Cell cycle phase-dependent effect of retinoic acid on the induction of granulocytic differentiation in HL-60 promyelocytic leukemia cells. Evidence for sphinganine potentiation of retinoic acid-induced differentiation

The application of microeconomic theory to the experimental analysis of behavior has been termed behavioral economics. There has been an increasing interest in applying the concepts of behavioral economics to the study of drug self-administration. In a previously published experiment (Nader and Woolverton, 1992), rhesus monkeys (N = 3) were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When cocaine or food was available under a fixed-ratio (FR) 30 schedule, cocaine intake increased in a dose-related manner for all monkeys. When the response requirement (FR) for cocaine was differentially increased by doubling or quadrupling, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right. The present paper is a reanalysis of data from that experiment. Several mathematical models, differentially incorporating the effects of FR, dose and number of food pellets, were compared. When cocaine consumption was analyzed using a multiple linear regression analysis with FR, dose and number of pellets as separate main effects (model I), the R2 was 0.82. When FR and dose were combined into one factor, unit price (UP, responses/mg/kg), and cocaine consumption was analyzed as a linear function of UP (model IIA), the R2 was 0.54. When cocaine consumption was analyzed as a curvilinear, negatively accelerated function of UP (model IIB), the R2 was 0.53. The difference between models I and IIA was statistically significant while models IIA and IIB were not different.(ABSTRACT TRUNCATED AT 250 WORDS)     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Cloning of a thermostable ascorbate oxidase gene from Acremonium sp. HI-25 and modification of the azide sensitivity of the enzyme by site-directed mutagenesis

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.     

Self-administration of GBR 12909 on a fixed ratio and progressive ratio schedule in rats

Intravenous self-administration of GBR 12909, an indirect dopamine agonist, was examined on a Fixed Ratio (FR 1) and a Progressive Ratio (PR) schedule of reinforcement in rats. Subjects were first trained to self-administer cocaine (1.5 mg/kg/inj) during daily 5 h sessions, after which GBR 12909 (0.187-1.5 mg/kg/inj) was substituted. On the FR 1 schedule, the inter-infusion interval for GBR 12909 self-administration was directly related to dose and was approximately three times longer than that established for equivalent doses of cocaine. Breaking points on the PR schedule were comparable for GBR 12909 and cocaine self-administration. The data indicate that, compared to cocaine, GBR 12909 has a longer duration of action and a similar reinforcing efficacy.     

Smoked heroin and cocaine based (speedball) combinations in Rhesus monkeys.

The purpose of this investigation was to compare the self-administration of heroin and cocaine base, alone and in combination, in rhesus monkeys (Macaca mulatta) self-administering a combination of heroin (0.1 mg/kg/delivery) and cocaine base (1.0 mg/kg/delivery) via the smoking route. Smoke deliveries were contingent on completion of a chained fixed ratio (FR; lever press), FR 5 (inhalation) schedule. The lever press FR values (64, 128, 256, 512, and 1,024) represented increasing drug price. Demand functions (Consumption x Price) were obtained for the heroin and cocaine combination and compared with previously determined demand functions for smoked heroin and cocaine alone. As the FR increased and the number of responses emitted increased, the number of drug deliveries decreased. The demand functions were not different for heroin versus cocaine alone or for cocaine alone versus the cocaine-heroin combination. However, the demand for heroin alone was significantly less than the demand for the cocaine-heroin combination, suggesting that smoked cocaine base enhances the behavioral effects of smoked heroin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of estrogen and progesterone on the escalation of cocaine self-administration in female rats during extended access.

Estrogen increases and progesterone decreases the acquisition and reinstatement of cocaine-seeking behavior in female rats. Here estrogen and progesterone were studied for their effects on the escalation of cocaine self-administration in female rats. The rats received ovariectomy (OVX) or sham (SH) surgery and were treated with estradiol benzoate (0.05 mg/kg sc) and/or progesterone (0.5 mg/kg) or vehicle (indicated by E, P, and V), resulting in 5 groups: SH+V, SH+P, OVX+V, OVX+E, OVX+E+P. Rats self-administered intravenous cocaine (0.4 mg/kg) under a fixed ratio 1 (FR 1) schedule during 2-hr sessions and were then given 6-hr sessions (long access; LgA) (FR 1) for 21 days. After LgA, self-administration was reassessed with 2-hr sessions under the FR 1 and a progressive ratio schedule with 4 cocaine doses. There were no differences among the 5 groups in cocaine self-administration during initial 2-hr sessions. During LgA, the SH+V, OVX+E, and OVX+V groups escalated their cocaine self-administration, whereas the OVX+E+P and SH+P groups did not. Estradiol increased escalation in the OVX+E group compared with the OVX+V group, and progesterone (SH+P) reduced escalation compared with the SH+V group. When estrogen and progesterone were both administered in OVX rats (OVX+E+P), escalation was significantly lower than in the OVX+E group. Cocaine infusions during the 2-hr sessions were significantly higher after escalation than before in all groups except the progesterone-treated groups (SH+P and OVX+E+P). Estrogen promoted and progesterone inhibited escalation of cocaine self-administration, illustrating the importance of female gonadal hormones in drug-seeking behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus).

