Evidence for learned skill during cocaine self-administration in rats. more

Psychopharmacology DOI 10.1007/s00213-011-2261-0 ORIGINAL INVESTIGATION Evidence for learned skill during cocaine self-administration in rats David H. Root & David J. Barker & Sisi Ma & Kevin R. Coffey & Anthony T. Fabbricatore & Mark O. West Received: 31 December 2010 / Accepted: 8 March 2011 # Springer-Verlag 2011 Abstract Rationale It has been proposed that cocaine abuse results in skilled or “automatic” drug-taking behaviors. Brain regions important for skill learning are implicated in cocaine selfadministration. However, the development of skill during self-administration has not been investigated. Objectives The present experiment investigated the development of skilled self-administration over extended drug use by employing a novel operant vertical head movement under discriminative stimulus (SD) control. In addition, the capacity of the head movement to serve as an operant was tested by manipulating drug levels above or below satiety drug levels via frequent noncontingent microinfusions (0.2 s) of cocaine. Results Animals acquired the vertical head movement operant, which increased in number over days. Task learning was demonstrated by reduced reaction time in response to the SD, increased propensity to self-administer upon SD presentation, and escalated drug consumption over days. Skill learning was demonstrated by (1) an increase over days in the velocity of operant movements, as a function of shorter duration but not altered distance, and (2) an increase over days in the probability of initiating the operant at the optimal starting position. Evidence that responding was specific to self-administration was revealed during periods of experimenter-manipulated drug level: maintaining drug levels above satiety decreased responding while maintaining drug levels below satiety increased responding. Conclusions Under the specific set of circumstances tested herein, cocaine self-administration became skilled over extended drug use. The vertical head movement can be used as an operant comparable to lever pressing with the additional benefit of quantifying skill learning. Keywords Striatum . Putamen . Accumbens . Pallidum . Habit . Abuse Abbreviations SD Discriminative stimulus DLS Dorsolateral striatum Introduction This research has been funded by grants from the National Institute on Drug Abuse; Contract grant numbers: DA 006886 DA 029873, DA 026252. D. H. Root : D. J. Barker : S. Ma : K. R. Coffey : A. T. Fabbricatore : M. O. West Department of Psychology, Rutgers University, New Brunswick, NJ 08903, USA M. O. West (*) Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ 08854, USA e-mail: markwest@rutgers.edu A seminal paper by Tiffany (1990) proposed that over extended drug use self-administration behavior becomes largely “automatic”, as demonstrated by skilled selfadministration. The rodent dorsolateral striatum (DLS), homologous with the primate putamen (Carelli and West 1991), is implicated in skill learning (Tang et al. 2007, 2009) as well as cocaine self-administration (Letchworth et al. 2001; Vanderschuren et al. 2005; Fuchs et al. 2006; Volkow et al. 2006, 2008). However, empirical tests of the existence of skilled drug self-administration behavior are lacking and are necessary if these views are to advance the Psychopharmacology neurobiological understanding of drug abuse. In order to investigate whether self-administration becomes skilled over extended drug use, animals self-administered cocaine 6 h every day for 3 weeks by using a novel vertical head movement as the operant. Instead of an all-or-none lever press, the vertical head movement enabled measurements of changes in distance, duration, velocity, start and end positions of operant responses as a function of training, as well as recording partial responses. Furthermore, given that animals will inhibit lever pressing when drug levels are maintained above satiety but increase lever pressing when drug levels are maintained below satiety (Pickens and Thompson 1968; Norman and Tsibulsky 2006), we tested whether animals’ use of the vertical head movement during cocaine self-administration was similar to that of the lever press. administration training ~8 days following surgery. Except during self-administration, water was available ad libitum. Standard rat lab chow was provided following daily selfadministration to maintain body weights approximately between 325 and 335 g. Protocols were performed in compliance with the Guide for the Care and Use of Laboratory