Schedule Of Drug Delivery Research Articles

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso: effect of adding a third dose to the standard two-dose regimen on low birth weight, anaemia and pregnancy outcomes

BackgroundIntermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW) and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome.MethodsPregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2) or 3 doses (SP3) of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW (<2500 g), severe anaemia (Hb < 8 g/dL) and premature birth was analysed using intention-to-treat (ITT) and per-protocol (PP) analysis.ResultsData from 1274 singleton pregnancies were analysed (641 in the SP3 and 633 in the SP2 group). The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24) in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 - 0.90). The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance.ConclusionThe risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal.

Impact of early life stress on the reinforcing and behavioral-stimulant effects of psychostimulants in rhesus monkeys

Early life stress has effects on behavior and stress reactivity, which are linked to enhanced sensitivity to stimulants in rodents. This study investigated whether rhesus monkeys that experienced early life stress would show altered sensitivity to the reinforcing effects of stimulants as compared with controls. Control (n=5) and maternally separated (n=4) monkeys were trained to self-administer cocaine (0.1 mg/kg/injection) under a second-order schedule of intravenous drug delivery. The rate of acquisition and subsequent dose-effect determinations for cocaine (0.01-1.0 mg/kg/injection) and amphetamine (0.003-0.3 mg/kg/injection) provided complementary measures of reinforcing effectiveness. In addition, stimulant-induced increases in home cage activity and dopamine D2 receptor binding potential were quantified with positron emission tomography neuroimaging. Compared with controls, maternally separated monkeys showed lower responding during the acquisition of self-administration and in the dose-response curves for both stimulants, and significantly lower response rates during maintenance of cocaine self-administration. Maternally separated monkeys also failed to exhibit stimulant-induced increases in motor activity. Groups did not differ in dopamine D2 receptor binding potential in the caudate nucleus or the putamen. Taken together, the results of this study do not provide support for early life stress leading to enhanced vulnerability to stimulant use in the nonhuman primate model employed.

Taxanes in the management of gynecologic malignancies

The taxanes (paclitaxel and docetaxel) currently play an important role in the managment of cancers of the ovary, uterus and cervix. In each of these gynecologic malignancies, the drugs are routinely employed in combination with a platinum agent, although when delivered as single agents they may provide substantial palliative benefit. It is important to recognize that despite the documented major utility of this class of agents in the treatment of gynecologic cancers, many highly relevant questions remain, including determining optimal drug delivery schedules, the duration of treatment and the role of regional paclitaxel administration.

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 <3.0 mg/kg, nor did they significantly differ in the rates and patterns of responding and number of infusions earned as a function of FR schedule or unit dose of cocaine available. The role of sex, estrus cycle, and drug-onset age on cocaine self-administration appears to be minimal under these experimental conditions. Experimental conditions that favor no sex or age differences in cocaine intake (1.0-mg/kg unit dose and low FR) may be useful for evaluating potential sex or age differences in the consequences of cocaine self-administration more reliably, as cocaine intake would not be an uncontrolled factor.

Context‐dependent prefrontal cortex regulation of cocaine self‐administration and reinstatement behaviors in rats

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.

Cocaine self-administration in rats with histories of cocaine exposure and discrimination

Interrelationships between the discriminative stimulus and reinforcing properties of psychoactive drugs and the way in which they may interact to control drug intake are unclear. Studies have shown that drug history can influence the expression of drug-produced behavioral effects. The present study examined the acquisition and maintenance of intravenous cocaine self-administration in rats with a history of drug discrimination. Two groups of male hooded rats (n=12 each) were successfully trained in a single-lever food-reinforced procedure to discriminate cocaine (10 mg/kg) from saline. Control groups (n=12 each) received drug injections and/or saline injections only and lever-pressed for food reinforcers with no discrimination training. Subsequently, all subjects were implanted with chronic jugular catheters and allowed to nose-poke for infusions of cocaine (0.2 mg/kg per infusion). Initial rates of responding were similar for all groups. Acquisition of self-administration on a FR-10 schedule of drug delivery was significantly faster for cocaine-exposed rats in comparison to all other groups (P<0.02). There were no differences between groups in the breaking points of cocaine and saline on a progressive ratio schedule of self-administration. Dose-response functions were obtained by two methods and were similar for all groups. These results are consistent with earlier studies demonstrating weakly sensitized primary reinforcing properties of cocaine in preexposed rats. Previous learning to discriminate cocaine impaired this sensitization.

