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. Author manuscript; available in PMC: 2026 Aug 13.
Published in final edited form as: Psychopharmacology (Berl). 1997 Sep;133(1):7–16. doi: 10.1007/s002130050365

Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat

Scott E Hemby 1,1,✉, Conchita Co 1, Timothy R Koves 1, James E Smith 1, Steven I Dworkin 1
PMCID: PMC13463260  NIHMSID: NIHMS822174  PMID: 9335075

Abstract

Studies indicate that nucleus accumbens (NAcc) dopamine neurotransmission is involved in the reinforcing and direct effects of cocaine. The present study was initiated to explore further the relationship of NAcc extracellular dopamine concentrations ([DA]e) and cocaine self-administration using a yoked littermate design. In the first experiment, one rat from each litter was trained to self-administer cocaine IV (SA; 0.33 mg/inf) under a fixed ratio 2 schedule, while a second rat received simultaneous infusions of cocaine yoked to the infusions of the SA (YC). NAcc [DA]e and cocaine concentrations ([COC]) were assessed during the test sessions using in vivo microdialysis combined with micro-bore HPLC procedures. [DA]e and [COC] were significantly elevated in the SA and YC groups during the self-administration session; however, [DA]e were greater in the SA group compared to the YC group in the first hour of the session, even though [COC] were not significantly different. On the following day, the rats previously allowed to self-administer cocaine were administered response-independent cocaine infusions yoked to the infusion pattern from the previous day. [DA]e were significantly elevated above baseline levels during the session but were significantly less than concentrations obtained when cocaine was self-administered by these subjects. [COC] during the sessions were not significantly different between the two days. Baseline [DA]e were not significantly different between the SA and YC groups or between Day 1 and Day 2. Furthermore, there was no significant difference in the in vitro probe recovery between one and two days following probe implantation. These results suggest that the context in which cocaine was administered significantly altered the neurochemical response to equivalent brain concentrations of cocaine. NAcc [DA]e was significantly increased when the delivery of cocaine infusions was contingent on the behavior of the rat, indicative of a role in the neural processes underlying cocaine reinforcement.

Keywords: Cocaine, Nucleus accumbens, Dopamine, Self-administration, Reinforcement, Microdialysis

Introduction

The neurochemical and behavioral effects of cocaine are mediated primarily by inhibition of monoaminergic uptake resulting in increased concentrations of these neurotransmitters in the extracellular space (Ross and Renyi 1967; Heikkila et al. 1975; Reith et al. 1986). Pharmacological manipulations of monoaminergic neurotransmission and receptor function have indicated a critical role for dopamine in cocaine reinforcement. Several studies have demonstrated that systemic administration of D1 or D2 receptor antagonists increase rates of cocaine self-administration in rats under fixed ratio schedules (DeWit and Wise 1977; Ettenberg et al. 1982; Roberts and Vickers 1984; Koob et al. 1987; Gerber and Wise 1989; Britton et al. 1991; Corrigall and Coen 1991; Caine and Koob 1994; Hemby et al. 1996; for review, see Hemby et al. 1997) and decrease break points under progressive ratio schedules (Hubner and Moreton 1991; Richardson et al. 1993), effects that may be interpreted in part as an attenuation of the reinforcing effects of cocaine. In contrast, cocaine self-administration is not attenuated by antagonists for noradrenergic receptors (DeWit and Wise 1977) or serotonergic receptors (Porrino et al. 1989; Peltier and Schenk 1991). The mesocorticolimbic dopamine pathway has been identified as a critical substrate for the expression of cocaine reinforcement (Ritz et al. 1987; Wise and Bozarth 1987; Koob and Bloom 1988). For example, 6-hydroxydopamine lesions of the ventral tegmental area (Roberts and Koob 1982) or NAcc (Roberts et al. 1977, 1980; Pettit et al. 1984) significantly attenuate cocaine self-administration in rats. Furthermore, intra-accumbens administration of D1 and D2 dopamine antagonists increase rates of cocaine self-administration under fixed ratio schedules (Maldonado et al. 1993; Phillips et al. 1994) and decrease break points under progressive ratio schedules (McGregor and Roberts 1993). In vivo microdialysis has been used to investigate directly the role of forebrain dopaminergic transmission in cocaine self-administration. Several studies have demonstrated that experimenter-administered cocaine dose-dependently increases NAcc [DA]e (Carboni et al. 1989; Kalivas and Duffy 1990; Kuczenski et al. 1991; Hemby et al. 1995a) and [COC] (Hemby et al. 1995a). Increases in NAcc [DA]e are also observed during cocaine self-administration sessions (Pettit and Justice 1989, 1991; Weiss et al. 1992; Meil et al. 1995) and the increases are paralleled by significant increases in [COC] in this region (S. E. Hemby et al., unpublished data). Recently, Wise et al. (1995) demonstrated NAcc [DA]e are increased following each self-administered cocaine infusion and decline until the next infusion, suggesting that [DA]e in the NAcc may be a critical stimulus for the initiation of subsequent responding.

The qualitative similarities in the NAcc dopaminergic response between response-independent and response-dependent (self-administration) cocaine administration have led to the suggestion that neurochemical changes resulting from response-independent drug administration provide insight into the processes underlying drug reinforcement (Di Chiara and Imperato 1988). However, abused drugs, such as cocaine, exert a variety of direct behavioral and neurobiological effects that may not be directly related to the reinforcing actions. One way in which to delineate the neurobiological mechanisms mediating the different actions is to compare the effects during response-dependent drug presentation (self-administration) with the effects following yoked response-independent drug presentation. Inasmuch as the contingency between a behavior and presentation of a stimulus is one of the defining features of reinforcement, neurobiological differences resulting from the contingency of stimulus presentation may be indicative of those processes involved in reinforcement.

