevent stress-induced reinstatement of cocaine-reinforced behavior in rats. OBJECTIVES: The effects of ketoconazole were extended to the acquisition of i.v. cocaine self-administration during food restriction, a form of stress. Food restriction accelerates the acquisition of cocaine self-administration, and the purpose of this experiment was to determine whether ketoconazole would block the food-restriction effect. As control conditions, the effects of ketoconazole on the acquisition of cocaine self-administration in food-satiated rats and acquisition of food-reinforced responding were also evaluated. METHODS: Six groups of rats (groups 1-6) were trained to self-administer i.v. cocaine (0.2 mg/kg; groups 1-4) or food pellets (45 mg; groups 5 and 6) under a fixed-ratio 1 (FR 1) schedule. Food availability was restricted to 20 g per day in groups 1, 2, 5, and 6, while groups 3 and 4 were fed ad libitum. Daily sessions included a 6-h autoshaping component followed by a 6-h self-administration component. During autoshaping, 10 infusions or food pellets were delivered each h under a random interval 15-s schedule after extension and retraction of a lever. During self-administration, the lever remained extended and infusions or food pellets were available under an FR 1 schedule. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions or 150 food pellets was obtained during the self-administration component. Rats were given 30 days to reach this criterion. They were pretreated with ketoconazole (25 mg/kg, i.p.; groups 1, 3, and 5) or vehicle (i.p.; groups 2, 4, and 6) 30 min prior to the autoshaping and self-administration components. RESULTS: Pretreatment with ketoconazole decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion but only under food-restricted conditions. Ketoconazole had no effect on the acquisition of food-reinforced responding. CONCLUSIONS: These results extended previous findings of the suppressant effects of ketoconazole on cocaine-reinforced responding in rats to the acquisition of cocaine self-administration using food restriction as a stressor.

Animals↗
PubMed1989

Food deprivation and acquisition of intravenous cocaine self-administration in rats: effect of naltrexone and haloperidol.

In order to create optimal conditions for the acquisition of i.v. cocaine self-administration in the rat, three groups of rats were deprived of food to different extents in order to obtain body weight reductions of 5 to 15, 15 to 25 and 25 to 35% of the pre-experimental body weights, and were tested for five consecutive 6-hr sessions in a continuous reinforcement procedure for self-administration of cocaine (0.12 mg/ml) or saline. Self-administration interacted with weight loss and indicated that: 1) a minimum level of 15 to 25% weight loss was required to obtain cocaine self-administration; 2) weight loss-induced potentiation of cocaine self-administration resulted from an interaction of increased nonspecific lever pressing activity and increased reinforcing effects of the compound; and 3) optimal differentiation between cocaine- and saline-induced responding was obtained at 15 to 25% weight loss. Daily pretreatment during the five test sessions, with 0.1 to 1.0 mg/kg of naltrexone or 43 to 375 micrograms/kg of haloperidol, dose-dependently decreased the number of cocaine (0.12 mg/ml) self-injections. Naltrexone pretreatment, and to a lesser extent haloperidol pretreatment, appeared to affect cocaine self-administration in a specific manner; both treatments affected responding on the reinforced lever, but not responding on the nonreinforced lever. Self-administration of 0.06 mg/ml of cocaine tended to be decreased by naltrexone (1 mg/kg) and haloperidol (375 micrograms/kg); whereas self-administration induced by 0.25 mg/ml of cocaine was not significantly affected by naltrexone or haloperidol. Both treatments failed to affect self-administration of saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Lisuride reduces intravenous cocaine self-administration in rats.

The maintenance of intravenous (i.v.) cocaine self-administration appears to depend upon activation of dopamine terminals within mesocorticolimbic areas. Since the nonaddictive ergot derivative lisuride is a direct dopamine receptor agonist, the present study was designed to investigate whether administration of lisuride to rats trained to lever-press for IV self-administration of cocaine could affect the intake of cocaine. IP administration of several doses of lisuride reduced, in a dose-dependent manner, cocaine self-administration. In a control experiment, lisuride did not increase the psychomotor-activating properties of cocaine as measured by locomotor activity, suggesting that lisuride did not simply potentiate the activating effects of cocaine. The present results show that lisuride reduced IV cocaine self-administration in rats; the possibility of a new therapeutic approach to the treatment of cocaine abuse in humans using lisuride may therefore deserve clinical attention.

