Which Substance Are Animals Likely To Self-administer?

Abstruse

Recent attempts to model the addiction procedure in rodents have focused on cocaine self-administration procedures that provide extended daily access. Such procedures produce a characteristic loading phase during which blood levels rapidly rise and then are maintained within an elevated range for the duration of the session. The nowadays experiments tested the hypothesis that multiple fast-rising spikes in cocaine levels contribute to the addiction process more robustly than constant, maintained drug levels. Hither, we compared the effects of various cocaine self-administration procedures that produced very different patterns of drug intake and drug dynamics on Pmax, a behavioral economic mensurate of the motivation to self-administer drug. Two groups received intermittent access (IntA) to cocaine during daily six-h sessions. Access was limited to twelve 5-min trials that alternated with 25-min timeout periods, using either a concord-downwardly procedure or a stock-still ratio 1 (FR1). Cocaine levels could non be maintained with this procedure; instead the animals experienced 12 fast-rising spikes in cocaine levels each day. The IntA groups were compared with groups given 6-h FR1 long admission and 2-h brusque access sessions and two other control groups. Here, we report that cocaine cocky-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase the motivation to self-administer cocaine.

INTRODUCTION

Drug addiction is a multifaceted disorder that presents with a variety of symptoms. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a diagnosis of drug dependence requires the presentation of any three of seven singled-out symptoms (American Psychiatric Association, 1994). These range from purely consumptive measures (eg, increased intake) to motivational criteria such every bit an inability to abstain. The diversity of these criteria suggests that drug dependence involves multiple neurobiological processes that may manifest differently in dissimilar individuals (Koob and Volkow, 2010). A comprehensive written report of these underlying neurobiological mechanisms requires creature models that reverberate the multiple addiction processes.

A number of cocaine self-administration procedures accept been developed in rodents to assess specific DSM-IV symptoms associated with cocaine addiction (Vanderschuren and Everitt, 2004). The schedules and access conditions used, and the resulting patterns of cocaine intake, greatly touch on the expression of the symptoms. It is important to note that many admission atmospheric condition produce remarkably stable patterns of drug intake with no apparent modify in motivational measures (Roberts et al, 2007). This demonstrates that just allowing an creature to cocky-administer cocaine is not sufficient to produce an fond phenotype. Successful rodent models of the progression of cocaine habit have identified a number of disquisitional features including increased daily admission (Ahmed and Koob, 1998, 1999), intermittency (Morgan et al, 2002; Morgan and Roberts, 2004), abstinence (Grimm et al, 2001; Pickens et al, 2011), and speed of drug injection (Liu et al, 2005b; Wakabayashi et al, 2010).

A long access (LgA) procedure in which rats self-administer cocaine during daily six-h sessions on a fixed ratio 1 (FR1) schedule is perhaps the most widely used model for examining changes in cocky-administration beliefs over time (Koob and Kreek, 2007; Koob and Volkow, 2010; Zernig et al, 2007). This process has been shown to produce a robust escalation in drug intake (∼30–twoscore%) over a 2-calendar week menses, which is not observed in brusque access (ShA) controls given access to only 1 h/solar day (Ahmed and Koob, 1998). These sessions, and all FR1 sessions, typically show a loading and maintenance phase (Ettenberg et al, 1982; Wilson et al, 1971). That is, animals load upwards at the beginning by cocky-administering several injections in a short menstruum of time, and for the remainder of the session, infusions get more evenly spaced resulting in cocaine levels existence maintained within relatively narrow limits (Ahmed and Koob, 2005). Every bit both LgA and ShA sessions provide animals with the opportunity to appoint in loading behavior, the critical divergence betwixt these procedures is the length of the maintenance phase. Therefore, information technology would appear that the escalation effect is due to brain levels of cocaine being maintained for an extended catamenia of time.

Although the LgA model in rodents, in many respects, mimics a 6-h cocaine 'binge' (Ahmed, 2005), clinical data suggest that humans take cocaine in a somewhat different blueprint. Recent survey information from cocaine users indicate that experienced individuals consume the aforementioned amount of cocaine in a similar menses of fourth dimension as less experienced ones. Notwithstanding, more experienced subjects reported getting significantly fewer 'uses' (<four) from each buy indicating that, compared with less experienced users, they were self-administering larger doses separated by longer intervals betwixt intoxicating events (Beveridge et al, 2012). The inter-use-interval was often much greater than an hr. Given that the one-half-life of cocaine in humans is ∼twoscore min (Javaid et al, 1983), claret concentrations are not maintained at a high level; instead, substantial reductions in claret levels occur which and then 'spike' with each intense intoxicating issue. It is likely, therefore, that at that place are qualitative differences in the dynamics of cocaine levels between human drug users and subjects in typical FR cocaine self-assistants experiments.

The clinical data suggesting that addicts exhibit spiking rather than relatively stable blood levels during a binge prompted this study. Here, we investigated the effects of two weeks of exposure to a cocaine self-administration procedure that engendered a spiking blueprint of cocaine intake. Rats were given intermittent access (IntA) to cocaine during 5-min trials that alternated with 25-min timeout periods. This IntA procedure, which was adult while investigating the relationship between the preferred dose of cocaine and the amount of drug on lath, results in substantial fluctuations in cocaine brain levels (Zimmer et al, 2011). The IntA procedure offers the opportunity to test whether maintained levels are necessary for a change in addiction phenotype and whether rapid spikes in brain levels are sufficient. 2 IntA groups were included in the present experiment; during each v-min trial one group was given access to cocaine using a hold-downward (Hard disk) process (IntA-Hard disk) while the other grouping was given access to cocaine on an FR1 schedule (IntA-FR). These 2 groups were compared with LgA, ShA, and ii other control groups. After two weeks of daily admission to cocaine, the performance of the six groups was compared using a within-session threshold (TH) process (Oleson et al, 2011). Pmax, defined as the unit-toll at which maximal responding occurs (Hursh, 1991), was assessed using a behavioral economical assay of information. Hither, we report that cocaine self-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine.