The present study explored the relationship between NAcc DA neurotransmission and cocaine reinforcement by comparing NAcc [DA]e and [COC] in rats self-administering cocaine (SA) with littermates received cocaine infusions yoked to the infusions of the respective SA littermate (YC) using in vivo microdialysis. The following hypothesis was investigated: if a NAcc dopaminergic response is critical for cocaine reinforcement, then NAcc [DA]e should be different between the SA and YC groups and this difference should not be attributable to the [COC]. The hypothesis was examined using two approaches. First, NAcc [DA]e and [COC] were compared between rats self-administering cocaine and those receiving response-independent infusions. Second, NAcc [DA]e and [COC] from SA rats were compared between Day 1, when rats were allowed to self-administer cocaine, and Day 2, when the same rats received response-independent cocaine infusions yoked to their respective infusion patterns from the previous day. In a separate experiment, in vitro probe recoveries were assessed following one and two days post-probe implantation to determine whether differences between Day 1 and Day 2 NAcc [DA]e could be attributable to changes in probe efficiency over this time period.

Materials and methods

Housing and surgical procedures

Male Fisher F-344 rats (90–150 days; 275–350 g) were used for all experiments. Rats were housed four per cage in a temperature-controlled vivarium on a reversed light-dark cycle (lights on: 1700 p.m.) with food and water available ad libitum. For surgery, rats were pretreated with atropine sulfate (10 mg/kg; IP) and anesthesia was induced by administration of sodium pentobarbital (Nembutal, 40 mg/kg; IP). For the self-administration experiments, rats were implanted with chronic indwelling venous catheters as described previously (Hemby et al. 1995b, 1996) followed by implantation of guide cannulae. Rats assigned to the in vitro probe recovery experiment were implanted with intracranial guide cannulae only. Rats were secured in a Kopf stereotaxic frame and implanted unilaterally with 20 ga (Plastics One, Roanoke, Va., USA) stainless steel guide cannulae, with the side of placement counter-balanced within groups. Cannulae tips were aimed for the dorsal surface of the NAcc (+9.5 mm from lambda, ±1.3 mm lateral from the midline, and –5.0 mm ventral from dura; König and Klippel 1974). Guide cannulae were secured with skull screws and dental acrylic cement and obturators (28 ga; Plastics One), cut flush with the bottom of the cannulae, were inserted to prevent blockage. Penicillin G procaine (75,000 units; 0.25 ml; IM) was administered immediately following surgery. The health of the rats was monitored daily by the experimenter and weekly by institutional veterinarians according to the guidelines issued by the Bowman Gray Animal Care and Use Committee and the National Institute of Health.

Self-administration apparatus

Following recovery from the surgical procedures (7–10 days), each rat was housed in a Coulbourn Instruments modular operant-conditioning chamber (Model E10-10; 29.5×24×27.5 cm). The front panel contained a water spout 4 cm from the left side panel and 1.5 cm above the floor and a fixed lever (Coulbourn Instruments, Model E21-03) centered between the side panels and positioned 2.5 cm above the floor. The levers required approximately 0.25 N to operate. Two glass food containers, which provided access to 12 one g food pellets each, were centered approximately 4 cm from the right panel and 6 cm above the floor. During the light phase of the cycle, the chamber was illuminated by a house light (Sylvania 1829) centered 3.5 cm from the right panel and 27.3 cm above the floor. A panel containing three lights (Sylvania 28ESB) spaced 1.5 cm apart was located 5.5 cm above the lever. The bulbs were covered with red, yellow and green translucent caps and only the green and red lights were used. A counter-balanced arm containing the single channel liquid swivel was located 8.5 cm above the chamber and attached to the outside of the front panel. Three operant-conditioning chambers were placed inside each sound-attenuated chamber (85.5×55×56 cm). The sound-attenuated chambers contained an exhaust fan, an 8-ohm speaker and a tone source. Extraneous noise was masked by the exhaust fan and white noise delivered continually through the speaker. Rockwell computers (AIM 65) with a MCS interface (Micro Interfaces) were used for session programming and data collection.

Self-administration procedures

Immediately following surgery, two littermates were placed in separate operant-conditioning chambers located within the same sound-attenuating enclosure. Twenty-four food pellets were placed in the glass feeding tubes the day after surgery. Over the next 10 days, rats received hourly infusions of heparinized saline (1.7 units/ml; 200 μl/h; 5.6 s) to maintain functional catheters. When food intake was stable for each pair of littermates, experimental procedures were initiated. One rat from each litter was allowed to self-administer (SA; n=5) cocaine HCl (0.33 mg/inf; 200 μl; 5.6 s) under an FR1 schedule of reinforcement that was subsequently increased to FR2 when responding was stable (defined as five consecutive sessions in which the total number of infusions did not vary by more than 10%). The other littermate received response-independent (yoked cocaine; YC; n=4) infusions of the same dose simultaneous with the infusion of the self-administering animal. Infusions initiated a 20 s time out period signaled by a tone, darkening of the green light and illumination of the red light in both chambers. Following the initiation of cocaine self-administration, the number of food pellets available for the YC subject was determined by the SA subject using a 24 h delay feeding procedure. At 1700 hours, the food pellet dispensers for the self-administering subject was refilled to a maximum of 24 and an amount of food equal to the amount consumed by the SA animal in the preceding 24 h period was placed in the YC animal’s food dispenser. The yoking of the food pellets was employed to decrease the possibility that any potential differences between the SA and the YC subjects were due to differences in food intake and body weight. Self-administration sessions were limited to 6 h of access (0900–1500 hours) or 60 infusions per day, 7 days per week.

Following 25 days of stable responding under an FR2 schedule, microdialysis procedures were initiated. On Day 1, samples were collected simultaneously from SA and YC subjects. On the following day, the SA subject was administered response-independent cocaine infusions yoked to the intake pattern from the previous day. On the days of microdialysis sampling, self-administration sessions were limited to 2 h. Samples were collected in 5 min intervals from 15 min prior to the beginning of the session until 30 min after the session ended.