Animals↗
PubMed1993

Caffeine self-administration and withdrawal: incidence, individual differences and interrelationships.

In four prior studies, caffeine (100 mg) self-administration was assessed by greater self-administration of caffeinated coffee than decaffeinated coffee and caffeine withdrawal was assessed by placebo substitution using six double-blind tests in each subject. This paper collates data across these studies to examine the incidence and predictors of the occurrence of caffeine self-administration and withdrawal. Caffeine self-administration occurred in 31% of subjects when a consistency criterion was used (n = 41) and 27% when a statistical criterion was used. Caffeine withdrawal occurred in 35% and 49% of subjects with each criteria (n = 37). Subjects who had withdrawal headaches and drowsiness were 2.3-2.6 times more likely to self-administer the caffeinated coffee. Several variables (e.g., average caffeine intake) did not predict caffeine self-administration or withdrawal.

Adult↗
PubMed1999

Repeated limited access to i.v. cocaine self-administration: conditioned autonomic rhythmicity illustrating "predictive homeostasis".

RATIONALE: Regular cocaine self-administration may act as a "Zeitgeber" in animals and humans, and physiological rhythms may peak at the time when the drug is usually self-administered. OBJECTIVE: To investigate whether or not daily sessions of cocaine self-administration for 2 weeks would synchronize autonomic rhythms to the time of daily access. METHODS: Two weeks after implant of a jugular catheter and telemetry sender, each rat's heart-rate (HR) and core temperature (Tc) rhythms were well entrained to the 12:12-h light:dark cycle (lights off: 0900 hours). For the next 2 weeks rats self-administered cocaine during daily sessions at 1300 hours. The circadian and ultradian oscillations of HR and Tc recorded during the 3 days after the last self-administration (SA) session were quantified by multi-oscillator cosinor analysis. RESULTS: The HR and Tc were elevated during the initial 0.25 mg cocaine infusions of the daily session. This initial tachycardia disappeared as cocaine continued to be self-administered in accumulating amounts, while the locomotor activity remained elevated. After the last SA session the peak (acrophase) of the two cycles/day component in HR and Tc rhythms aligned to the time of day when cocaine self-administration had previously been scheduled. The amplitude of the circadian and ultradian HR and Tc oscillations as well as their circadian acrophase were not impacted by repeated daily time-limited cocaine self-administration. CONCLUSIONS: Cocaine controls the behavior and autonomic functions of rats self-administering limited amounts of cocaine during regular daily sessions, and this controlling influence extends beyond the last daily access period.

Animals↗
PubMed2006

Intravenous drug self-administration in mice: practical considerations.

Chronic intravenous drug self-administration in rodents is a useful procedure for predicting the abuse liability of novel drugs in humans, for evaluating candidate treatments for drug abuse and dependence, and for studying the biological basis of addiction. Despite the technical challenge in achieving chronic self-administration behavior in the mouse species, researchers are increasingly using genetically engineered mice to investigate the role of specific genes in abuse-related effects of drugs. This review focuses on recent technical innovations as well as theoretical considerations for comparing intravenous (i.v.) drug self-administration behavior between mouse strains, including mice with targeted mutations. Part I of the present article describes techniques for successfully conducting self-administration studies in mice, including advantages, disadvantages and possible implications of employing various experimental approaches. Part II provides a review of recent data that address how the genetic background on which mutations are expressed may influence results from gene-targeting studies.

Animals↗
PubMed1996

Self-administration of D1 receptor agonists by squirrel monkeys.