Comparing the physiological and subjective effects of self-administered vs yoked cocaine in humans

Studies with laboratory animals demonstrating different effects of self- vs experimenter-administered drug suggest that the ability to control or predict drug delivery may be an important determinant of drug action. This study assessed whether self-administered and yoked cocaine injections produce different effects in humans. Ten inpatient volunteers with experience in using cocaine participated in a double-blind, yoked design during which four experimental test sessions were conducted. During two sessions, participants controlled if and when up to six 40 mg/70 kg i.v. cocaine injections were given. During two sessions, participants received noncontingent exposure to the same pattern of injections given during the preceding session (i.e., yoked) under blind conditions. Sessions followed a fixed-order, ABAB design. Measures of subjective and physiological response to cocaine were taken throughout each session. Cardiovascular safety parameters were exceeded in some individuals after yoked, but not self-administered, cocaine resulting in some scheduled injections being delayed or withheld. Mean systolic and diastolic blood pressures were higher following yoked compared to self-administered cocaine. In contrast, analysis of the subjective effects revealed only small and generally nonsignificant differences in the effects of self-administered vs yoked cocaine. These results suggest that under the laboratory methods employed, control over the schedule of drug delivery may not alter the subjective effects of cocaine in humans. In contrast, the cardiovascular effects of cocaine appear to be greater when the drug is administered noncontingently.

Methamphetamine-induced striatal apoptosis in the mouse brain: Comparison of a binge to an acute bolus drug administration

Methamphetamine (METH) is a psychostimulant that induces neural damage in experimental animals and humans. A binge (usually in the 5–10 mg/kg dose range 4× at 2 h intervals) and the acute bolus drug administration (20–40 mg/kg) of METH have been employed frequently to study neurotoxicity in the brain. In this study we have compared these drug delivery schedules to determine their efficacy to induce striatal apoptosis. Exposure of male mice to a binge of METH at 10 mg/kg 4× at 2 h intervals (cumulative dose of 40 mg/kg) was approximately four times less effective in inducing apoptotic cell death (TUNEL staining) 24 h after METH treatment in the striatum than a single bolus administration of 30 mg/kg of METH. The residual TUNEL staining observed three days after METH treatment is proportionately equivalent between a binge and the acute bolus drug administration. Interestingly, a binge of METH induces a hyperthermic response of longer duration. This study demonstrates that an acute bolus drug administration of METH is more effective inducing striatal apoptosis in mice, and therefore, is more suitable for studies assessing the impact of METH on sites post-synaptic to the striatonigral dopamine terminals.

Influence of cocaine self-administration on learning related to prefrontal cortex or hippocampus functioning in rats

Individuals who abuse cocaine have cognitive deficits, particularly in functions associated with the orbitofrontal cortex. It is not clear to what extent the impact of cocaine on cognitive functioning is related to its role as a behavioral reinforcer. A preclinical means to investigate this issue is to use a yoked-triad procedure in which sets of three animals either contingently self-administer cocaine or receive passive administration of cocaine or saline in a noncontingent manner. Using this procedure, we assessed cocaine's effect on learning that requires a functionally intact prefrontal cortex (prelimbic or insular/orbital subregions) or hippocampus. Rats self-administering 1-mg/kg unit doses of cocaine responded under a fixed-ratio 5, time-out 20-s schedule of drug delivery. Testing took place in a radial-arm maze within the first 30 min after 2-hr drug sessions ended, beginning after 2.5 months of cocaine or saline exposure. Rats self-administering cocaine earned 14-18 infusions on average throughout different phases of the study. In groupwise comparisons, learning in the visually guided delayed win-shift (prelimbic prefrontal cortex-related) and win-shift (hippocampus-related) tasks was not influenced by contingent or noncontingent cocaine exposure. Session latency, though, was shorter in both cocaine-exposed groups during the win-shift task. During the odor-guided delayed win-shift task (insular/orbital prefrontal cortex-related), learning was disrupted in rats self-administering cocaine, with no influence of noncontingent cocaine exposure. Based on these and previous findings, learning related to functioning of the insular/orbital prefrontal cortex and amygdala is the most consistently disrupted in cocaine-intoxicated rats after long-term drug exposure.