In vitro probe recovery

The in vitro recovery experiment was performed to determine whether probe efficiency changed over the course of two days. Subjects were assigned to one of two groups. After 1 h of baseline sampling, subjects in Group I (n=3) were administered cocaine (10 mg/kg; IP) and samples were collected for an additional hour. Following a 2 h period, samples were collected for an additional hour. For Group II (n=4), the sample collection and drug injection procedures were repeated the following day. Samples were collected in 15 min intervals and assayed for dopamine. Immediately following collection of the last sample, the probe was removed and immersed in a beaker containing aCSF. After 2 h, samples were collected in 15 min intervals for 1 h and assayed for DA. Next, the probe was immersed in aCSF containing 100 nM DA and allowed to equilibrate for 2 h. Samples were collected in 15 min intervals for 1 h and assayed for DA. This procedure was repeated for 200 and 500 nM DA. Relative probe recoveries were calculated in the following manner: (concentration in the dialysate/concentration in the beaker)×100.

Microdialysis procedures

The microdialysis procedures and probe construction have been described previously (Hemby et al. 1995a,b). Briefly, two pieces of fused silica were inserted into 6 mm regenerated cellulose membrane (250 μm OD, 5000 MW cutoff; Spectra/Por, Los Angeles, Calif., USA). For the present experiment, the active portion of the probes was 2 mm, defined by the distance between the ends of the fused silica. The inlet silica line was connected to a syringe filled with artificial cerebrospinal fluid, used as the perfusion medium. Artificial cerebrospinal fluid (aCSF) was used as the perfusate and consisted of 145 mM NaCl, 1.2 mM CaCl2, 2.8 mM KCl, 1.2 mM MgCl2, 5.4 mM d-glucose, and 1.25 mM NaH2PO4, pH=7.2.

Approximately 18 h before the microdialysis session, microdialysis probes were inserted through previously implanted guide cannulae. The perfusion flow rate was increased from 0.5 to 1.0 μl/min 3 h before the experimental session. Dialysate samples were collected in microcentrifuge tubes from the free end of the outlet silica line, immediately frozen on dry ice and later stored at –70°C until analysis.

High performance liquid chromatography (HPLC) procedures

A 3 μl aliquot of the sample were assayed for dopamine using microbore HPLC with electrochemical detection, while the remaining 2 μl were assayed for cocaine using microbore HPLC with ultraviolet detection. The HPLC for dopamine analysis consisted of a syringe pump (model LC-260D; Isco, Lincoln, Neb., USA) an air-actuated injection valve (model ACI4UW; Valco) with a 1.0 μl sample loop, a Spherisorb microbore column (0.5 mm i.d.×100 mm, 5 μm C18 silica), a dual glassy carbon working electrode (model PM; EG&G Princeton Applied Research, Princeton, N.J., USA), a reference electrode (RE-1; Bioanalytical Systems, W. Lafayette, Ind., USA), and an electrochemical detector (model 400; EG&G Princeton Applied Research). Columns were packed in the laboratory with silica purchased from Phase Separations, Inc. (Norwalk, Conn., USA). The applied potential was +700 mV as referenced to Ag/AgCl. The mobile phase consisted of 27.2 mM sodium phosphate-monobasic, 10% v/v methanol, 4.9 mM triethylamine, 13 mM disodium-EDTA, and 0.99 mM sodium octyl sulfate, with the pH adjusted to 5.75 with 0.1 N phosphoric acid. The flow rate of the mobile phase was 10–12 μl/min and the detection limit for dopamine was 100 pM. Quantification of dopamine was achieved by comparing samples with standards of known concentration. The HPLC for cocaine analysis consisted of an SSI pump (model 222D) adapted for microbore use, a Rheodyne injection valve (model 7520) with a 0.5 μl sample loop, a Spherisorb microbore column (0.5 mm i.d.×100 mm, 3 μm C18) and an LDC analytical variable wavelength detector (model 3200) customized for microbore chromatography. The wavelength was 235 nm and the absorbance was 0.0001, full scale. The mobile phase consisted of 50 mM sodium phosphate monobasic, 10 mM triethylamine, 17% acetonitrile, 10% methanol with the pH adjusted to 5.6 with a flow rate of 25 μl/min. The detection limit for cocaine was 200 nM. Quantification of cocaine was achieved by comparing samples with standards of known concentration.

Histology

Verification of guide cannulae tracts and assessment of gliosis at the probe site were made in all subjects. Brains were removed and coronal sections (20 μm) were taken from 100 μm rostral to 100 μm caudal to the cannula tract. Sections were fixed and stained according to previous methods (Kluver and Barrera 1953). Probe placements were verified by light microscopy in a “blind” manner to reduce experimenter bias of the results. Probe placements were within the NAcc for all subjects in this study (Fig. 1).

Fig. 1.

Fig. 1

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Composite representation of microdialysis probe placements in the NAcc for the SA (top) and YC (bottom) subjects. Bars indicate the location of the active area of individual probes and are drawn to scale (length 2 mm, width 200 mm). The area of the NAcc is identified by the dashed line. Sections are 9650 μm rostral to lambda according to the atlas of König and Klippel (1974)

Data analysis

Microdialysis data were analyzed using a two-way repeated measures analysis of variance (ANOVA) with Group as the main factor and Time as the repeated measure. Post hoc analyses were conducted as needed using Student’s Newman-Keuls test (Neter et al. 1985). The null hypothesis was rejected when P<0.05. There was no YC littermate for subject TD2 and therefore this subject was not included in the comparison of SA and YC. However, the subject was included in the Day 1 and Day 2 comparisons. In vitro probe recoveries were compared using Student’s t-test for each concentration of dopamine.