Dopaminergic mechanisms are believed to play a prominent role in the self-administration of cocaine and other abused stimulants. The contribution of D2 receptors is now well established, but less is known about the role of D1 receptors in the reinforcing effects of these drugs. To help clarify the role of D1 mechanisms in stimulant self-administration, agonists differing in D1 receptor selectivity (SKF 81297 > SKF 82958 > SKF 77434) and efficacy (SKF 82958 > SKF 81297 > SKF 77434) were studied for their ability to maintain IV self-administration in squirrel monkeys previously trained to self-administer cocaine. Up to a 100-fold range of doses of each D1 agonist was studied under both a fixed-ratio (FR) and a second-order fixed-interval (FI) schedule of reinforcement. Parallel studies were conducted with the D2 receptor agonists, (+)-PHNO and quinpirole, under the second-order FI schedule. Of the three D1 agonists, only SKF 82958 maintained consistent self-administration under both the FR and second-order FI schedules and had dose-related effects that were qualitatively similar to those of (+)-PHNO and quinpirole under the latter condition. SKF 81297, which has high selectivity at D1 receptors and intermediate agonist efficacy, maintained self-administration in the majority of monkeys under the FR schedule, but did not maintain self-administration under the second-order FI schedule. SKF 77434, which has moderate selectivity at D1 receptors and low agonist efficacy, did not maintain self-administration under either schedule. The results suggest that the ability of D1 agonists to maintain IV self-administration in squirrel monkeys depends both on the type of schedule and on the pharmacological properties (i.e. selectivity and efficacy) of the particular drug. These results are also consistent with the view that D1, in addition to D2, receptor mechanisms play a role in the self-administration of abused stimulants.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

A method for analyzing strain differences in acquisition of IV cocaine self-administration in mice.

The techniques currently available for studying drug self-administration in animals offer the unique opportunity to carry out micro-analysis of initial episodes of drug use which are extremely difficult to obtain for human subjects. Nonetheless, traditional self-administration techniques do not allow a cost-effective output of large sample sizes needed for genetic analysis. Additionally, the statistical techniques that allow the integration of within-subject temporal data with genetic information are scant. We therefore propose a two-stage method for analyzing strain differences in dynamic phenotypes for a high-throughput version of the self-administration procedure. On a first phenotype-refinement stage, a change-point algorithm (Gallistel et al. (2004) Proc. Natl Acad. Sci. USA 101:13124-13131) was used to separate individual drug self-administration response curves into three distinct components. In a second stage, strains differences in these indexes were assessed. This two-stage approach is illustrated with drug self-administration data and through a computer simulation.

Animals↗
PubMed1988

Effects of desglycinamide9, (Arg8) vasopressin and vasopressin antiserum on the acquisition of intravenous cocaine self-administration in the rat.

The effect of the vasopressin neuropeptide desglycinamide9, (Arg8) vasopressin (DGAVP) on the acquisition of intravenous cocaine self-administration was studied. Rats were tested under conditions of reduced body weight in a continuous reinforcement operant procedure, during five daily 3 h sessions. Under these conditions, the rate of self-administration obtained with 0.125 and 0.25, but not 0.063 mg.ml-1 cocaine, exceeded the rate obtained with saline. Daily pretreatment with DGAVP (5 micrograms/rat, s.c.) decreased self-administration of 0.125 and 0.25 mg.ml-1 cocaine to the level obtained with saline, but had no effect on self-administration of 0.063 mg.ml-1 cocaine and saline. Using a similar procedure, it was shown that daily intracerebroventricular pretreatment with vasopressin antiserum significantly increased self-administration of 0.125 mg.ml-1 cocaine, without affecting self-administration of 0.063 and 0.25 mg.ml-1 cocaine and saline. The results support previous findings obtained with vasopressin neuropeptides in drug self-administration studies and suggest that DGAVP decreases the acquisition of cocaine self-administration by attenuating the reinforcing effects of cocaine and that endogenous vasopressin may be involved in the acquisition of cocaine self-administration.

Animals↗
PubMed2004

Effects of murine-derived anti-methamphetamine monoclonal antibodies on (+)-methamphetamine self-administration in the rat.

Two murine-derived anti-methamphetamine monoclonal antibodies were studied as potential pharmacokinetic antagonists of (+)-methamphetamine self-administration by rats. Intravenous administration of a 1 g/kg dose of the lower affinity [antibody equilibrium dissociation constant (K(d)) = 250 nM] monoclonal antibody (mAb) designated mAb6H8, 1 day before the start of several daily 2-h self-administration sessions produced effects that depended on the dose of (+)-methamphetamine. mAb6H8 increased the rate of self-administration of a unit dose of 0.06 mg/kg (+)-methamphetamine, had little effect on the rate of self-administration of a unit dose of 0.03 mg/kg (+)methamphetamine, and lowered the rate of self-administration of a unit dose of 0.01 mg/kg (+)-methamphetamine to a level similar to that after saline substitution. mAb-induced changes in rates of self-administration occurred very early in self-administration sessions and lasted for 3 to 7 days. Intravenous administration of a 1 or a 0.6 g/kg dose of a higher affinity (K(d) = 11 nM) mAb designated mAb6H4, 24 h before the first of several self-administration sessions, produced very similar effects to the lower affinity mAb, despite the more than 20-fold greater affinity for (+)-methamphetamine. It is proposed that these anti-methamphetamine antibodies bind some of the self-administered (+)-methamphetamine before it can penetrate into brain, thereby reducing the amount of free drug available to function as a reinforcer. Although neither of these mAb medications are optimal antibodies for treating (+)-methamphetamine abuse, the experiments demonstrate that anti-(+)-methamphetamine monoclonal antibodies can attenuate the self-administration of the drug and suggest the potential of using monoclonal antibodies as pharmacokinetic antagonists of (+)-methamphetamine.