Three-month, zero-order piroxicam release from monodispersed double-walled microspheres of controlled shell thickness.

Double-walled microspheres represent an increasingly important class of drug delivery devices that provide enhanced control of drug delivery schedules. Clearly, the overall particle size and shell thickness are important parameters in modulating the drug release rates. Precision particle fabrication technology has been used to fabricate double-walled microspheres of predefined uniform diameters of 40-60 microm exhibiting a poly(D,L-lactide-co-glycolide) (PLG) core and poly(L-lactide) (PL) shell of controllable thickness from approximately 2 to 10 microm. The release of a model small-molecule drug, piroxicam, from uniform microspheres of pure PLG and PL is compared to the release from double-walled microspheres exhibiting different PL shell thicknesses. The presence of the PL shell enveloping a PLG core essentially eliminated the initial "burst" of piroxicam that was observed when the drug was released from pure PLG microspheres. In addition, increasing the PL shell thickness shifted the release profile from a biphasic shape for pure PLG microspheres to zero-order piroxicam release over 3 months for the thickest (approximately 10 microm) PL shell.

Differential in vivo activity of docetaxel plus PS-341 combination therapy in non-small cell lung carcinoma (NSCLC) xenografts

7144 Background: Velcade (PS-341) is a selective proteasome inhibitor in early clinical trials in NSCLC patients. Docetaxel (Txt) is a microtubule-stabilizing taxane in wide clinical use for first- and second-line NSCLC therapy. We previously showed in NSCLC cell lines in vitro that the sequence of Txt prior to PS-341 showed the greatest levels of apoptosis by sub-G1 content and PARP cleavage, which was associated with accumulation of p27 and loss of Bcl2. Our hypothesis was that the combination of both agents will be more effective than either agent alone, and that the sequence of drugs will influence the response to treatment. Methods: We used the p53-null NSCLC Calu-1 xenograft model to evaluate responses to Txt or PS-341 and to combinations in the sequences of PS-341 before Txt, Txt before PS-341, and both simultaneously. Cells (5x106) were injected subcutaneously into each flank of male athymic nu/nu mice with 2 mice per group. The agents in the combination treatments were administered either together or 24hrs apart, with all regimens given weekly [IP doses: Txt: 10mg/kg; PS-341: 0.5mg/kg]. Tumor growth was measured up to six weeks after initial treatment. Results: PS-341 had a modest effect on tumor growth as a single agent (12% inhibition), while Txt had no effect. However, with each of the alternate sequences of drug administration (Txt→PS-341 and PS-341→Txt), tumor growth was inhibited approximately 40%. The simultaneous delivery of both drugs showed no inhibition of tumor growth compared to the control, demonstrating antagonism compared to PS-341 alone. Conclusions: Our studies demonstrate that different schedules of drug delivery affect the response to combinations of PS-341 with Txt. Furthermore, antagonism was suggested with simultaneous administration of both agents in vivo. Additional studies of alternate schedules are warranted, and these in vivo data set the stage for future clinical trials. Examination of apoptosis-associated proteins PARP, Caspase-3, p27, and Bcl2 is ongoing. (Aventis and Millennium provided docetaxel and PS-341, respectively.) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Oncology

Differential in vivo activity of docetaxel plus PS-341 combination therapy in non-small cell lung carcinoma (NSCLC) xenografts