MATERIALS AND METHODS

Animals, Surgery, and Housing

The Wake Forest University Institutional Fauna Intendance and Use Committee canonical all experiments before the study commenced. Male Sprague–Dawley rats (Harlan, Indianapolis, IN), weighing approximately 350 yard at the fourth dimension of surgery were used as subjects. Before entering the written report, rats were anesthetized with ketamine (100 mg/kg) and xylazine (eight mg/kg) and implanted with chronically indwelling Silastic cannulae (CamCaths, Cambridgshire, UK) as previously described (Liu et al, 2007). On recovery, animals were individually housed in 30 × 30 × 30 cm experimental chambers located in a temperature-controlled room (20–21 °C) maintained on a 12-h light–dark cycle (lights on at 1500 hours). A counterbalanced fluid swivel (Instech Laboratories, Plymouth Meeting, PA) mounted to a higher place the experimental chamber was used to connect an infusion pump (Razel Scientific Instruments, Stamford, CT) to the cannula using Tygon tubing enclosed within a stainless steel tether. Cannulae were flushed daily with heparinized saline to assistance maintain patency. Food and h2o were bachelor ad libitum.

Self-Administration Training

After a iii- to five-twenty-four hour period recovery period, all animals were given access (FR1) to a cocaine-paired lever which, when depressed, initiated an intravenous injection of cocaine (0.75 mg/kg, infused over iv due south). When each infusion was initiated, the lever was retracted and a stimulus light higher up the lever was illuminated, signaling a 20-s timeout flow. Sessions occurred 7 days per week and began in the center of the dark bicycle. Sessions were terminated later on a maximum of xx infusions or after 6 h, whichever occurred commencement. An beast was considered to have acquired if twenty injections were cocky-administered for 2 sequent days and a stable pattern of postal service-infusion pauses was credible. Following training, separate groups of animals were assigned to 1 of 6 daily access procedures (ShA, LgA, HD, TH, IntA-HD, or IntA-FR—see beneath) for a two-week access catamenia later on which Pmax was evaluated using a within-session Th process.

IntA-HD Group

Following acquisition, rats (N=6) were given access to cocaine using a Hd procedure as previously described (Morgan et al, 2009). Briefly, the subjects were provided access to a lever which, when depressed, activated an infusion pump until the lever was released. An LED stimulus lite above the lever was illuminated when the lever was depressed; that is, the light and pump were activated–inactivated concurrently. The dose cocky-administered was determined by the length of fourth dimension the brute held the lever down (infusion rate was 0.375 mg/kg/south) and by the pattern of responding. In that location were no timeout periods during these Hard disk training sessions. The concentration of cocaine was 5 mg/ml. Rats were given daily iii-h sessions until the response pattern stabilized (which by and large took 2–3 days). After they had caused the HD response, the schedule was switched to an IntA schedule in which subjects were given access to the retractable HD lever for twelve 5-min admission periods on the Hd schedule as previously described (Zimmer et al, 2011). In between each 5-min trial, a 25-min timeout period was enforced during which the lever was retracted. The lever presence–absence served as the simply signal for drug availability. Animals received daily IntA-HD sessions for 14 consecutive days.

IntA-FR Grouping

A separate group (N=v) was tested using the same IntA procedure described higher up (twelve 5-min trials separated past 25-min timeout periods) except that, instead of using a HD procedure, responding was reinforced on an FR1 schedule. The concentration of cocaine was five mg/ml. Each response produced a i-s infusion of drug (0.375 mg/kg/inf) signaled by the illumination of a i-due south presentation of an LED stimulus light. Apart from the i-s interval during which the pump was active, no timeouts were imposed to limit the number or timing of infusions within the five-min access periods. This procedure lies midway in the continuum of control of drug dose and injection speed with the Hd procedure on the ane extreme and a fixed unit of measurement dose on the other. That is, with a small unit dose and no timeout it is possible for an fauna to self-administer, for example, 4–5 small-scale injections in an viii- to 10-s interval. Pilot studies take shown that the patterns of intake with this procedure are similar to those observed on the Hard disk drive schedule.

LgA Group

Subjects in the LgA grouping (Northward=9) were given access to cocaine (0.75 mg/kg; infused over 4 southward) on an FR1 schedule during daily half-dozen-h sessions for fourteen sequent days. At the commencement of each infusion, a stimulus light signaled a 20-s timeout period during which the lever was retracted.

ShA Group

One grouping (N=half-dozen) was given admission to cocaine (0.75 mg/kg; infused over 4 s) on an FR1 schedule during 2-h daily sessions for 14 consecutive days. At the start of each infusion, a stimulus light signaled a 20-due south timeout menses during which the lever was retracted.

Hard disk Grouping

Subjects (Due north=7) in this group self-administered for fourteen daily, ii-h sessions on the Hard disk drive schedule of reinforcement as described past Morgan et al (2009). Briefly, the syringe-pump became active when the lever was depressed and became inactive when the lever was released. The size and speed of each dose was adamant by the duration and spacing of HD responses (infusion rate was 0.375 mg/kg/s). An LED stimulus low-cal in a higher place the lever was illuminated when the lever was depressed; that is, the low-cal and pump were activated–inactivated concurrently. No timeout periods were imposed to limit the size or number of doses self-administered.

Within-Session TH Group

Subjects in the TH group (North=5) were given admission to cocaine for 14 consecutive days on the within-session TH process (Oleson et al, 2011). Rats were given admission to a descending serial of 12 unit of measurement doses of cocaine (421, 237, 133, 75, 41, 24, 13, vii.five, 4.1, 2.four, ane.3, and 0 μg/injection) on an FR1 schedule during consecutive 10-min bins inside a two-h daily session. An LED stimulus light signaled the duration of the infusion and the corresponding fourth dimension-out catamenia (ie, equal to the pump duration). The lever was not retracted at whatsoever time during the session. Doses were manipulated by property the concentration abiding and adjusting the pump duration (run across supplementary cloth of Oleson and Roberts (2009) for a full characterization of this arroyo and validation that the appropriate quantity of drug is delivered across all pump durations). Each TH session lasted 2 h. The Th group was exposed to these conditions during the xiv-mean solar day examination period. All groups, including the Th group, cocky-administered on this schedule following their fourteen-mean solar day test period for three consecutive days.