Adrenergic Agents↗
PubMed2006

Enhanced acquisition of cocaine self-administration by increasing percentages of C57BL/6J genes in mice with a nonpreferring outbred background.

RATIONALE: Individual differences in the propensity to acquire drug self-administration may have a substantial genetic basis. OBJECTIVES: To study the genetic contribution to cocaine self-administration by comparing hybrids of cocaine preferring (C57BL/6J) and nonpreferring (ICR) mice. METHODS: ICR and C57BL/6J parental strains were compared to hybrids with 75% ICR:25% C57BL/6J, 50% ICR:50% C57BL/6J, and 25% ICR:75% C57BL/6J genetic backgrounds for acquisition of sucrose pellet and intravenous cocaine self-administration in 1-h test sessions. Mice that acquired cocaine self-administration were subsequently tested in a between-session self-administration dose-response procedure. RESULTS: Increasing presence of C57BL/6J genes increased the percentage of mice that acquired sucrose pellet self-administration in the first test session. In lever-trained mice, only 19% of ICR mice met acquisition criteria for cocaine self-administration after 15 sessions, whereas 76% of C57BL/6J mice met acquisition criteria, although both strains initially sampled a similar number of cocaine injections. Increasing the percentage of C57BL/6J genes in the nonpreferring ICR background to 50 and 75% led to increasing percentages of mice that met acquisition criteria to 31 and 52%, respectively. In mice that acquired self-administration, only mice with 75% C57BL/6J genes showed a typical inverted U-shaped self-administration dose-response curve, whereas the curve was flat across doses for mice with < or = 50 and 100% C57BL/6J genes. CONCLUSIONS: The findings are consistent with a genetically based dose-dependent enhancement of cocaine reinforcement by C57BL/6J genes. These results suggest that heritable traits impart a substantial genetic load that facilitates the propensity for cocaine addiction among individuals in outbred populations.

Animals↗
PubMed2003

Adolescent-onset nicotine self-administration modeled in female rats.

RATIONALE: Although the great majority of tobacco addiction begins during adolescence, little is known about differential nicotine effects in adolescents versus adults. OBJECTIVES: A rat model was used to determine the impact of the age of onset on nicotine self-administration. METHODS: In expt 1, nicotine self-administration of female Sprague-Dawley rats over a range of acute doses (0.01-0.08 mg/kg per infusion) was determined in adolescent (beginning at 54-62 days) versus adult (beginning at 84-90 days). In expt 2, chronic nicotine self-administration over 4 weeks from adolescence into adulthood was compared with the chronic self-administration beginning in adulthood. In expt 3, adolescent-adult differences in nicotine effects on body temperature and locomotor responses were determined. RESULTS: Adolescent-onset rats showed a significant main effect of increased nicotine intake compared with adult-onset rats in an eight-fold range of acute unit doses/infusion. Significant age differences were also seen in the chronic level of nicotine self-administration. Over 4 weeks, the adolescent-onset group had nearly double the rate of nicotine self-administration of the benchmark nicotine dose (0.03 mg/kg per infusion) compared to the adult-onset group. This increased nicotine intake persisted into adulthood. Adolescent rats had significantly greater response than adults to the hypothermic effects of nicotine, but had significantly less response than adults to the reduction in locomotor activity seen after nicotine. CONCLUSIONS: Adolescent-onset nicotine self-administration in female rats was associated with significantly higher levels of nicotine self-administration versus rats, which began nicotine self-administration in adulthood. This greater self-administration persists into adulthood and may underlie greater propensity of adolescents to nicotine addiction.