7144 Background: Velcade (PS-341) is a selective proteasome inhibitor in early clinical trials in NSCLC patients. Docetaxel (Txt) is a microtubule-stabilizing taxane in wide clinical use for first- and second-line NSCLC therapy. We previously showed in NSCLC cell lines in vitro that the sequence of Txt prior to PS-341 showed the greatest levels of apoptosis by sub-G1 content and PARP cleavage, which was associated with accumulation of p27 and loss of Bcl2. Our hypothesis was that the combination of both agents will be more effective than either agent alone, and that the sequence of drugs will influence the response to treatment. Methods: We used the p53-null NSCLC Calu-1 xenograft model to evaluate responses to Txt or PS-341 and to combinations in the sequences of PS-341 before Txt, Txt before PS-341, and both simultaneously. Cells (5x106) were injected subcutaneously into each flank of male athymic nu/nu mice with 2 mice per group. The agents in the combination treatments were administered either together or 24hrs apart, with all regimens given weekly [IP doses: Txt: 10mg/kg; PS-341: 0.5mg/kg]. Tumor growth was measured up to six weeks after initial treatment. Results: PS-341 had a modest effect on tumor growth as a single agent (12% inhibition), while Txt had no effect. However, with each of the alternate sequences of drug administration (Txt→PS-341 and PS-341→Txt), tumor growth was inhibited approximately 40%. The simultaneous delivery of both drugs showed no inhibition of tumor growth compared to the control, demonstrating antagonism compared to PS-341 alone. Conclusions: Our studies demonstrate that different schedules of drug delivery affect the response to combinations of PS-341 with Txt. Furthermore, antagonism was suggested with simultaneous administration of both agents in vivo. Additional studies of alternate schedules are warranted, and these in vivo data set the stage for future clinical trials. Examination of apoptosis-associated proteins PARP, Caspase-3, p27, and Bcl2 is ongoing. (Aventis and Millennium provided docetaxel and PS-341, respectively.) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Oncology

Stimulus-response functions of the lateral dorsal striatum and regulation of behavior studied in a cocaine maintenance/cue reinstatement model in rats.

To investigate potential neurocognitive mechanisms underlying drug-seeking and drug-taking behavior, the effects of reversible lidocaine-induced inactivation of the lateral dorsal striatum (DST) on behavior studied in a drug maintenance/cue reinstatement model were evaluated. This region of the DST was investigated because it selectively regulates stimulus-response learning that is disrupted by 10 microg of bilaterally infused lidocaine. Rats ( n=6) were trained to self-administer 1 mg/kg per infusion cocaine under a second-order schedule of drug delivery. The effects of bilateral lidocaine (30-100 microg) inactivation of the lateral DST were evaluated during drug maintenance tests as well as during tests in which responding was reinstated by cocaine-associated cues presented in combination with a cocaine priming injection. The lower 10 microg dose was used to examine the effects of lidocaine on reinstatement of responding induced by presentation of cues alone. During drug maintenance tests, drug-seeking behavior was significantly increased after inactivation by 100 microg lidocaine. The number of infusions earned did not change. During cue-induced reinstatement tests preceded by a cocaine priming injection, 100 microg lidocaine significantly decreased both drug-seeking behavior and the number of infusion-paired light deliveries earned. During reinstatement tests with cues presented alone, inactivation of the lateral DST by 10 microg lidocaine did not influence either behavior. These findings suggest that stimulus-response functions of the lateral DST may regulate the dose-related effects of self-administered cocaine because the lidocaine-induced changes in behavior during the maintenance and cocaine priming tests resembled the effects of exposure to increasingly lower doses of cocaine, respectively. Given the lack of an effect of lidocaine during the cues-alone tests, the lateral DST does not appear to regulate drug-seeking behavior per se (i.e., responding maintained by drug-associated cues at times when drug is not available).