Animals (NIH Publications 865–23) and were approved by the Institutional Animal Care and Use Committee, Rutgers University. Procedure Vertical head movements were tracked using six infraredemitting diodes capable of transistor-transistor logic (HOA6299, Honeywell, Morristown, NJ). The light of each photocell was contained within a 5.59-mm diameter beam at 880 nm wavelength, outside the visual spectrum of the rat retina under normal illuminated conditions (Green 1971; Pardue et al. 2001). Six photocells and the opposing six diodes were arranged along a 50° arc over 69 mm and attached outside the clear Plexiglas walls in one corner of the self-administration chamber. This arrangement enabled us to condition instrumental head movements that approximate the vertical head movements in a prior water selfadministration task (Fig. 1; Tang et al. 2007) in which operant head movements became skilled and habitual. Since the photocells were arranged vertically in the corner, horizontal or slanted movements were restricted. All photocell beam breaks were recorded for offline analysis of different movements using custom Matlab scripts. Except during self-administration or testing sessions, a rectangular opaque Plexiglas block (approximately 50 mm×50 mm×200 mm) was attached inside the chamber to block access to the “photocell corner” to prevent any possible extinction learning. An experiment flow chart is displayed in Fig. 2. Selfadministration began daily (7 days a week for 3 weeks) Methods Subjects and surgery Male Long–Evans rats (n=13; 325–335 g; Charles River, Wilmington, MA) were implanted with a catheter in the right jugular vein while deeply anesthetized (sodium pentobarbital, 50 mg/kg, i.p). Prior to surgery, subjects received injections of atropine methyl nitrate (10 mg/kg, i.p.) and penicillin G (75,000 U/0.25 ml, i.m.) in order to protect subjects from airway congestion and infection, respectively. Anesthesia was maintained with periodic injections of ketamine hydrochloride (60 mg/kg, i.m.). Following surgery and for the remainder of the experiment, animals were housed in Plexiglas self-administration chambers with the catheter connected to a fluid swivel. They were perfused with 0.2 ml heparinized bacteriostatic saline (0.9%) every 25 min to maintain catheter patency, except during self-administration. Rats started self- Fig. 1 Head-movement apparatus. Numbers refer to photocell number and are always located on the “receiving” photocell. Apparatus is shown with a front view (a), side view (b), and mounted to the rear corner of the chamber (“photocell corner”) in its operative position outside the chamber (c) Psychopharmacology Fig. 2 Experimental flow diagram. Following recovery from surgery, animals trained on the vertical head movement self-administration paradigm for 21 days. Subsequent to training, animals received two counterbalanced tests, the supra-satiety or sub-satiety tests, separated by a training session with the onset of the house light and removal of the Plexiglas block that prohibited access to the photocell corner. At the beginning of the first day of training, vertical head movements in the photocell corner were shaped via delivery of cocaine HCl infusion (0.24 mg/0.2 ml/inf) in the presence of the discriminative stimulus (SD; 3.5 kHz, 70 dB). The shaping process began with reinforcing a nose poke response into the photocell corner (breaking photocell 2) for several instances, then reinforcing an upward movement that consecutively breaks photocells 2 and 3 within 1 s for several instances. Shaping continued by reinforcing movements consecutively breaking photocells 2, 3, and 4 within 1 s, for several instances, and lastly reinforcing the final contingency of consecutively breaking photocells 2, 3, 4, and 5 within 1 s (termed “criterion head movement”). The criterion head movement required at least a 43.4 mm movement along the arc, starting at or below the second photocell beam (13.5 mm from the floor) and crossing at least the fifth photocell. During shaping days, prior to the first selfinfusion, the SD was continuously sounded until a single response (breaking photocell 2) was made, at which time the SD was terminated, cocaine was delivered, and a 40-s timeout period began. Following the first self-infusion, the SD was sounded for 2 min or until a single response was made that satisfied the current shaping criterion, at which time the SD was terminated and cocaine was delivered. All time-out periods following the first shaping self-infusion were 10 s and the SD was presented again following