Results

Self-administration

Response patterns and baseline concentrations of DA

The mean (±SEM) number of infusions for the four littermate pairs was 20.2 ± 1.1 and the overall mean (±SEM) inter-infusion interval was 5.4 ± 0.5 min. Individual infusion patterns are depicted in Fig. 2. There were no recorded responses for the YC subjects during the self-administration session. Stable baseline concentrations of DA were obtained within 3 h after increasing the perfusion flow rate to 1 μl/min. Fifteen minutes prior to the self-administration sessions, baseline concentrations of DA were assessed in each subject with three samples collected in 5 min intervals. All subsequent samples were expressed as the mean (± SEM) percent variation of the baseline value. The mean baseline concentrations were 4.25 ± 1.4 and 3.24 ± 0.9 nM for the SA and YC groups, respectively, and were not significantly different. Comparison of baseline [DA]e in the SA group between Day 1 and Day 2 (3.82 ± 1.1 and 3.49 ± 0.7, respectively) revealed no significant difference between days.

Fig. 2.

Fig. 2

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Infusion records for SA subjects for the self-administration test session. Each vertical tick represents an infusion. The first arrow indicates the beginning of the self-administration session and the second arrow indicates when cocaine was no longer available

Comparison of [DA]e and [COC] between SA and YC

NAcc [DA]e was significantly increased above baseline levels in the SA group [F(1, 191)=42.127; P=0.0006] and the YC group [F(1, 191)=8.255; P=0.0283] following the first injection of cocaine and for the duration of the self-administration session (Fig. 3, top panel). [DA]e were elevated approximately 546% of baseline in the SA group, with a range of 425–800%, whereas [DA]e were elevated approximately 350% of baseline in the YC group with a range of 250–425%. [DA]e declined to approximately 175% of baseline levels within 30 min following the end of self-administration session. In contrast, [COC] were not different between groups during the self-administration session (0.70 μM and 0.66 μM for the SA and the YC groups, respectively). [COC] declined in a manner similar to [DA]e following the end of the self-administration session (Fig. 3, bottom panel). During the first hour of the session, [DA]e were significantly greater in the SA versus the YC groups [F(1, 95)=7.118; P=0.0371]. However, there was no significant difference in [DA]e during the second hr, an effect attributed to increased variability in these measures. In contrast, [COC] in the NAcc were not significantly different during the first or second hour, suggesting that the differences in [DA]e between the two groups were not due to differences in NAcc [COC]. This observation indicates that the context in which cocaine is administered can alter the neurochemical response to equivalent brain concentrations of the drug.

Fig. 3.

Fig. 3

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The effect of IV cocaine administration (0.33 mg/inf) on [DA]e (top panel) and [COC] (bottom panel) in the NAcc for the SA (●) and YC (□) groups (n=4/group). Baseline values were not significantly different between the groups. Samples were collected in 5-min intervals. Data are presented as the mean (±SEM). The first arrow indicates the beginning of the self-administration session and the second arrow indicates the end of cocaine availability. [DA]e were significantly greater in the SA group for the first hour of the session, although [COC] were not significantly different

Comparison of [DA]e and [COC] between Day 1 and Day 2

SA subjects were administered response-independent cocaine infusions on the second day according to the respective infusion pattern from the previous day. Samples collected on Day 2 were assayed for [DA]e and [COC] and compared with samples from Day 1. Response patterns exhibited on Day 2 were extinction-like in three of the subjects with a repeating sequence of several responses followed by a period of no responding. In two of the subjects, responding was less frequent, although irregular nonetheless. The number of responses of day 1 was 40.4 ± 1.7 compared with 20.4 ± 6.5 (Fig. 4).

Fig. 4.

Fig. 4

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Infusion records for individual SA subjects from Day 1 (top line) and responses recorded on Day 2 (bottom line). Each vertical tick represents an infusion (top) or a response (bottom). The first arrow indicates the beginning of the self-administration session and the second arrow indicates when cocaine was no longer available

NAcc [DA]e was significantly increased above baseline levels on Day 2 for the SA animals [F(1, 239)=24.945; P=0.0011] during the session in which response-independent infusions were administered according to the infusion pattern from the previous day (Fig. 5, top panel). [DA]e were increased to approximately 313% of baseline, although a maximum of 475% was reached. [COC] were approximately 0.63 μM for the session on day 2 (Fig. 5, bottom panel). Similar to the comparison of [DA]e between the SA and YC groups, [DA]e were significantly greater on Day 1 compared with Day 2 [F(1, 239)=9.448; P=0.0153], an effect evident in the first hour [F(1, 119)=12.313; P=0.008] and the second hour [F(1, 119)=5.620; P=0.0452]. Again, [COC] were not significantly different between Day 1 and Day 2 for the first or second hour of the self-administration session. These data further support the previous results that differences in NAcc [DA]e between Day 1 and Day 2 were not attributable to differences in [COC].

Fig. 5.

Fig. 5

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The effect of IV cocaine administration (0.33 mg/inf) on [DA]e (top panel) and [COC] (bottom panel) in the NAcc for Day 1 (●) and Day 2 (□) (n=5/day). On day 2, SA subjects received response-independent cocaine infusions according to the infusion pattern from the previous day. Baseline [DA]e were not significantly different between the two days. Samples were collected in 5 min intervals and data are presented as the mean (±SEM). The first arrow indicates the beginning of the self-administration session and the second arrow indicates the end of cocaine availability. [DA]e were significantly greater on Day 1 than on Day 2 for the SA group, although [COC] were not significantly different

However, the differences in number of responses between Day 1 and Day 2 do not appear to account completely for differences in [DA]e. For example, subject TD3 emitted a greater number of responses on Day 2 than Day 1 (40 versus 36) yet [DA]e were significantly greater on day 1 compared with Day 2 (Fig. 6). Conversely, subject TD5 responded more on Day 1 than day 2 (46 versus 19) and [DA]e were also significantly greater on Day 1 (Fig. 7). These data suggest that differences in NAcc [DA]e between rats self-administering cocaine and those receiving response-independent infusions does not appear to be attributable to responding.