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Regulation of intravenously self-administered nicotine in rats.

Ten male Wistar rats had access to 9 doses of nicotine (0.01–0.10 mg/kg iv) during daily 5-hr sessions. Once responding for nicotine stabilized, nicotine infusions were replaced with either cocaine infusions (0.0–2.4 mg/kg) or saline infusions. Saline substitution results indicate that nicotine functioned as a reinforcer. Regulation of nicotine intake was compared with that of cocaine by obtaining the correlation between mean interdose interval and preceding dose size. Results reveal that although this correlation was significant for both nicotine and cocaine self-administration, nicotine self-administration was less precisely regulated than cocaine self-administration. This procedure suggests that there are differences in regulation among self-administered drugs and that it may serve as a useful baseline for studying differences in vulnerability to drug abuse and potential treatment strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.     

Detection of Legionella pneumophila in wastewater by nested polymerase chain reaction

Behavioral economics defines unit price (UP) as the ratio of the response requirement to magnitude of reinforcer. When applied to drug self-administration, the UP model defines UP as the ratio of the response requirement to the unit dose of drug. This model makes two predictions about drug self-administration: increasing UP decreases consumption and consumption at a given UP will be constant regardless of the response requirement and dose that make up the UP. In previous experiments conducted in rhesus monkeys allowed to choose between an i.v. injection of cocaine and food, the UP model has failed to adequately predict drug consumption in that consumption varied (increased with dose) at a given UP. However, previous experiments have allowed a fixed number of choice trials/day, thereby imposing a procedural ceiling on consumption that may have influenced conformity to the UP model. In the present experiment, the number of choice trials available was varied in such a way that constant drug consumption was possible over the range of UPs tested. The response requirement for cocaine was varied between 15 and 1200 lever presses/injection and the dose of cocaine was varied between 0.05 and 0.2 mg/kg/inj, yielding UPs from 300 to 5600 responses/mg/kg. The response requirement for food was always 30. As predicted by the UP model, cocaine consumption decreased as UP increased. Moreover, in contrast to previous experiments, consumption did not vary significantly across the response requirement/dose combinations that made up a UP. A detailed analysis suggested that a decrease in magnitude of the alternative reinforcer (one rather than three food pellets), rather than the increase in trials, was responsible for the improved conformity to the UP model in the present experiment relative to previous experiments. Taken together with previous experiments, the present experiment suggests that conformity to the UP model of drug consumption in a choice situation is dependent upon the magnitude of alternative reinforcers that are available. Consumption was best predicted by the UP model when the magnitude of the alternative reinforcer was small.     

Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats.

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADs ≤9 seconds) or low (LoI; MADs ≥13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the effects of methamphetamine, bupropion, and methylphenidate on the self-administration of methamphetamine by rhesus monkeys.

The effectiveness of methadone as a treatment for opioid abuse and nicotine preparations as treatments for tobacco smoking has led to an interest in developing a similar strategy for treating psychostimulant abuse. The current study investigated the effects of three such potential therapies on intravenous methamphetamine self-administration (1 – 30 μg/kg/injection) in rhesus monkeys. When given as a presession intramuscular injection, a high dose of methamphetamine (1.0 mg/kg) decreased intravenous methamphetamine self-administration but did not affect responding for a food reinforcer during the same sessions. However, the dose of intramuscular methamphetamine required to reduce intravenous methamphetamine self-administration exceeded the cumulative amount taken during a typical self-administration session, and pretreatment with a low dose of methamphetamine (0.3 mg/kg) actually increased self-administration in some monkeys at the lower self-administration dose. Like pretreatment with methamphetamine, pretreatment with bupropion (3.2 mg/kg) decreased methamphetamine self-administration but did not affect responding for food. Pretreatment with methylphenidate (0.56 mg/kg) did not significantly alter methamphetamine self-administration. These results suggest that some agonist-like agents can decrease methamphetamine self-administration. Although the most robust effects occurred with a high dose of methamphetamine, safety and abuse liability considerations suggest that bupropion should also be considered for further evaluation as a methamphetamine addiction treatment. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Role of anorexia and behavioral activation in amphetamine-induced suppression of feeding: Implications for understanding tolerance.