Data Assay

A behavioral economical analysis was used to quantify results from this process. Behavioral economic theory has been successfully applied to drug self-administration in general (Bickel et al, 1993; Hursh, 1991) and Th procedures in detail (Espana et al, 2010; Oleson et al, 2011; Oleson and Roberts, 2009). In the current Th procedure, the descending series of doses (listed above) resulted in rats receiving admission to cocaine across the following 11 ascending unit-prices: ii.4, four.two, 7.v, xiii.iii, 23.seven, 39.9, 75, 134, 242, 417, and 750 responses/mg. The principal dependent measure analyzed was the maximal price paid for cocaine (Pmax), which was determined to be the unit of measurement-price respective to the apex of the price-response office as previously described (Espana et al, 2010; Oleson et al, 2011). An case of the calculation of Pmax is shown in Figure 4a. The dose that maintains the highest rate of responding is defined hither as the TH dose. This can be converted to Pmax past calculating the responses required at the observed TH dose to obtain 1 mg cocaine. For example, if the Th dose were establish to be vii.v μg/inj, then the Pmax would be 133.iii responses/one mg cocaine. In the vocabulary of behavioral economics, Pmax coincides with the signal at which cocaine consumption changes from being maintained (inelastic demand) to non being maintained (elastic demand). Pmax was calculated from data averaged across 3 consecutive days of TH test sessions.

The TH procedure affords the opportunity to appraise both appetitive and consummatory responding (as discussed in Oleson et al, 2011). Drug intake measured during early phases (10–40 min) of the Th procedure yields a measure of consummatory responding relatively unconstrained past price. Mean intake during 10–40 min were calculated for each beast. Intake was calculated in the early on phase of the Th procedure considering this is a period when the price of cocaine is relatively inexpensive and therefore less likely to constrain the fauna's intake. The outset 10 min were excluded to avoid the loading stage of the session.

Brain-Cocaine Concentration Model

Brain-cocaine concentrations were calculated as previously described (Zimmer et al, 2011) using equations employed by Pan et al (1991). Briefly, the equation

estimates the corporeality of cocaine in the encephalon compartment at fourth dimension t. This equation accounts for the dose of cocaine (d), the transfer of cocaine betwixt the blood and the brain (k=0.233 min⁻ⁱ), the apparent brain volume (5=0.xv l kg⁻¹), and the removal of cocaine from the claret through redistribution (α=0.642 min⁻¹) and emptying (β=0.097 min^−ane).

Drugs

Cocaine HCl, obtained from the National Constitute on Drug Corruption (Inquiry Triangle Institute, NC), was dissolved in a solution of sterilized saline 0.9% and passed through a microfilter (0.45 μm pore size). A five mg/ml cocaine solution was used for HD, within-session TH, and IntA experiments; a 2.5 mg/ml solution was used for acquisition, ShA and LgA.

RESULTS

Figure ane illustrates representative response patterns generated past each of the six procedures and the corresponding modeled encephalon levels. Each panel consists of the mathematically modeled brain-cocaine concentration (left centrality) and the cumulative dose (right axis) self-administered throughout the session. Animals self-administering on an FR1 schedule (ShA and LgA) titrated their brain levels of cocaine past regularly spacing their responses (Figures 1a and b). The HD group displayed a steady rate of responding as previously described (Morgan et al, 2009). This led to a relatively stable level of cocaine throughout the session (Figure 1c). The within-session TH grouping also showed a stable level of cocaine only during the showtime office of the session with brain levels of cocaine falling every bit the cost of cocaine increased beyond the beast's Pmax (Effigy 1e). The IntA animals had access to cocaine on either an FR1 (0.375 mg/kg/inf) or Hd procedure during 5-min trials followed by a 25-min timeout period. This pattern of access led to large fluctuations of encephalon-cocaine concentrations throughout the vi-h session (Figures 1d and f). The pattern of intake was virtually identical between the IntA-Hard disk and the IntA-FR groups. Subjects were observed to self-administer big doses (>3.0 mg/kg) mostly in the commencement minute of the trial as previously described (Zimmer et al, 2011). It is important to note that the IntA-FR animals had no timeouts inside their 5-min access period allowing them to cocky-administrate clusters of injections at the beginning of the access period in a similar manner every bit the IntA-Hard disk group.

Figure 2a illustrates the mean daily intake for each grouping during the 2-week test period. The data failed a examination for homogeneity of variance and normality and were therefore transformed to rank orders. A two-style repeated-measures analysis of variance (ANOVA) revealed a meaning DAYS effect (F(13, 406)=iv.19, p<0.001), and measures of the LgA group intake showed a 21.8% increase. No significant GROUP × DAYS interaction was observed. The average intake per session for each group is shown in Effigy 2b. A significant Group effect was observed (F(five, 32)=98.19, p<0.001) and a Holm–Sidak post-hoc exam revealed a meaning difference of the LgA group compared with each of the other groups. No other comparisons were statistically significant.

The average number of responses per session is shown in Figure 2c. The data set failed a test of homogeneity of variance, therefore a Kruskal–Wallis H-test was conducted instead of an ANOVA. A statistically pregnant Group outcome was observed (H (five)=31.73, p<0.001). A Dunns multiple comparison procedure revealed that the animals in the Thursday, HD, and IntA-Hard disk drive groups responded more than ShA animals. The TH and Hard disk groups also differed from the IntA-FR group.

Post-obit the ii-calendar week test period, during which each grouping self-administered on their respective schedules, all animals were tested using a inside-session TH procedure. Figure 3 shows representative event records for a ShA (top) and an IntA-HD subject (bottom). This comparison illustrates how animals might take like rates of responding in the early on function of the session just end responding at very different times (respective to different doses). The IntA-Hd animal increased its response charge per unit throughout the session compensating for the decrease in unit dose and connected responding into the eleventh bin, whereas the ShA creature ceased responding afterward the sixth bin. Hateful (±SEM) responses during each 10-min bin for every group are shown (Figure 3, bottom) illustrating the differences between groups in response rate during the Th schedule. These differences in intake were subjected to a behavioral economic analysis.