Fig. 6.

Fig. 6

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Comparison of NAcc [DA]e (top panel) and [COC] (bottom panel) between Day 1 (●) and Day 2 (□) for a representative subject (TD3). A greater number of responses were emitted on day 2 compared with Day 1 (40 versus 36)

Fig. 7.

Fig. 7

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Comparison of NAcc [DA]e (top panel) and [COC] (bottom panel) between Day 1 (●) and Day 2 (□) for a representative subject (TD5). A greater number of responses were recorded on Day 1 compared with Day 2 (46 versus 19)

In vitro probe recovery

Baseline [DA]e were not significantly different between Groups I and II or between Day 1 and Day 2 from group II. Following cocaine administration, NAcc [DA]e was increased significantly above baseline levels in Group I [F(1, 23)=12.82; P=0.0232] and Group II for Day 1 [F(1, 31)=61.05; P=0.0002] and Day 2 [F(1, 31)=11.09; P=0.0447]. NAcc [DA]e returned to baseline values within 3 h following cocaine administration. There was no significant difference in the cocaine-stimulated NAcc [DA]e between Group I and Group II on Day 1 or between Day 1 and Day 2 for group II.

For Group I, the in vitro probe recovery for 100, 200, and 500 nM was 10.6 ± 0.74, 12.1 ± 1.09, and 9.10 ± 1.12, respectively. For Group II, the in vitro probe recovery for 100, 200, and 500 nM was 12.0 ± 2.78, 12.4 ± 2.06, and 8.32 ± 1.83, respectively. There was no significant difference in probe recovery between Group I and Group II at the three dopamine concentrations assessed.

Discussion

Cocaine is known to exert effects on behavior and neurochemistry that are independent of the contingency of presentation (direct effects; Katz 1989). The yoked-box procedure was used to differentiate the direct effects (e.g. locomotor stimulating and increased stereotypies) from those associated with the reinforcing effects of cocaine. The present results demonstrate that the context of cocaine administration can alter the in vivo neurochemical response of the drug. Intravenous cocaine administration increased NAcc [DA]e in all groups with corresponding increases in [COC]. This finding confirms the results from earlier studies (Pettit and Justice 1989, 1991; Weiss et al. 1992; Meil et al. 1995) and extends these results by assessing [DA]e and [COC] from the same sample and assessing [COC] in self-administering subjects. More importantly, these results demonstrate that the magnitude of the elevation in NAcc [DA]e was significantly greater when infusions were delivered in a response-dependent versus a response-independent manner. The lack of significant differences in [COC], baseline [DA]e, and probe recovery between Day 1 and Day 2 suggests that differences in [DA]e are attributable to the behavioral context of drug administration. Thus, differences in NAcc [DA]e between SA versus YC and Day 1 versus Day 2 are a reflection of the involvement of dopamine in the primary reinforcing effects of cocaine and the potential conditioned reinforcing effects of stimuli associated with response-dependent drug administration. These findings emphasize the importance of using appropriate behavioral models when assessing neural mechanisms of reinforcement. Procedures utilizing response-independent drug administration do not induce the array of neurophysiological effects associated with self-administration and therefore are not sufficient evidence for ascribing reinforcement to such changes.

The yoked box procedure has been used to compare neurobiological measures between subjects self-administering a drug and subjects receiving response-independent infusions yoked to the self-administering subject (Smith et al. 1980, 1982, 1984; Wilson et al. 1994; Dworkin et al. 1995a,b). Data from the present study directly support the results of previous studies demonstrating differences in NAcc electrophysiology and neurotransmitter turnover rates between cocaine self-administration and yoked cocaine administration. First, Carrelli et al. (1993) reported that NAcc neurons exhibited phasic increases in firing patterns following response-dependent infusions of cocaine (0.33 mg/inf) which were not observed when cocaine was delivered response-independently. Under similar experimental conditions, it has been demonstrated recently that dopamine turnover rates in the NAcc were increased by 46% in subjects self-administering cocaine compared with subjects receiving yoked response-independent infusions of cocaine (J. E. Smith et al., unpublished data). Increases in turnover rates were observed even though tissue concentrations of dopamine were not significantly different, as previously reported (Wilson et al. 1994). Together, these data support a critical role of NAcc dopamine in cocaine self-administration (Wise and Bozarth 1987; Koob and Bloom 1988). Previously, significant differences have been demonstrated between subjects self-administering morphine compared with those receiving yoked-response-independent infusions for NAcc biogenic amine, amino acid and acetylcholine turnover rates and for membrane receptor binding (Smith et al. 1982, 1984). More recently, Dworkin et al. (1995a) demonstrated differences in biogenic amine turnover rates in the NAcc, and several other brain regions, between subjects self-administering cocaine (0.33 mg/inf) compared with subjects receiving yoked cocaine infusions following an 18-h abstinence period. These studies emphasize the utility of the yoked littermate procedure when attempting to differentiate the reinforcing and direct effects of drugs.

The present findings are consistent with and extend previous findings (Pettit and Justice 1989, 1991; Weiss et al. 1992; Meil et al. 1995) by i) assessing changes in NAcc [DA]e and [COC] from the same samples and ii) demonstrating that response-dependent administration resulted in greater increases in NAcc [DA]e than observed with response-independent administration. Previous results obtained using in vivo microdialysis and cocaine self-administration could be interpreted as a generalized neurochemical effect, unrelated to cocaine reinforcement inasmuch as response-independent infusions also induce increases in NAcc [DA]e (Carboni et al. 1989; Kalivas and Duffy 1990; Kuczenski et al. 1991; Hemby et al. 1995a). These data provide direct in vivo neurochemical evidence of NAcc dopaminergic involvement by demonstrating that the increases in NAcc [DA]e were related to the response-infusion contingency. However, these results are in contrast with those from an earlier study reporting that response-dependent infusions of cocaine did not increase [DA]e in the NAcc whereas response-independent infusions to drug-naive subjects resulted in a marked elevation (Hurd et al. 1989). The reasons for the differences remain unclear, although the results from the present study corroborate previous findings (Pettit and Justice 1989, 1991; Weiss et al. 1992).