Dissociable Effects of Lidocaine Inactivation of the Rostral and Caudal Basolateral Amygdala on the Maintenance and Reinstatement of Cocaine-Seeking Behavior in Rats

Cocaine addiction is a chronically relapsing brain disease, but its neural basis is not yet well understood. Clinical reports underscore the possible importance of associative processes for regulating at least some aspects of cocaine addiction. The present study reports the effects of reversible lidocaine-induced inactivation of rostral basolateral amygdala (rBLA) and caudal basolateral amygdala (cBLA) regions on the maintenance and reinstatement of drug-seeking behavior in rats trained to self-administer 1 mg/kg cocaine under a second order schedule of drug delivery. Both regions of the basolateral amygdala were investigated because they have dissociable effects on cognitive task performance. Results demonstrated that after self-administration training and a period of extinction and abstinence, lidocaine inactivation of the rBLA and cBLA attenuated the reinstatement of drug-seeking behavior induced by cocaine-associated cues examined in conjunction with a single priming injection of cocaine. In contrast, lidocaine inactivation of only the rBLA blocked reinstatement of drug-seeking behavior induced by cocaine-associated cues examined alone. Additional differences were shown during cocaine maintenance testing where inactivation of only the cBLA attenuated drug-seeking behavior. Drug intake was not altered. Thus, the rBLA and cBLA appear to selectively and dissociably regulate drug-seeking behavior under conditions of cocaine abstinence (cue-induced reinstatement) and repeated cocaine use (maintenance), respectively. These findings suggest that the basolateral amygdala may be more functionally heterogeneous than commonly thought for regulating drug-seeking behavior. The basis for this dissociation might be related to neuroanatomical connections of the rBLA and cBLA with segregated, but parallel, corticostriatalpallidothalamic circuits.

Abuse liability of the anesthetic propofol: self-administration of propofol in rats under fixed-ratio schedules of drug delivery

Previous reports suggest that propofol (PPF) may have abuse potential in humans. Hence, we hypothesized that PPF could reinforce self-administration behavior in other species. Positive reinforcing effects of PPF could be interpreted as an index of abuse liability. Acquisition and maintenance of i.v. PPF self-administration were examined in 12 rats. Six rats were initially given access to methohexital (MHX, 2.0 mg/kg per infusion) under a fixed ratio (FR) 1 schedule, while the other six were initially given access to PPF (1.7 mg/kg per infusion). Once stable responding was established, various doses of PPF (0.56, 1.0, and 1.7 mg/kg per infusion) and vehicle (Intralipid 20%) were made available. The number of PPF infusions per session was an inverse function of dose, with 0.56 mg/kg and 1.0 mg/kg per infusion maintaining significantly more infusions per session than vehicle in most rats under the FR 1 schedule. For some rats, the number of vehicle infusions per session was equal to or greater than the number of PPF infusions. Increasing the response requirement to FR 5 decreased the number of vehicle infusions per session in these rats, while PPF maintained a higher number of infusions than vehicle under this FR value in six of seven rats. PPF served as a reinforcer in rats under FR schedules of i.v. drug delivery, adding to the extant evidence that it has abuse potential.

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model.

Previous pre-clinical studies with an anti-cocaine monoclonal antibody left open several issues critical to assessing the effectiveness of a vaccine for altering cocaine self-administration behavior. The objectives of this study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine. Two experiments were conducted using a second-order schedule of drug delivery in rats. The first was a passive-administration study using the anti-cocaine monoclonal antibody MO240 to examine the relationship between antibody level and cocaine self-administration behavior, and the second was an active-immunization study to examine the efficacy of the cocaine vaccine IPC-1010 for blocking various doses of self-administered cocaine. The passive-administration experiment with control and 4-mg or 12-mg MO240 treatments showed that antagonism of the 1 mg/kg cocaine training dose was dependent on antibody level. In animals whose serum antibody levels were sustained above 0.05 mg/ml, there was a sufficient amount of antibody to reduce drug-seeking behavior and drug intake. In the active-immunization experiment, the cocaine vaccine IPC-1010 induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of behavior by 1 mg/kg cocaine. Antagonism of cocaine self-administration after immunization was evident across a range of doses of cocaine and was only apparent in animals whose serum antibody levels exceeded 0.05 mg/ml. Furthermore, there was no evidence that the antagonism was surmountable within the dose range examined (up to 5.6 mg/kg). Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

Optimum chemotherapy for ovarian cancer.