48 male Sprague-Dawley albino rats administered chronic injections of either saline or dextroamphetamine (DAM) sulfate (2 or 4 mg/kg, intraperitoneally) were given milk either directly into the mouth through an intraoral cannula or in a standard drinking tube. Results reveal that bottle-fed Ss given DAM showed substantially greater suppression of intake than cannula-fed Ss. Saline-treated Ss showed almost identical milk intake with the 2 methods. Recovery of intake occurred in all drugged Ss except those given 4 mg/kg and fed by bottle. In the tolerant groups, Ss fed by bottle and given 2 mg/kg recovered at a faster rate than cannula-fed Ss at either dose. Findings demonstrate that in a normal drinking condition, the initial suppression of intake is caused by a combination of anorexia and behavioral interference and that tolerance occurs to both of these effects. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intravenous self-injection of psychomotor stimulant--anorectics in the baboon.

The present study evaluated the intravenous (IV) self-injection of 3 psychomotor stimulantanorectics in 5 baboons (Papio cynocephalus) A cocaine substitution procedure was used. IV self-injections were available 24 hr/day according to a fixed-ratio (FR) schedule with a 3-hr time-out following each injection. Doses of aminorex (0.01–0.32 mg/kg/injection), propylhexedrine (0.1–3.2 mg/kg/injection), mazindol (0.001–0.1 mg/kg/injection), and their vehicles were substituted for cocaine for 15 or more days. A concurrent FR schedule of food pellet delivery allowed evaluation of changes in food intake. The highest dose of each drug maintained self-injection at rates higher than vehicle control, suppressed food intake, and produced gross behavioral changes similar to those produced by classic psychomotor stimulants such as d-amphetamine. The present data indicate that each of the drugs functions as a positive reinforcer in baboons and suggest that each may have abuse potential. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Differences in the liability to self-administer intravenous cocaine between C57BL/6 x SJL and BALB/cByJ mice

Application of animal models of psychostimulant abuse for experimentation in mice is becoming increasingly important for studying the contribution of genetic differences, as well as the roles of selected (targeted) genes, in specific behaviors. The purpose of this study was to investigate strain differences in cocaine self-administration behavior between C57BL/6 x SJL hybrid mice and BALB/cByJ mice. These two strains were chosen because BALB/cByJ mice have a well-developed behavioral pharmacological profile, and hybrid strains on a C57BL/6 background are commonly used for generating transgenic expressing and knockout mutant mice. C57BL/6 x SJL mice dose-dependently acquired cocaine self-administration (1.0 mg/kg/injection but not 0.25 mg/kg/injection) by responding selectively in the active nose-poke hole and maintaining stable levels of daily drug intake; they also exhibited a characteristic inverted-U-shaped cocaine dose-effect function. BALB/cByJ mice failed to acquire cocaine self-administration at either dose under the same test conditions. The strain differences observed in self-administration did not seem to be attributed to other behavioral differences because the two strains exhibited similar amounts of spontaneous nose-poking in the absence of reinforcers, and BALB/cByJ mice responded more than C57BL/6 x SJL mice in a food-reinforced nose-poke operant task. Importantly, the dose-effect function for the motor stimulating effects of cocaine (3.8-30 mg/kg intraperitoneally) suggests enhanced sensitivity but reduced efficacy of cocaine in stimulating motor activity in BALB/cByJ mice relative to the C57BL/6 x SJL hybrid mice. These results indicate that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is not the result of differences in spontaneous activity or performance, but may reflect different sensitivities to the reinforcing, or rate-disrupting, properties of cocaine. The data support an influence of genetic background in the liability to self-administer cocaine. Thus, a hypothesis is proposed that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is related to differences in brain monoamine systems linked to the high "emotionality" profile of BALB/c mice in novel or fearful situations, including perhaps cocaine administration.     

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats.

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine.

The effects of the high-affinity dopamine reuptake inhibitor, GBR 12909, were studied on responding maintained under multiple fixed ratio (FR) schedules of food and cocaine delivery in rhesus monkeys (Macaca mulatta). GBR 12909 decreased rates of responding maintained by both events in a dose-related manner, however, large decreases in cocaine-maintained responding could be obtained with doses of GBR 12909 that had little effect on food-maintained responding. This behavioral selective effect of GBR 12909 on cocaine-maintained responding was inversely related to the unit dose of cocaine. When responding was maintained by low doses of cocaine, GBR 12909 (1 mg/kg) decreased cocaine-maintained responding almost completely. When responding was maintained by the highest dose, the same dose of GBR 12909 had little effect on responding. To the extent that higher doses of cocaine may be expected to be more reinforcing, the current results suggest that the effect of GBR 12909 on cocaine-maintained responding was determined by the reinforcing efficacy of the unit dose of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)