Figure 4 shows the behavioral economic analysis of information derived from the Th procedure. An instance session is shown in Figure 4a to illustrate the method used to determine Pmax. Responses (closed circles) and intake (open circles) are graphed during the 120-min session. Notation that the brute in this example maintained a stable intake during the start lxxx min of the session by increasing the response output in each sequent bin. In bin 8, the highest number of responses is observed, and all subsequent bins were marked by a failure to maintain stable cocaine intake. This inflection point (Pmax—dotted line) was adamant for each animal. Effigy 4b shows the boilerplate (±SEM) Pmax for each grouping. As the Pmax values were derived from an exponential series of doses, a log transform was performed on all data before ANOVA. This transform was necessary in society to encounter the requirement of homogeneity of variance.

A two role analysis was performed. The first addressed the various control atmospheric condition. The Thursday and Hd control groups were compared with the ShA group in order to test whether the Hard disk response pattern and/or the high rate of responding engendered by the TH and Hard disk procedures had an effect. No pregnant divergence was revealed by a one-fashion ANOVA (F(2, 17)=1.37, p=0.28). No statistically significant difference was observed between the IntA-Hd and IntA-FR groups (mean Pmax=480.half-dozen±114.7 and 480.1±96.2, respectively) and data from these 2 groups were combined in the subsequent analysis. The primal hypothesis that spiking blood levels would take a greater impact on Pmax relative to LgA and ShA was tested using a i-fashion ANOVA, which revealed a significant difference (F(2, 25)=13.07, p<0.001) betwixt groups. A Holm–Sidak postal service-hoc assay demonstrated that LgA and IntA animals had higher Pmax values than ShA, and IntA animals had college Pmax values than LgA animals.

Drug intake measured during early phases (ten–forty min) of the TH procedure yields a mensurate of consummatory responding relatively unconstrained by toll. A 2 part analysis was performed on the groups as described above. A 1-way ANOVA (F(2, 17) <1) on the 3 control groups (ShA, Thursday, and HD) revealed no pregnant differences in consumption during the early phase of the Th procedure. Similarly, a one-way ANOVA (F(ii, 25) <1) revealed no significant differences betwixt the main exam groups (ShA, LgA, and IntA).

Discussion

The present experiment was designed to test the hypothesis that IntA is sufficient to increment Pmax values, a behavioral economic mensurate of the motivation to self-administrate drug (Bickel et al, 1993; Hursh and Winger, 1995; Oleson et al, 2011; Oleson and Roberts, 2009). Half-dozen groups with histories of unlike self-assistants procedures, which produced very different patterns of drug intake and drug dynamics, were compared. Combined data from the two IntA groups (IntA-HD and IntA-FR) showed robust increases in Pmax relative to both ShA and LgA animals. These groups received 12 opportunities to self-administrate each day during 5-min trials separated by 25-min timeouts. Rats in these groups often self-administered large doses of cocaine (eg, >iii.0 mg/kg) unremarkably in the beginning of the trial and in a relatively short period of time (∼60 s). This design is consequent with our previous report (Zimmer et al, 2011) showing that rats rapidly cocky-administrate large doses of drug when blood levels have been forced to low levels. These results propose that rapid spiking of brain-cocaine levels is sufficient to increase Pmax.

The application of a well-established mathematical model for estimating cocaine levels in brain (Ahmed and Koob, 2005; Nicola and Deadwyler, 2000; Pan et al, 1991; Wise et al, 1995) helps illustrate the important differences between the groups during daily cocky-administration sessions. Brain concentrations of cocaine rose relatively rapidly in all groups at the kickoff of the session. This well-characterized phenomenon has been referred to as a loading stage (Wilson et al, 1971), and is typically followed by a maintenance phase during which drug levels are maintained within relatively narrow limits. In this study, four groups were immune to progress into the maintenance phase for varying lengths of time. The TH grouping maintained claret levels for but 60–90 min (depending on individual Pmax), the ShA and Hard disk groups maintained blood levels for two h, and the LgA group for half-dozen h. By contrast, the two IntA groups were exposed to a very dissimilar drug-level dynamic—that is, 12 distinct cocaine spikes within each half dozen-h session. This spiking design of intake was associated with the highest Pmax values. Annotation that equally the IntA procedures do not allow claret levels to be maintained, it would appear that sustained blood levels are not necessary and that spiking blood levels are sufficient to increase the maximum price paid for cocaine.

The hypothesis tested here that spiking cocaine levels might be important to the addiction procedure was prompted by both preclinical and clinical information. On the clinical side, textbooks and the research literature emphasize the importance of the 'rush' or intense subjective effects, which are mediated past larger doses and faster routes of administration (Seecof and Tennant, 1986; Kumor et al, 1989; Gorelick, 2009; Volkow and Li, 2009). Presumably, these intense intoxicating events increase the probability of future use. Over fourth dimension, individual or grouped intoxicating events can progress to a cyclical binge-abstinent style of intake (Gawin, 1991). The thought that 'binge-similar' intake is an of import part of the addiction process has prompted the evolution of rodent models that allow for daily 'binges' to occur, such as in the LgA process (Ahmed and Koob, 1998). What has been missing from the clinical literature is data on the pattern of drug utilise within a binge. A contempo survey of experienced cocaine users shows the interval between uses within a cocaine rampage might be, on average, well over an 60 minutes (Beveridge et al, 2012). Given the brusk half-life of cocaine (∼40 min; Javaid et al, 1983) in humans, these survey data advise that blood levels are not maintained throughout the binge menstruation just may decrease substantially betwixt each intoxicating event. Although more clinical data on dose size and inter-use interval inside a rampage would be helpful, information technology appears that fast-rising and subsequent decline in blood levels is a pattern that can lead individuals down the addiction bike.