the end of each time out. Shaping was considered complete following three self-infusions at the criterion head movement. Criterion movements within the time-out period of training or testing sessions were recorded but had no programmed consequence. Shaping sessions were between 4 and 6 h in duration. Normal training began at the start of the subsequent training session, following acquisition of the criterion head movement (typically 1–2 days). Normal training consisted of SD presentations for 2 min (limited hold) or until an operant response was emitted. To allow for rapid “loading” infusions, until the tenth self-infusion, the time out period was a fixed 40-s interval. All subsequent (maintenance) time out periods were pseudorandomly selected from a 30-item Fleshler–Hoffman (Fleshler and Hoffman 1962) distribution on a variable interval 1–6 min schedule. Regardless of “loading” or “maintenance” time out conditions, a criterion head movement during SD presentation produced an intravenous infusion of cocaine (0.24 mg/0.2 ml/inf), terminated the SD, and started the time out period. Given that the median inter-infusioninterval under free-access conditions at the present dose (approximately 0.77 mg/kg/inf) is 7.5 min (Fabbricatore et al. 2010), the 1–6 min time-out was designed to allow animals the ability to attain drug satiety levels (see next paragraph). Specifically, the 1–6-min time-out schedule was used in an attempt to balance the animal’s suprasatiety and subsatiety experiences such that rats would experience both conditions prior to the suprasatiety and subsatiety tests. Self-administration sessions ended after 6 h elapsed or 80 infusions were earned, whichever occurred first. Rats were never “primed”, i.e., noncontingently administered infusions of cocaine to initiate self-administration. Following the last self-administration training day, subjects were tested for sensitivity to high (n=12) or low drug levels (n=12) with an ABA design termed the suprasatiety and subsatiety tests, respectively. All phases were 2 h in duration, totaling 6 h. During the initial A phase of the suprasatiety test, animals self-administered cocaine under normal training conditions for 2 h. At the start of the third hour of self-administration (onset of B phase), the animal’s drug level was clamped by microinfusions (0.2 s) administered at an inter-infusion-interval adjusted for each animal (average and SEM: 8.96±0.54 s) to maintain drug levels at 0.1 mg/kg above satiety. Drug satiety (Wise et al. 1995) was operationally defined as a drug level 0.1 mg/kg above the animal’s peak drug level during the initial A phase. SD presentations continued at the same rate as the A phase (1 to 6 min) with all contingencies programmed Psychopharmacology the same as the A phase. All contingencies were left intact during the B phase because the alternative, extinction conditions, could potentially inflate responding by an extinction burst, or potentially deflate responding by extinction learning. At the start of the fifth hour of self-administration (onset of the second A phase), microinfusions were terminated and all other contingencies were unchanged, i.e., a resumption of the same conditions as during the first 2 h of the test (initial A phase). The within-subjects “subsatiety” control test was conducted to examine the effect of noncontingent infusions on behavioral measures with an ABA design. During the initial A phase of the subsatiety test, animals self-administered cocaine under normal training conditions for 2 h. At the start of the third hour of self-administration (onset of B phase), the animal’s drug level was clamped by: (a) presenting the SD at elongated intervals (between 21 and 29 min) derived from subjects’ performance in the initial A phase, which prevented the animal from achieving satiety; and (b) administering microinfusions (0.2 s) at an interinfusion-interval adjusted for each animal (average ± SEM, 20.82±0.56 s; significantly longer than suprasatiety intervals, t(10)=−12.95, p<10−6), which prevented drug levels from falling below 2–2.5 mg/kg. All operant contingencies were left intact during the B phase. At the start of the fifth hour (onset of the second A phase), microinfusions were terminated, SD presentations were returned to the same conditions (1–6 min) as in the initial A phase, and all other contingencies were unchanged. The order of suprasatiety and subsatiety tests was counterbalanced between animals and separated by a self-administration session under normal training conditions. Drug level calculation