Several alternative interpretations may account for the differences in [DA]e between response-dependent and response-independent cocaine administration, in addition to the interpretation that attributes differences to response-contingency. However, the differences in NAcc [DA]e between Day 1 and Day 2 can not be ascribed to changes in probe recovery over the sampling period. Results from the in vitro probe recovery experiment demonstrate that there is no significant change in the recovery efficiency of the probe over two days. A potential mechanism underlying the differences in SA versus YC and Day 1 and Day 2 may be differences in basal [DA]e. Such differences may exist without significant alterations in baseline levels (Parsons et al. 1991). Previous studies have demonstrated significant changes in basal [DA]e following chronic response-independent cocaine administration (Parsons and Justice 1992; Kalivas and Duffy 1993a,b) and the relevance of such findings should be extended to subjects with a history of self-administration as well as those with a history of yoked cocaine infusions.

Inasmuch as NAcc dopamine is known to mediate cocaine-induced motor activity (Kelly and Iversen 1976; Delfs et al. 1990; Hemby et al. 1992), differences in [DA]e may be attributed to motor activity involved in responding. The response requirement was held to a minimal value (FR2) to minimize the influence of this variable. Two results from the present study would not support this explanation. No significant differences in [DA]e were observed between the two groups receiving response-independent cocaine infusions, YC versus Day 2, even though the number of responses was significantly greater for the Day 2 group (0 versus 20). Moreover, [DA]e were significantly less on Day 2, whether the subjects emitted either more (TD3) or less (TD5) responses on Day 2 compared with previous day when cocaine was administered in a response-dependent manner.

A third alternative interpretation of the differences in [DA]e between response-dependent and response-independent cocaine administration is based on recent results of Humby et al. (1996) demonstrating decreases in NAcc [DA]e following presentation of a “startling” stimulus. In the present study, there were no discrete exteroceptive cues signaling cocaine infusions in the YC or Day 2 groups, suggesting that unsignaled yoked cocaine infusions may be analogous to a “startling” stimulus. Therefore, one would predict a “suppression” of the cocaine-induced increases in NAcc [DA]e in subjects administered unsignaled yoked cocaine infusions. Until future studies are undertaken to determine the influence of such variables, this interpretation remains as viable as one based on response-contingency.

The possibility exists that a behavior or class of behaviors may have been adventitiously reinforced in the subjects administered response-independent infusions if that behavior(s) consistently preceded the infusion, although this scenario is not likely. In the first experiment, the probability of the occurrence of adventitious reinforcement is unlikely, since there were no distinguishable stimuli (e.g. light, tone or ability to observe SA subject) that had an observable effect on behavior. No observational learning appeared to have occurred, since there were no responses emitted by the YC subjects during the test session. Moreover, YC subjects were less active than SA subjects during the sessions. In the second experiment, responses were observed during the presentation of response-independent cocaine infusions. Subjects with a history of cocaine self-administration received response-independent infusions according to the infusion pattern from the previous day. Close examination of the response patterns in the subjects revealed that only a small percentage of responses preceded response-independent infusions. Responding by three of the five subjects was extinction-like in that several responses were emitted in a short period of time followed by a period of no responding, whereas responding by the other two subjects was minimal but occurred in an irregular manner compared with previous patterns when cocaine was administered response-dependently. These data are consistent with the results of Pickens and Thompson (1968), which demonstrated that response-independent cocaine infusions to rats with a history of self-administration elicited extinction-like responding. They concluded that the contingency between the response and the infusion, not a generalized effect of the drug, was necessary for cocaine to function as a reinforcer. The present results extend the conclusions of Pickens and Thompson (1968) by demonstrating that differences in the NAcc [DA]e are attributable to the contingency between the response and the infusion and do not merely represent a generalized neurochemical effect of cocaine.

Numerous studies have related neurochemical or neuropharmacological changes following response-independent drug administration to mechanisms of reinforcement assuming that changes should be similar to response-dependent drug administration. Results from studies that compare response-dependent and response-independent drug administration indicate that substantial neurochemical differences exist that are based on the context of presentation and suggest inferences of reinforcement mechanisms drawn from studies using only response-independent administration procedures could be misleading. The present study supports this assertion by demonstrating significant differences in NAcc [DA]e, even though [COC] are not significantly different. In addition, these differences are not attributable to differences in the efficiency of the probes as demonstrated in the in vitro probe recovery experiment. Thus, these changes are related to the context of presentation and cannot be interpreted solely on the basis of the pharmacological actions of cocaine. These data provide additional support for an important role of NAcc [DA]e in the reinforcing effects of cocaine and emphasize the importance of response-dependency as a defining feature of reinforcement and the importance of this relationship when assessing the neurobiological substrates of reinforcement.

Acknowledgments

All research was conducted according to the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institute on Health. This study served as a partial requirement for a Ph.D. degree in Pharmacology from the Bowman Gray School of Medicine, Wake Forest University for Scott E. Hemby

Support for this research was provided in part by USPHS research grants DA-06634 (J. E. S., S. I. D.), DA-00114 (J. E. S.) and DA-03628 (J. E. S.).