The spiking cocaine-level hypothesis was as well suggested by recent preclinical data. A self-administration process that produces spiking brain levels in rats was developed in our lab while we were investigating the human relationship between the preferred dose of cocaine and drug levels in the brain (Zimmer et al, 2011). Animals were given access to drug during v-min trials, and, in lodge to force a pass up in claret levels, the trials were separated by timeout periods ranging from 10 to 25 min. The primary finding of the experiment was that the selected dose of cocaine was inversely related to claret levels. That is, rats selected relatively depression doses of drug when claret levels were high and selected very large doses (∼3 mg/kg/inj) of cocaine when claret levels were low. After completion of the experiment, animals were given access to cocaine on a progressive ratio (PR) schedule and were found to accept markedly elevated breakpoints (unpublished). Although we had no control grouping to compare results with, it appeared that animals that had experienced a spiking design of cocaine intake showed much higher breakpoints than was typically seen in our lab. This study represents an attempt to quantify the increases in motivation we observed relative to groups that self-administered cocaine with varying drug dynamics.

A within-session Thursday procedure was called to compare the effects of the unlike cocaine cocky-administration histories. This process was adapted from a between-session TH procedure in which a series of doses were tested on consecutive days (Oleson and Roberts, 2009; Zittel-Lazarini et al, 2007). The procedure involves giving access to cocaine on an FR1 schedule at a stock-still unit dose, which is reduced through a serial of 11 doses every 10 min (come across Materials and methods section). A behavioral economical assay of the response rate and drug intake at each interval yields measures of both consumption and maximum toll paid and thus affords the opportunity to investigate appetitive and consummatory aspects of cocky-administration within the same procedure. Consummatory behavior is reflected equally cocaine intake early on in the session (at loftier unit doses) when the response toll is low. Appetitive behavior is assessed later in the session by determining the everyman unit dose (ie, highest unit cost) that maintains consumption. Typically in self-administration studies, price is manipulated past property a drug dose abiding and increasing the response requirement (Cosgrove and Carroll, 2002; Wade-Galuska et al, 2007); nonetheless, fixing the response requirement and decreasing the available unit dose accomplishes the same thing (Bickel et al, 1990). Here, the decreasing series of unit doses resulted in an ascending serial of unit prices (2.four, 4.two, seven.five, 13, 24, forty, 77, 133, 244, 416, and 750 responses/mg). Pmax values are theoretically related to breakpoints derived from a PR schedule. Although the PR and TH procedures measure dissimilar aspects of appetitive behavior—work output to obtain a large bolus injection (PR) vs work output to maintain a constant claret level despite diminishing returns (TH)—there seems to be a high correlation betwixt the 2 dependent measures. Indeed, several pharmacological manipulations that have been shown to have an upshot on PR breakpoints such as haloperidol (Depoortere et al, 1993; Roberts et al, 1989) or baclofen (Roberts et al, 1996; Brebner et al, 2000) had a similar outcome on TH Pmax (Oleson et al, 2011). The PR breakpoint and the Th Pmax thus let detailed assessment of the relationship betwixt piece of work output and obtained reinforcement and together may exist particularly helpful in characterizing changes in drug intake produced by prolonged drug exposure (Vezina, 2004).

In the present experiments, spiking brain levels were produced using an IntA procedure with 2 dissimilar response requirements. The Hard disk response was first described by Morgan et al (2009) as an try to bypass unit dose and give the animal more control over the size and speed of injections. Animals appeared to titrate their blood levels within a narrow range and adjusted their response design to compensate changes beyond a 16-fold range of cocaine concentrations (Morgan et al, 2009). For comparing, we also included an IntA group reinforced under an FR1 schedule during the 5-min access periods. Information technology is important to note that no timeout was used with the FR1. Thus, animals were permitted to self-administer multiple injections (0.375 mg/kg/inf) inside a few seconds. The IntA-FR and IntA-HD groups showed similar intakes during the 5-min trials and across sessions. We institute no observable differences in intake or Pmax values between these two groups. Comparing the 2 IntA groups with controls also immune the states to rule out the possibility that the increment in Pmax was produced by overall cocaine intake (Figure 2b) or by high rates of responding (Effigy 2c). Therefore, the increases in Pmax observed in IntA animals are likely due to the spiking brain levels of cocaine throughout the session. Although the IntA-HD group offers some unique advantages in terms of data analysis (eg, selected dose size, speed), the IntA-FR schedule represents an easier method of generating the phenotype reported in this study.

The LgA procedure represents the best current model of escalation of intake. Animals in this paradigm reliably show increases in intake of xxx–40% over the course of two weeks (Ahmed and Koob, 1998). In most cases, this procedure has resulted in an increase in motivational measures such equally PR breakpoints (Paterson and Markou, 2003; Wee et al, 2008; but see Liu et al, 2005a; Quadros and Miczek, 2009) and drug-induced reinstatement responding (Mantsch et al, 2008). The event of LgA on Pmax appears to depend on procedural variables. We previously observed a subtract in Pmax in LgA animals using a between-session Th procedure (Oleson and Roberts, 2009). In that procedure, the dose of cocaine decreased each day over the course of eleven days. In this study, the entire dose-event bend was evaluated within a single session, and the LgA group showed an increase in Pmax. These ii TH procedures address dissimilar aspects of the motivation to self-administer cocaine. The within-session Thursday procedure allows animals to accept big loading doses of cocaine when the price is relatively inexpensive; the price then increases through the session. Pmax in this instance appears to measure out the maximal price a rat will pay to maintain brain levels of cocaine. By contrast, the between-session TH procedure effectively measures the maximal toll an animal will pay to load cocaine brain levels. It appears that LgA can, under some circumstances, produce an increase in some motivational measures.