Assuming first-order pharmacokinetics, calculated drug level (milligrams per kilogram body weight) was determined over successive infusions by the equation: Bn ¼ ðBnÀ1 þ DÞeÀKTn (Yokel and Pickens 1974) where Tn D Bn−1 K the time since the previous cocaine infusion (min) infusion dose/bodyweight (mg/kg) cocaine level at time of last infusion (mg/kg) rate constant of 0.028875, reflecting a 0.4-h metabolic half-life for cocaine (Nayak et al. 1976). test, the target drug level between 2–2.5 mg/kg was entered into both Bn and Bn−1 terms. For both tests, D was defined as 0.0189 mg (dose per infusion at 0.2 s pump duration) divided by bodyweight (kg). Given that the rate constant of 0.028875 was entered into term K, interval Tn was arithmetically solved. Statistical analysis Outcome variables, e.g., criterion head movements, selfadministered milligrams per kilogram per day, etc., were analyzed as a function of training day or testing phase using repeated measures ANOVAs (PASW 18.0.0, SPSS, Chicago, IL). For analyzing test results, data were taken from the second hour of each 2-h phase in order to remove the influence of initially changing drug levels (e.g., loading behavior in the first A phase and the effects of the satiety clamp in the second A phase). Pairwise comparisons (least squares difference) were computed for significant main effects of testing phase to assess differences between phases. Alpha criterion for all tests was 0.05. Reaction time was defined as the daily average of all differences in time between the end of a criterion head movement and preceding SD presentation (onset). Hit probability was calculated by a daily fraction in which the numerator was number of self-infusions and the denominator was number of SD presentations. To determine escalation of intake, the time of the tenth self-infusion and total consumption (mg/kg) of cocaine were determined each day. Four animals did not reach ten infusions on day 1. These data points were included as missing data points in the repeated measures ANOVA. Results Animals self-administered cocaine using the discrete SD paradigm, in which SD presentation at 1–6 min intervals set the occasion for every cocaine infusion. In response to the SD, average daily reaction time (hits only) decreased over days of self-administration training (Fig. 3a), F(2,240)= 4.38, p<10−7. The probability of self-administering cocaine upon SD presentation also increased over days (Fig. 3b), F(2,240)=21.062, p<10−41, to a value of 0.68±0.03 (mean± SEM) hit probability on the final training day. If one assumes that a miss reflects a suprasatiety drug level on that trial, this result suggests animals gained both subsatiety and suprasatiety experience during training. Furthermore, animals escalated their daily consumption of cocaine (Fig 3c; F(2,240)=0.305, p<10−21) as well as decreased their latency to load up to high drug levels (Fig. 3d; F(2,160)=2.150, p<0.01) over days of training. The number of criterion head movements increased over days (Fig. 3e), F(2,240)=6.375, p<10−12. The number of Using this formula, custom infusion intervals were determined for phase B during suprasatiety and subsatiety tests. For the suprasatiety test, the target satiety drug level was entered into both Bn and Bn−1 terms. For the subsatiety Psychopharmacology Fig. 3 Self-administration and cue learning. Reaction time in response to the SD (a), probability of self-administering cocaine upon SD presentation (b), cocaine consumption (c), latency to load up to the tenth infusion (d), number of criterion movements (e), and number of inverse criterion movements (f). Values are average±SEM (y axes) per day (x axes) vertical head movements initiated at photocells 1 or 2 that were less than the criterion head movement distance did not change over days. The number of inverse criterion movements (downward movements starting at or above photocell 5 and ending at or below photocell 2) did not change over days (Fig. 3f, black circles). These results suggest that animals learned to discriminate the upward criterion head movement as the operant. One animal was an outlier with regard to inverse criterion movements. For this rat, stereotypical movements included a downward (but not upward criterion) movement within the photocell corner. The number of inverse criterion movements with the outlier animal removed (Fig. 3f, white circles) did not change over days. All other animals exhibited a locus of stereotypy away from the photocell corner. Moreover, the stereotypyinducing properties of cocaine did not interfere with