A series of prospective randomized trials recently have defined the new standard of care for chemotherapy patients with ovarian cancer. The current preferred regimen consists of carboplatin (dosed to an area-under-the-curve [AUC] of 5.0-7.5) plus paclitaxel (175 mg/m2-3 h infusion). This is an outpatient regimen that does not require growth factor support and six cycles are administered on a 21-day schedule. There is no evidence that any type of additional therapy impacts upon survival, including additional cycles of the same chemotherapy or switching to an alternative intravenous chemotherapy, high-dose chemotherapy with hematologic support, intraperitoneal chemotherapy, or whole abdominal radiation. The majority of patients will achieve a clinical complete remission with the regimen although the relapse rate remains high. Current trials are exploring new schedules of drug delivery as well as new combinations which include new agents such as gemcitabine and topotecan.

Acquisition of intravenous cocaine self-administration with concurrent access to food in cynomolgus monkeys.

The present study used a concurrent schedule of food and drug delivery in socially housed male cynomolgus monkeys (Macacafascicularis; N = 15) to study variables that influence cocaine acquisition. Each monkey was implanted with subcutaneous vascular access ports, and responding was maintained under a concurrent food, saline schedule with the lever associated with each stimulus presentation varied daily. Next, increasing cocaine doses (0.003-0.3 mg/kg/inj) were concurrently available with food for at least 5 consecutive sessions per dose. Under these conditions, an unexpected lever bias emerged in all 15 monkeys. The development of the lever bias could not be predicted on the basis of cocaine dose or total intake and was not related to social rank. These findings suggest that in monkeys, concurrent fixed-ratio schedules of food and cocaine presentation may result in persistent biased responding that overshadows cocaine preference in studies of acquisition.

Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review.

Drugs, like other reinforcers, can vary in their relative abilities to support operant responding. Considerable research has been designed to obtain useful measures of a given drug's or dose's "reinforcing efficacy" and to identify the ways in which a variety of behavioral and pharmacological variables impact these measures. Progressive-ratio schedules of drug delivery generate an index of a drug's or dose's reinforcing efficacy (the breaking point) and are being used increasingly as tools in the analysis of drug self-administration. Progressive-ratio schedules of drug delivery have been used to characterize the effects of pretreatment drugs, lesions, drug deprivation, physical dependence, and repeated non-contingent drug exposure on breaking points. Behavioral factors, including food restriction and electric shock, and organismic factors, including gender and strain, have also been investigated using progressive-ratio schedules of drug delivery. To the extent that breaking points provide an index of reinforcing efficacy, these studies demonstrate that a wide range of variables can influence the reinforcing efficacy of self-administered drugs. The objectives of this review are to critique existing research themes, outline potential limitations of progressive-ratio procedures, and to suggest potentially fruitful uses of these procedures in future research.

Acquisition of nicotine self-administration in rats: the effects of dose, feeding schedule, and drug contingency.

The studies presented here were designed to further clarify the nature of nicotine self-administration (SA) based on a limited access model in which rats are food restricted, receive operant training using food reinforcement, and are then tested in daily 1-h drug sessions. We examined the effects of dose, feeding schedule, and contingency of drug delivery on acquisition of nicotine SA. Two doses of nicotine bitartrate, 0.03 and 0.06 mg/kg per infusion (free base), supported the transition from food-reinforced to drug-reinforced responding, although the pattern of behavior differed between these doses. In contrast, 0.01 mg/kg per infusion failed to maintain nicotine SA. In a second study, animals were divided into three groups according to feeding schedule. Rats that were both weight restricted and food deprived showed the highest level of SA behavior, although neither food deprivation nor weight restriction was necessary to establish SA. In the third experiment, rats that were switched from food to nicotine as the response-dependent reinforcer maintained higher response rates throughout a 9-day period than animals switched to response-independent (i.e., yoked) nicotine which showed minimal responding after day 1. Furthermore, the differences between self-administering and yoked animals emerged during the first session, suggesting that nicotine may serve as a reinforcer during the first drug exposure in naive animals. These results indicate that acquisition of nicotine SA can be influenced by both dose of nicotine and feeding schedule and that, in animals previously trained on a food-reinforced operant, active lever pressing is maintained only when nicotine delivery is contingent upon responding.