Our conclusion, that spiking brain levels of cocaine produce an increment in the motivation to self-administer drug, depends on the accurateness of the mathematical model used to estimate brain-cocaine concentrations. The equation used by Pan et al (1991) is based on standard pharmacokinetic principles that have been validated for many dissimilar drugs and in many unlike systems (Karan et al, 2009). However, the specific variables used to represent rat claret volume, cocaine redistribution and deposition must exist verified in order to have confidence in applying the equation to this written report. Fortunately, use of this model has been widespread. Many cocky-administration studies accept applied the equation to estimate brain concentrations of cocaine in alive animals (Ahmed and Koob, 2005; Samaha et al, 2002; Zernig et al, 2007; Zimmer et al, 2011), and the equations have also been applied in studies using electrophysiology (Nicola and Deadwyler, 2000; Peoples and Cavanaugh, 2003; Peoples et al, 2004, 2007), microdialysis (Wise et al, 1995) and voltammetry (Hermans et al, 2008; Stuber et al, 2005a, 2005b). These studies have demonstrated that the modeled brain-cocaine concentrations are highly correlated with NAc dopamine levels (Hermans et al, 2008; Shou et al, 2006; Wise et al, 1995) as well as cocaine-induced locomotor behavior (Shou et al, 2006).

An extensive literature has demonstrated that continuous vs intermittent administration of psychostimulant drugs produces very different consequences on beliefs and neurochemistry (for review, see Robinson and Berridge, 2008). For case, it has been shown that daily injections of cocaine induce long-lasting behavioral sensitization whereas continuous (minipump) administration produces behavioral tolerance (Reith et al, 1987; King et al, 1992). Differences in neurochemistry have also been shown, such as subsensitivity or supersensitivity of the D2 autoreceptor post-obit intermittent or continuous administration of cocaine respectively (Jones et al, 1996). Intermittency typically refers to daily or every-other-day assistants of drug; however, the present data propose that the theoretical intermittency/continuous stardom might reasonably apply to six-h cocaine self-administration sessions. Given that a 25-min timeout menstruation allows for a ∼90% clearance of cocaine, the twelve 5-min access periods used here would plant an intermittent dosing regimen; a 6-h LgA session would more closely correspond continuous drug delivery. It has been suggested that continuous assistants is the ameliorate model of a man binge (eg, Rex et al, 1994) based on the supposition that addicts self-administrate at frequencies that effect in sustained cocaine levels. Nevertheless, recent clinical studies have challenged this assumption (Beveridge et al, 2012; come across Introduction section). In fact, the design of homo intake may more closely resemble intermittent administration. Future studies will be necessary to fully characterize the role of intermittency on the transition to drug addiction likewise as the underlying neurobiological mechanisms involved.

Here, we report that the schedules that induce both fast ascent-times and large fluctuations in encephalon-cocaine concentrations produce the most robust increases in motivation to self-administer cocaine. The observed increases in Pmax could not be deemed for by intake, contingency or rates of responding. Measures of Pmax were higher in IntA animals than LgA animals, indicating that when information technology comes to producing an increase in motivation the pattern of intake is likely more important than the total corporeality consumed.

References

Ahmed SH (2005). Imbalance between drug and non-drug reward availability: a major risk factor for addiction. Eur J Pharmacol 526: 9–20.

CAS Article Google Scholar
Ahmed SH, Koob GF (1998). Transition from moderate to excessive drug intake: change in hedonic fix indicate. Science 282: 298–300.

CAS Commodity Google Scholar
Ahmed SH, Koob GF (1999). Long-lasting increase in the set betoken for cocaine self-administration afterwards escalation in rats. Psychopharmacology (Berl) 146: 303–312.

CAS Commodity Google Scholar
Ahmed SH, Koob GF (2005). Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward part. Psychopharmacology (Berl) 180: 473–490.

CAS Commodity Google Scholar
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC.
Beveridge TJR, Wray P, Brewer A, Shapiro B, Mahoney JJ, Newton TF et al (2012). Analyzing Man Cocaine Use Patterns to Inform Animal Habit Model Development. Published abstract for the College on Issues of Drug Dependence Annual Meeting, Palm Springs, CA.

Google Scholar
Bickel WK, DeGrandpre RJ, Higgins ST (1993). Behavioral economics: a novel experimental arroyo to the study of drug dependence. Drug Alcohol Depend 33: 173–192.

CAS Article Google Scholar
Bickel WK, DeGrandpre RJ, Higgins ST, Hughes JR (1990). Behavioral economics of drug cocky-assistants. I. Functional equivalence of response requirement and drug dose. Life Sci 47: 1501–1510.

CAS Article Google Scholar
Brebner K, Phelan R, Roberts DCS (2000). Effect of baclofen on cocaine self-assistants in rats reinforced under stock-still-ratio 1 and progress-ratio schedules. Psychopharmacol Berl 148: 314–321.

CAS Article Google Scholar
Cosgrove KP, Carroll ME (2002). Effects of bremazocine on cocky-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economical assay. J Pharmacol Exp Ther 301: 993–1002.

CAS Article Google Scholar
Depoortere RY, Li DH, Lane JD, Emmet-Oglesby MW (1993). Parameters of cocky-administration of cocaine in rats under a progress-ratio schedule. Pharmacol Biochem Behav 45: 539–548.

CAS Article Google Scholar
Espana RA, Oleson EB, Locke JL, Brookshire BR, Roberts DCS, Jones SR (2010). The hypocretin-orexin system regulates cocaine cocky-assistants via actions on the mesolimbic dopamine system. Eur J Neurosci 31: 336–348.

Article Google Scholar
Ettenberg A, Pettit HO, Bloom Atomic number 26, Koob GF (1982). Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology (Berl) 78: 204–209.

CAS Article Google Scholar
Gawin FH (1991). Cocaine addiction: psychology and neurophysiology. Science 251: 1580–1586.

CAS Article Google Scholar
Gorelick DA (2009). The pharmacology of cocaine, amphetamines, and other stimulants. In: Ries RK, Fiellin DA, Miller SC, Saitz R (eds). Principles of Addiction Medicine, quaternary edn. Lippincott Williams & Wilkins: Philadelphia, PA, pp 133–157.

Google Scholar
Grimm JW, Hope BT, Wise RA, Shaham Y (2001). Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412: 141–142.

CAS Article Google Scholar
Hermans A, Keithley RB, Kita JM, Sombers LA, Wightman RM (2008). Dopamine detection with fast-scan circadian voltammetry used with analog groundwork subtraction. Anal Chem 80: 4040–4048.

CAS Article Google Scholar
Hursh SR (1991). Behavioral economics of drug self-administration and drug abuse policy. J Exp Anal Behav 56: 377–393.