criterion head movements: during week 3, a comparatively longer latency (average ± SEM 30.22±8.09 s) was observed between a criterion head movement and the subsequent head movement than would be expected from stereotypical head movements (e.g. “head-bobbing” at several head movements per second). After shaping was complete, criterion head movements gradually became more efficient and skilled over training Psychopharmacology days, although this was not required (i.e., the programmed criterion movement never changed). Over days of training, the average daily criterion head movement increased in average velocity, i.e., distance/duration (Fig. 4a) (F(2,240)= 13.250, p<10−27) via primarily a decrease in duration (Fig. 4b; F(2,240)=14.314, p<10−29) rather than a change in total distance (Fig. 4c). The most efficient criterion movement was one that began at photocell 2 and ended at photocell 5. The probability of a criterion movement starting at photocell 2 increased over days (Fig. 4d; F(2,240)=3.98, p<10−6) but the probability of ending at photocell 5 did not change (Fig. 4e). Fig. 4 Skill learning: changes in criterion head movement characteristics with extensive repetition. Changes in velocity (a), duration (b), distance (c), probability of starting at photocell two, the minimum required for a criterion movement (d), and the probability of ending at photocell 5 (e). Values for a, b, and c are average median±SEM per day for criterion head movements (y axes). Values for d and e are average probability ±SEM. All x axes refer to training day In order to test whether the frequency of criterion head movements was sensitive to drug level manipulations, animals underwent a suprasatiety test using an ABA design. The repeated measures ANOVA yielded a significant main effect of test phase for criterion head movements, F(2, 22)= 17.260, p<10−4 (Fig. 5; black circles). Pairwise comparisons revealed that the number of criterion head movements during the suprasatiety B phase significantly decreased below that observed during the initial A phase (p<10−3) and significantly increased during the second A phase compared with the B phase (p<10−5) but not the initial A phase. The average±SEM drug levels during the supra- Psychopharmacology Fig. 5 Drug level testing. Average criterion head movements during the suprasatiety test (black circles) or subsatiety test (white circles). Values are average±SEM criterion movements per specified phase (x axis, initial A phase, B phase, second A phase) satiety phases were 4.90±0.35 mg/kg during the initial A phase, 6.67±0.37 mg/kg during the suprasatiety B phase, and 4.98±0.33 mg/kg in the second A phase. Animals underwent similar testing when drug level was clamped below satiety levels. A repeated measures ANOVA yielded a significant main effect of test phase for criterion head movements (Fig. 5; white circles), F(2, 22)= 24.434, p<10−5. In spite of noncontingent infusions of cocaine, experimentally maintaining drug levels below satiety significantly increased criterion head movements (pairwise comparison p<10−3) during the subsatiety B phase, when compared with the initial A phase. Animals significantly decreased criterion head movements (p<10−3) during the second A phase compared with the B phase but did not differ in comparison to the first A phase. The average±SEM drug levels were 5.06±0.29 mg/kg during the initial A phase, 3.66±0.08 mg/kg during the subsatiety B phase, and 4.66±0.20 mg/kg in the second A phase. Discussion Animals acquired drug self-administration responding in the form of a vertical criterion head movement that increased in number over days. Animals discriminated the vertical head movement as the operant, as evidenced by the finding that inverse criterion movements (downward movements starting at photocell 5 or 6 and ending at photocell 2 or 1) did not change over days. Task learning was evidenced by the observed decreased reaction time in response to the SD, increased probability of self-infusion when animals were presented with the SD, and escalated drug consumption with a decreasing latency to load to high drug levels over days. These data are consistent with lever press experiments using an SD (Ghitza et al. 2003; Root et al. 2009; Barker et al. 2010). It is possible that tonic food restriction used in the present experiment played a role in self-administration behavior. However, Bongiovanni and See (2008) observed no differences in response rates or cocaine intake per bodyweight in animals food restricted or fed ad libitum, suggesting our food restriction protocol