Adolescent↗
PubMed1980

D-ala2-methionine-enkephalinamide self-administration in the morphine-dependent rat.

The self-administration of D-enkephalin was studied in the dependent rat self-administering morphine. The rats were prepared with chronic IV and bilateral intraventricular (IVT) injection cannulae. They were made physically dependent on morphine and trained to lever press for IV morphine self-injections (inj) (10 mg/kg) on a fixed ratio (20) (FR20) schedule of reinforcement. Substitution of D-enkephalin either IVT (40 microgram/inj) or IV (10 mg/kg/inj) in the morphine-dependent rat maintained consistent lever pressing and self-administration behavior similar to morphine self-administration. No signs of abstinence were observed during the D-enkephalin substitution. However, saline substitution (0.05 ml/inj IV) for morphine in the self-administering rat produced an abstinence syndrome characterized by extinction of responding, wet-dog shakes, writhes, and diarrhea, which were reversed for 1 h by a single IVT injection of D-enkephalin (40 or 80 microgram). These results indicate that D-enkephalin will serve as a reinforcer to maintain opiate-seeking behavior and support physical dependence in the rat.

Animals↗
PubMed1995

Inhibitory effects of dopamine and methylenedioxymethamphetamine (MDMA) on glutamate-evoked firing of nucleus accumbens and caudate/putamen cells are enhanced following cocaine self-administration.

Rats were allowed to self-administer cocaine during a 3-h session for 15 days. One to 11 days after the last cocaine exposure, rats were anesthetized with urethane and effects of microiontophoretically-applied dopamine on glutamate-evoked firing of neurons in the nucleus accumbens and in the caudate/putamen were tested. Dopamine produced a dose-dependent inhibition of glutamate-evoked firing in both the nucleus accumbens and the caudate/putamen of rats that had been repeatedly exposed to self-administered cocaine and in control rats. However, the DA-induced inhibition was significantly greater in the group that had self-administered cocaine. The cocaine self-administration group was significantly sensitized to the inhibitory effects of dopamine in both early (1-3 day) and later (9-11 days) periods of cocaine abstinence. Following cessation of repeated cocaine self-administration sessions, nucleus accumbens cells were also sensitized to the inhibitory effects of methylenedioxymethamphetamine (MDMA), a drug that increases extracellular levels of DA and serotonin in the nucleus accumbens. This sensitization to DA- and MDMA-induced inhibition in the nucleus accumbens and in the striatum indicates that long-term neuroadaptations occur in these regions of the nervous system following repeated exposure to self-administered cocaine.

Animals↗
PubMed1987

Animal models of intravenous phencyclinoid self-administration.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as "phencyclinoids" are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented.

Animals↗
PubMed1992

The effects of chronic buprenorphine treatment on cocaine and food self-administration by rhesus monkeys.

The goal of this study was to determine if buprenorphine continues to reduce cocaine self-administration over long periods of treatment, or if tolerance develops to this effect. The effects of 30 to 120 days of buprenorphine treatment (0.32 mg/kg/day) on cocaine and food self-administration were examined in six rhesus monkeys. Saline control treatment was studied for 15 days before and after buprenorphine treatment. Intravenous cocaine (0.05 or 0.10 mg/kg) and food (1 g banana pellet) self-administration were maintained on a FR 4 (VR 16:S) schedule of reinforcement. Cocaine self-administration decreased significantly (P less than .0001) and remained 60 to 97% below saline treatment baseline levels (52 +/- 2 injections/day) throughout 120 days of buprenorphine treatment (P less than .01). After substitution of saline for buprenorphine, cocaine self-administration resumed and averaged between 21 (+/- 3.6) and 56 (+/- 6.5) injections per day over 20 days. Buprenorphine plasma levels averaged 18 (+/- 2.84) ng/ml (range 10.9-30 ng/ml) during buprenorphine treatment. Buprenorphine plasma levels usually decreased by 50% or more within 27 hr after the last buprenorphine dose. Low levels of buprenorphine (0.10-0.19 ng/ml) were measured for 30 to 74 days after abrupt termination of daily buprenorphine treatment. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding developed over 30 to 70 days of treatment. Food self-administration returned to and significantly exceeded (P less than .05-.01) saline treatment base-line levels, whereas cocaine self-administration remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