CAS Commodity Google Scholar
Hursh SR, Winger G (1995). Normalized demand for drugs and other reinforcers. J Exp Anal Behav 64: 373–384.

CAS Commodity Google Scholar
Javaid JI, Musa MN, Fischman M, Schuster CR, Davis JM (1983). Kinetics of cocaine in humans later on intravenous and intranasal administration. Biopharm Drug Dispos four: ix–eighteen.

CAS Commodity Google Scholar
Jones SR, Lee Thursday, Wightman RM, Ellinwood EH (1996). Effects of intermittent and continuous cocaine administration on dopamine release and uptake regulation in the striatum: in vitro voltammetric assessment. Psychopharmacology (Berl) 126: 331–338.

CAS Article Google Scholar
Karan LD, McCance-Katz E, Zajicek A (2009). Pharmacokinetic and pharmacodynamic principles. In: Ries RK, Fiellin DA, Miller SC, Saitz R (eds). Principles of Addiction Medicine, 4th edn. Lippincott Williams & Wilkins: Philadelphia, PA, pp 133–157.

Google Scholar
King GR, Joyner C, Ellinwood Jr EH (1994). Continuous or intermittent cocaine administration: effects of flupenthixol treatment during withdrawal. Pharmacol Biochem Behav 49: 883–889.

CAS Commodity Google Scholar
King GR, Joyner C, Lee T, Kuhn C, Ellinwood Jr EH (1992). Intermittent and continuous cocaine administration: residual behavioral states during withdrawal. Pharmacol Biochem Behav 43: 243–248.

CAS Article Google Scholar
Koob G, Kreek MJ (2007). Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164: 1149–1159.

Commodity Google Scholar
Koob GF, Volkow ND (2010). Neurocircuitry of addiction. Neuropsychopharmacology 35: 217–238.

Article Google Scholar
Kumor KM, Sherer MA, Gomez J, Cone E, Jaffe JH (1989). Subjective response during continuous infusion of cocaine. Pharmacol Biochem Behav 33: 443–452.

CAS Commodity Google Scholar
Liu Y, Morgan D, Roberts DCS (2007). Cantankerous-sensitization of the reinforcing furnishings of cocaine and amphetamine in rats. Psychopharmacology (Berl) 195: 369–375.

CAS Article Google Scholar
Liu Y, Roberts DCS, Morgan D (2005a). Furnishings of extended-access cocky-administration and deprivation on breakpoints maintained by cocaine in rats. Psychopharmacology (Berl) 179: 644–651.

CAS Article Google Scholar
Liu Y, Roberts DCS, Morgan D (2005b). Sensitization of the reinforcing effects of self-administered cocaine in rats: effects of dose and intravenous injection speed. Eur J Neurosci 22: 195–200.

Article Google Scholar
Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP (2008). Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented post-obit long-access cocaine cocky-administration past rats. Psychopharmacology (Berl) 195: 591–603.

CAS Commodity Google Scholar
Morgan D, Brebner 1000, Lynch WJ, Roberts DCS (2002). Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement. Behav Pharmacol thirteen: 389–396.

CAS Article Google Scholar
Morgan D, Liu Y, Oleson EB, Roberts DCS (2009). Cocaine self-assistants on a hold-down schedule of reinforcement in rats. Psychopharmacology (Berl) 201: 601–609.

CAS Commodity Google Scholar
Morgan D, Roberts DCS (2004). Sensitization to the reinforcing effects of cocaine following binge-abstemious self-administration. Neurosci Biobehav Rev 27: 803–812.

CAS Commodity Google Scholar
Nicola SM, Deadwyler SA (2000). Firing charge per unit of nucleus accumbens neurons is dopamine-dependent and reflects the timing of cocaine-seeking beliefs in rats on a progressive ratio schedule of reinforcement. J Neurosci xx: 5526–5537.

CAS Commodity Google Scholar
Oleson EB, Richardson JM, Roberts DCS (2011). A novel Iv cocaine self-administration procedure in rats: differential effects of dopamine, serotonin, and GABA drug pre-treatments on cocaine consumption and maximal price paid. Psychopharmacology (Berl) 214: 567–577.

CAS Article Google Scholar
Oleson EB, Roberts DCS (2009). Behavioral economic cess of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake. Neuropsychopharmacology 34: 796–804.

Article Google Scholar
Pan HT, Menacherry South, Justice Jr JB (1991). Differences in the pharmacokinetics of cocaine in naive and cocaine-experienced rats. J Neurochem 56: 1299–1306.

CAS Article Google Scholar
Paterson NE, Markou A (2003). Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport xiv: 2229–2232.

CAS Commodity Google Scholar
Peoples LL, Cavanaugh D (2003). Differential changes in signal and background firing of accumbal neurons during cocaine cocky-administration. J Neurophysiol ninety: 993–1010.

CAS Article Google Scholar
Peoples LL, Kravitz AV, Lynch KG, Cavanaugh DJ (2007). Accumbal neurons that are activated during cocaine self-administration are spared from inhibitory effects of repeated cocaine cocky-administration. Neuropsychopharmacology 32: 1141–1158.

CAS Commodity Google Scholar
Peoples LL, Lynch KG, Lesnock J, Gangadhar Northward (2004). Accumbal neural responses during the initiation and maintenance of intravenous cocaine self-administration. J Neurophysiol 91: 314–323.

Article Google Scholar
Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y (2011). Neurobiology of the incubation of drug craving. Trends Neurosci 34: 411–420.

CAS Article Google Scholar
Quadros IM, Miczek KA (2009). Two modes of intense cocaine bingeing: increased persistence later on social defeat stress and increased charge per unit of intake due to extended access atmospheric condition in rats. Psychopharmacology (Berl) 206: 109–120.

CAS Article Google Scholar
Reith MEA, Benuck Grand, Lajtha A (1987). Cocaine disposition in the brain afterwards continuous or intermittent treatment and locomotor stimulation in mice. J Pharmacol Exp Ther 243: 281–287.