References

  1. Britton DR, Curzon P, Mackenzie RG, Kebabian JW, Williams JEG, Kerkman D. Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration. Pharmacol Biochem Behav. 1991;39:911–915. doi: 10.1016/0091-3057(91)90052-4. [DOI] [PubMed] [Google Scholar]
  2. Caine SB, Koob GF. Effects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther. 1994;270:209–218. [PubMed] [Google Scholar]
  3. Carboni E, Imperato A, Perezzani L, Di Chiara G. Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats. Neuroscience. 1989;28:653–661. doi: 10.1016/0306-4522(89)90012-2. [DOI] [PubMed] [Google Scholar]
  4. Carrelli RM, King VC, Hampson RE, Deadwyler SA. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res. 1993;626:14–22. doi: 10.1016/0006-8993(93)90557-4. [DOI] [PubMed] [Google Scholar]
  5. Corrigall WA, Coen KM. Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. Pharmacol Biochem Behav. 1991;39:799–802. doi: 10.1016/0091-3057(91)90168-2. [DOI] [PubMed] [Google Scholar]
  6. Delfs JM, Schreiber L, Kelley AE. Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat. J Neurosci. 1990;10:303–310. doi: 10.1523/JNEUROSCI.10-01-00303.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DeWit H, Wise RA. Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can J Psychol. 1977;31:195–203. doi: 10.1037/h0081662. [DOI] [PubMed] [Google Scholar]
  8. DiChiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–5278. doi: 10.1073/pnas.85.14.5274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dworkin SI, Co C, Smith JE. Rat brain neurotransmitter rates altered during withdrawal from chronic cocaine administration. Brain Res. 1995a;682:116–126. doi: 10.1016/0006-8993(95)00327-m. [DOI] [PubMed] [Google Scholar]
  10. Dworkin SI, Mirkis S, Smith JE. Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology. 1995b;117:262–266. doi: 10.1007/BF02246100. [DOI] [PubMed] [Google Scholar]
  11. Ettenberg A, Pettit HO, Bloom FE, Koob GF. Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology. 1982;78:204–209. doi: 10.1007/BF00428151. [DOI] [PubMed] [Google Scholar]
  12. Gerber GJ, Wise RA. Pharmacological regulation of intravenous cocaine and heroin self-administration in rats: a variable dose paradigm. Pharmacol Biochem Behav. 1989;32:527–531. doi: 10.1016/0091-3057(89)90192-5. [DOI] [PubMed] [Google Scholar]
  13. Heikkila RE, Orlansy H, Cohen G. Studies on the distinction between uptake inhibition and release of [3H]-dopamine in rat brain tissue slices. Biochem Pharmacol. 1975;24:847–852. doi: 10.1016/0006-2952(75)90152-5. [DOI] [PubMed] [Google Scholar]
  14. Hemby SE, Jones GH, Justice JB, Jr, Neill DB. Conditioned locomotor activity but not conditioned place preference following microinjections of cocaine into the nucleus accumbens. Psychopharmacology. 1992;106:330–336. doi: 10.1007/BF02245413. [DOI] [PubMed] [Google Scholar]
  15. Hemby SE, Co C, Reboussin D, Davies HML, Dworkin SI, Smith JE. Comparison of a novel tropane analog, 2β-propanoyl-3β-(4-tolyl) tropane (PTT) with cocaine HCl in rats: nucleus accumbens extracellular dopamine and motor activity. J Pharmacol Exp Ther. 1995a;273:656–666. [PubMed] [Google Scholar]
  16. Hemby SE, Martin TJ, Co C, Dworkin SI, Smith JE. The effects of intravenous heroin administration on extracellular nucleus accumbens dopamine concentrations as determined by in vivo microdialysis. J Pharmacol Exp Ther. 1995b;273:591–598. [PubMed] [Google Scholar]
  17. Hemby SE, Smith JE, Dworkin SI. The effects of eticlopride and naltrexone on cocaine, heroin and cocaine/heroin combination self-administration. J Pharmacol Exp Ther. 1996;277:247–258. [PubMed] [Google Scholar]
  18. Hemby SE, Johnson BA, Dworkin SI. Neuropharmacological basis of drug reinforcement. In: Johnson BA, Roach JD, editors. Drug addiction and its treatment: nexus of neuroscience and behavior. Raven Press; New York: 1997. pp. 137–169. [Google Scholar]
  19. Hubner CB, Moreton JE. Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat. Psychopharmacology. 1991;105:151–156. doi: 10.1007/BF02244301. [DOI] [PubMed] [Google Scholar]
  20. Humby T, Wilkinson LS, Robbins TW, Geyer MA. Prepulses inhibit startle-induced reductions of extracellular dopamine in the nucleus accumbens of rat. J Neurosci. 1996;16:2149–2156. doi: 10.1523/JNEUROSCI.16-06-02149.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hurd YL, Weiss F, Koob GF, Andén N-A, Ungerstedt U. Cocaine reinforcement and extracellular dopamine overflow: an in vivo microdialysis study. Brain Res. 1989;498:199–203. doi: 10.1016/0006-8993(89)90422-8. [DOI] [PubMed] [Google Scholar]
  22. Kalivas PW, Duffy P. Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse. 1990;5:48–58. doi: 10.1002/syn.890050104. [DOI] [PubMed] [Google Scholar]
  23. Kalivas PW, Duffy P. Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. J Neurosci. 1993a;13:266–275. doi: 10.1523/JNEUROSCI.13-01-00266.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kalivas PW, Duffy P. Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya. J Neurosci. 1993b;13:276–284. doi: 10.1523/JNEUROSCI.13-01-00276.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Katz JL. Drugs as reinforcers: pharmacological and behavioural factors. In: Liebman JM, Cooper SJ, editors. The neuropharmacological basis of reward. Clarendon Press; Oxford: 1989. pp. 164–213. [Google Scholar]
  26. Kelly PH, Iversen SD. Selective 6-OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol. 1976;40:45–56. doi: 10.1016/0014-2999(76)90352-6. [DOI] [PubMed] [Google Scholar]