did not cause deviations from normal self-administration behavior. Visual inspection of behavior clearly showed increased locomotor behavior during the earliest training days followed by predominant focused stereotypy over the remaining training days, suggesting that animals became sensitized to the psychomotor effects of cocaine. However, available measures automated by the photocell corner operant device, e.g., the number of inverse criterion movements and vertical head movements shorter in distance than the criterion head movement, did not change over training days. These observations suggest that this device is conditioned, similar to a lever, because it is discriminated as the manipulandum where responding produces cocaine infusion, may not allow for adequate assessment of behavioral sensitization. Stemming from the observations of Pickens and Thompson (1968), animals press a lever to self-administer cocaine when below a certain satiety threshold. This led to the observation that animals do not press the lever to selfadminister while above the satiety threshold (Pickens and Thompson 1971; Yokel and Pickens 1973, 1974; Dougherty and Pickens 1974; Wise 1987; Wise et al. 1995; Markou et al. 1999; Tsibulsky and Norman 1999; Norman et al. 2003; Lynch and Carroll 2001; Norman and Tsibulsky 2006; Olmstead et al. 2000; Panlilio et al. 2006). Consistent with these observations, the vertical head movement was used by animals as an operant similar to the lever press, in that criterion head movements were increased when drug levels were clamped below satiety and decreased when drug levels were clamped above satiety. The observed decrease in criterion head movements during supra-satiety was not the result of stereotypy interfering with criterion head movements. All indices from automated data analyses and video monitoring of selfadministration behavior indicate that animals differentiate stereotypy from operant responding, whether the operant is a head movement or a lever press. The present animals (12/13 rats) exhibited a locus of stereotypy away from the photocell corner. They demonstrated clear approaches toward the photocell corner, vertical responses within the photocell corner, and retreats away from the photocell corner to return to the locus of stereotypy. The stereotypical movements induced by cocaine (e.g., head-bobbing) were not the operant movements that earned cocaine. That is, the average latency for the next movement after a criterion movement was approximately 30 s, longer than stimulant- Psychopharmacology induced unconditioned, stereotypical head movements detailed in previous studies occurring at approximately 10 Hz (Fowler et al 2003; 2007). These results are consistent with previous research demonstrating that animals can intracranially self-stimulate by pressing one lever while self-administering with another lever (Wise et al. 1977). Indeed, most animals (75%) in the present study exhibited at least one criterion movement during the suprasatiety phase. Specifically, stimulants induced circling, and head bobbing in one place. Taken together, these results indicate that (a) stereotypy does not interfere with operant responding and (b) stereotypical head movements were not the operant responses in the present task. Rats self-administered cocaine for 6 h/day for nearly 1 month. The specific set of circumstances (the photocell corner device and the vertical head movement operant) allowed us to address whether skilled cocaine selfadministration developed in the rat. Although programmed criterion movement requirements remained constant, parameters of the operant movement changed over days, indicative of motor skill learning. The velocity of the criterion head movement increased over days as a function of decreasing duration, but not as a function of changed overall distance. In addition, animals increased the probability of starting criterion movements at photocell 2, the optimal starting movement position. In contrast, the probability of ending at photocell 5, the optimal ending movement position, did not change. It appears that over time, rats learn several aspects of the self-administration task. First, animals learn to respond in reaction to the SD (Ghitza et al. 2003; Root et al. 2009). Second, animals learn to discriminate the operant response, which becomes skilled with respect to movement parameters (velocity, duration) and efficiency (starting position), supporting the prediction by Tiffany (1990) that self-administration of drugs of abuse becomes highly skilled over extended use. Third, animals