CAS PubMed PubMed Central Google Scholar
Roberts DCS, Andrews MM, Vickers GJ (1996). Baclofen attenuates the reinforcing effects of cocaine in rats. Neuropsychopharmacology 15: 417–423.

CAS Article Google Scholar
Roberts DCS, Loh EA, Vicerks Chiliad (1989). Self-adminsitration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment. Psychopharmacol (Berl) 97: 535–538.

CAS Article Google Scholar
Roberts DCS, Morgan D, Liu Y (2007). How to make a rat addicted to cocaine. Prog Neuropsychopharmacol Biol Psychiatry 31: 1614–1624.

CAS Article Google Scholar
Robinson TE, Berridge KC (2008). Review. The incentive sensitization theory of habit: some current bug. Philos Trans R Soc Lond B Biol Sci 363: 3137–3146.

Commodity Google Scholar
Samaha AN, Li Y, Robinson TE (2002). The charge per unit of intravenous cocaine assistants determines susceptibility to sensitization. J Neurosci 22: 3244–3250.

CAS Commodity Google Scholar
Seecof R, Tennant Jr FS (1986). Subjective perceptions to the intravenous ″rush″ of heroin and cocaine in opioid addicts. Am J Drug Alcohol Abuse 12: 79–87.

CAS Commodity Google Scholar
Shou M, Ferrario CR, Schultz KN, Robinson TE, Kennedy RT (2006). Monitoring dopamine in vivo by microdialysis sampling and on-line CE-light amplification by stimulated emission of radiation-induced fluorescence. Anal Chem 78: 6717–6725.

CAS Article Google Scholar
Stuber GD, Roitman MF, Phillips PE, Carelli RM, Wightman RM (2005a). Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration. Neuropsychopharmacology 30: 853–863.

CAS Article Google Scholar
Stuber GD, Wightman RM, Carelli RM (2005b). Extinction of cocaine cocky-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens. Neuron 46: 661–669.

CAS Article Google Scholar
Vanderschuren LJ, Everitt BJ (2004). Drug seeking becomes compulsive afterward prolonged cocaine self-administration. Science 305: 1017–1019.

CAS Article Google Scholar
Vezina P (2004). Sensitization of midbrain dopamine neuron reactivity and the cocky-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27: 827–839.

CAS Article Google Scholar
Volkow ND, Li TK (2009). Drug habit: the neurobiology of behavior gone amiss. In: Ries RK, Fiellin DA, Miller SC, Saitz R (eds). Principles of Addiction Medicine, 4th edn. Lippincott Williams & Wilkins: Philadelphia, PA, pp 133–157.

Google Scholar
Wade-Galuska T, Winger G, Woods JH (2007). A behavioral economic assay of cocaine and remifentanil self-administration in rhesus monkeys. Psychopharmacology (Berl) 194: 563–572.

CAS Article Google Scholar
Wakabayashi KT, Weiss MJ, Pickup KN, Robinson TE (2010). Rats markedly escalate their intake and show a persistent susceptibility to reinstatement only when cocaine is injected rapidly. J Neurosci 30: 11346–11355.

CAS Commodity Google Scholar
Wee Southward, Mandyam CD, Lekic DM, Koob GF (2008). Blastoff 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access. Eur Neuropsychopharmacol 18: 303–311.

CAS Commodity Google Scholar
Wilson MC, Hitomi G, Schuster CR (1971). Psychomotor stimulant self administration every bit a function of dosage per injection in the rhesus monkey. Psychopharmacologia 22: 271–281.

CAS Commodity Google Scholar
Wise RA, Newton P, Leeb Grand, Burnette B, Pocock D, Justice Jr JB (1995). Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology (Berl) 120: 10–20.

CAS Article Google Scholar
Zernig Grand, Ahmed SH, Cardinal RN, Morgan D, Acquas East, Foltin RW et al (2007). Explaining the escalation of drug employ in substance dependence: models and appropriate animal laboratory tests. Pharmacology 80: 65–119.

CAS Article Google Scholar
Zimmer BA, Dobrin CV, Roberts DCS (2011). Encephalon-cocaine concentrations determine the dose self-administered by rats on a novel behaviorally dependent dosing schedule. Neuropsychopharmacology 36: 2741–2749.

CAS Article Google Scholar
Zittel-Lazarini A, Cador M, Ahmed SH (2007). A critical transition in cocaine self-administration: behavioral and neurobiological implications. Psychopharmacology (Berl) 192: 337–346.

CAS Article Google Scholar

Download references

Acknowledgements

This study was supported by the NIDA research Grants R01 DA14030 (DCSR), P50 DA06634 and R21 DA029405 (Freeman). The excellent technical assistance of Leanne N Thomas and Holly V Buben is gratefully acknowledged.

Author information

Writer notes

Erik B Oleson

Present accost: 3Current accost: Department of Anatomy and Neurobiology, University of Maryland Schoolhouse of Medicine, Baltimore, Physician, Us,
Benjamin A Zimmer and Erik B Oleson: These authors contributed equally to this work.

Affiliations

Neuroscience Program, Wake Forest Academy Health Sciences, Winston-Salem, NC, The states

Benjamin A Zimmer & Erik B Oleson
Section of Physiology and Pharmacology, Wake Forest University Wellness Sciences, Winston-Salem, NC, USA

Benjamin A Zimmer, Erik B Oleson & David CS Roberts

Corresponding author

Correspondence to Benjamin A Zimmer.

Ethics declarations

Competing interests

The authors declare no disharmonize of involvement.

PowerPoint slides

Rights and permissions

Almost this article

Cite this article

Zimmer, B., Oleson, Due east. & Roberts, D. The Motivation to Self-Administrate is Increased After a History of Spiking Brain Levels of Cocaine. Neuropsychopharmacol 37, 1901–1910 (2012). https://doi.org/x.1038/npp.2012.37

Download citation

Received: 28 Dec 2011
Revised: 17 Feb 2012
Accepted: 27 February 2012
Published: 28 March 2012
Issue Engagement: July 2012
DOI : https://doi.org/ten.1038/npp.2012.37

Keywords

cocaine
self-assistants
spiking
loading
maintenance
behavioral economic science