learn to control responding such that responding is increased during subsatiety and decreased during suprasatiety. One limitation of the present design was the lack of an additional neutral cue in addition to the SD. Discrimination training with two tones of different frequencies serving as S+ and S− may result in stronger stimulus control than that in which the S− is the absence of the S+ tone (Jenkins and Harrison 1960). However, this approach also introduces more complexity, unpredictability, and expectations/anticipations resulting from S+/S− sequences. These factors were specifically avoided in the present design, whose purpose was to reduce variability while maximizing familiarity and predictability, to avoid complicating the measurement of skill acquisition. The nigrostriatal system, including the DLS, is important for skill learning. Compromised function results in motor deficits such as those observed in Parkinson’s patients (Marsden 1982; Ferro et al. 2005; Desmerget and Turner 2010), including deficits in acquiring motor programs (Flowers 1975; Sheridan et al. 1987). Neurons in the DLS region receive robust topographic, convergent S1 and M1 innervation (Künzle 1975, 1977; Selemon and GoldmanRakic 1985; McGeorge and Faull 1989; West et al. 1990; Carelli and West 1991; Ebrahimi et al. 1992; Flaherty and Graybiel 1993, 1994; Kincaid and Wilson 1996), underlying their increased firing rates during somatosensory or motor manipulations of single body parts (Liles 1979; Crutcher and DeLong 1984a, b; Alexander and DeLong 1985; Liles and Updyke 1985; Carelli and West 1991; Mittler et al. 1994; Cho and West 1997) and their lack of responsiveness to conditioned auditory cues (Root et al. 2010a). It has recently been observed that DLS manipulations disrupt cocaine self-administration in rodents (Vanderschuren et al. 2005). Furthermore, drug-related videoinduced cravings correlate with dopamine receptor availability in human DLS (Volkow et al. 2006, 2008). Thus, the demonstrated skill learning in the present experiment suggests the involvement of the DLS. However, this has not been directly tested using single-unit recordings. The vertical head movement paradigm was developed to achieve compatibility between specific stimulant-induced movements and their representation in the DLS, namely, neurons related to vertical head movement. The present study represents the last in a series of studies validating the head movement paradigm as a model for studying DLS activity during extended stimulant self-administration (West et al. 1997; Pederson et al. 1997; Tang et al. 2007; Pawlak et al. 2010). While not likely involved in the processing of skilled movements of specific body parts as observed in DLS, the ventral striatopallidal system is likely to process the criterion head movement as an operant. The accumbens is necessary for learning and performance of instrumental behavior (Atallah et al. 2007). Neurons in the nucleus accumbens (Ghitza et al. 2004; Fabbricatore et al. 2010) and ventral pallidum (Root et al. 2010b) exhibit changes in firing rate surrounding the seconds of cocaine-reinforced lever presses without exhibiting unconditioned forepaw-sensitive somatomotor firing properties. In contrast to the DLS with its discrete somatomotor firing properties, firing patterns exhibited following extensive cocaine self-administration in the ventral striatopallidal system might reflect approach, response, retreat, or other operant-related firing properties. In conclusion, the present results demonstrate that cocaine self-administration can become skilled over extended drug use as previously hypothesized (Tiffany 1990). Furthermore, the vertical head movement is a practical operant response alternative used as an operant response similar to lever pressing with the additional benefits of enabling quantification of skill learning and analyses of simultaneously recorded DLS firing patterns. Psychopharmacology Acknowledgments We thank Linda King, Thomas Grace Sr., Jacqueline D. Thomas, and Jacquelin M. Mueller for technical assistance. Conflicts of interest None. Fowler SC, Birkenstrand B, Chen R, Vorontsova E, Zarcone T (2003) Behavioral sensitization toamphetamine in rats: changes in the rhythm of head movements during focused stereotypies. Psychopharmacology 170(2):167–177 Fowler SC, Covington HE, Miczek KA (2007) Stereotyped and complex motor routines expressed during cocaine selfadministration: results from a 24-h binge of unlimited cocaine access in rats. 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