  27. Kluver H, Barrera EA. A method for the combined staining of cell and fibers in the nervous system. J Neuropathol Exp Neurol. 1953;12:400–403. doi: 10.1097/00005072-195312040-00008. [DOI] [PubMed] [Google Scholar]
  28. König JFR, Klippel RA. The rat brain: a stereotaxic atlas of the forebrain and lower parts of the brainstem. Kreiger Publishing; Huntington, N.Y: 1974. [Google Scholar]
  29. Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science. 1988;242:715–723. doi: 10.1126/science.2903550. [DOI] [PubMed] [Google Scholar]
  30. Koob GF, Vaccarino FJ, Almaric M, Bloom FE. Positive reinforcement properties of drugs: search for neural substrates. In: Engel J, Oreland L, editors. Brain reward systems and abuse. Raven Press; New York: 1987. pp. 35–50. [Google Scholar]
  31. Kuczenski R, Segal DS, Aizenstein ML. Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics. J Neurosci. 1991;11:2703–2712. doi: 10.1523/JNEUROSCI.11-09-02703.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Maldanado R, Robledo P, Chover AJ, Caine SB, Koob GF. D-1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol Biochem Behav. 1993;45:239–242. doi: 10.1016/0091-3057(93)90112-7. [DOI] [PubMed] [Google Scholar]
  33. McGregor A, Roberts DCS. Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Res. 1993;624:245–252. doi: 10.1016/0006-8993(93)90084-z. [DOI] [PubMed] [Google Scholar]
  34. Meil WM, Roll JM, Grimm JW, Lynch AM, See RE. Tolerance-like attenuation to contingent and noncontingent cocaine-induced elevation of extracellular dopamine in the ventral striatum following 7 days of withdrawal from chronic treatment. Psychopharmacology. 1995;118:338–346. doi: 10.1007/BF02245964. [DOI] [PubMed] [Google Scholar]
  35. Neter J, Wasserman W, Kutner MJ. Applied linear statistical models: regression, analysis of variance, and experimental designs. 2. Irwin; Homewood, Ill: 1985. [Google Scholar]
  36. Parsons LH, Justice JB., Jr Extracellular concentration and in vivo recovery of dopamine in the nucleus accumbens using microdialysis. J Neurochem. 1992;58:212–218. doi: 10.1111/j.1471-4159.1992.tb09298.x. [DOI] [PubMed] [Google Scholar]
  37. Parsons LH, Smith AD, Justice JB., Jr Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine. Synapse. 1991;9:60–65. doi: 10.1002/syn.890090109. [DOI] [PubMed] [Google Scholar]
  38. Peltier P, Schenk S. GR38032F, a serotonin 5-HT3 antagonist, fails to alter cocaine self-administration in rats. Pharmacol Biochem Behav. 1991;39:133–136. doi: 10.1016/0091-3057(91)90410-4. [DOI] [PubMed] [Google Scholar]
  39. Pettit HO, Justice JB., Jr Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis. Pharmacol Biochem Behav. 1989;34:899–904. doi: 10.1016/0091-3057(89)90291-8. [DOI] [PubMed] [Google Scholar]
  40. Pettit HO, Justice JB., Jr Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens. Brain Res. 1991;539:94–102. doi: 10.1016/0006-8993(91)90690-w. [DOI] [PubMed] [Google Scholar]
  41. Pettit HO, Ettenberg A, Bloom FE, Koob GF. Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology. 1984;84:167–173. doi: 10.1007/BF00427441. [DOI] [PubMed] [Google Scholar]
  42. Phillips GD, Howes SR, Whitelaw RB, Robbins TW, Everitt BJ. Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbens d-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists. Psychopharmacology. 1994;115:419–429. doi: 10.1007/BF02245085. [DOI] [PubMed] [Google Scholar]
  43. Pickens R, Thompson T. Cocaine-reinforced behavior in rats: effects of reinforcement magnitude and fixed ratio size. J Pharmacol Exp Ther. 1968;161:122–129. [PubMed] [Google Scholar]
  44. Porrino MC, Ritz MC, Goodman NL, Sharpe LG, Kuhar MJ, Goldberg SR. Differential effects of the pharmacological manipulations of serotonin systems on cocaine and amphetamine self-administration in rats. Life Sci. 1989;45:1529–1535. doi: 10.1016/0024-3205(89)90418-9. [DOI] [PubMed] [Google Scholar]
  45. Reith MEA, Meisler BE, Sershen H, Lajtha A. Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior. Biochem Pharmacol. 1986;35:1123–1129. doi: 10.1016/0006-2952(86)90148-6. [DOI] [PubMed] [Google Scholar]
  46. Richardson NR, Piercey MF, Svennson K, Collins RJ, Myers JE, Roberts DCS. Antagonism of cocaine self-administration by the preferential dopamine autoreceptor antagonist, (+)-AJ76. Brain Res. 1993;619:15–21. doi: 10.1016/0006-8993(93)91591-f. [DOI] [PubMed] [Google Scholar]
  47. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237:1219–1223. doi: 10.1126/science.2820058. [DOI] [PubMed] [Google Scholar]
  48. Roberts DCS, Koob GF. Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats. Pharmacol Biochem Behav. 1982;17:901–904. doi: 10.1016/0091-3057(82)90469-5. [DOI] [PubMed] [Google Scholar]
  49. Roberts DCS, Vickers G. Atypical neuroleptics increase self-administration of cocaine: an evaluation of a behavioural screen for antipsychotic activity. Psychopharmacology. 1984;82:135–139. doi: 10.1007/BF00426397. [DOI] [PubMed] [Google Scholar]
  50. Roberts DCS, Corcoran ME, Fibiger HC. On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav. 1977;6:615–620. doi: 10.1016/0091-3057(77)90084-3. [DOI] [PubMed] [Google Scholar]
  51. Roberts DCS, Koob GF, Klonoff P, Fibiger HC. Extinction and recovery of cocaine self-administration following 6-hy-droxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav. 1980;12:781–787. doi: 10.1016/0091-3057(80)90166-5. [DOI] [PubMed] [Google Scholar]
  52. Ross SB, Renyi AL. Inhibition of the uptake of tritiated catecholamines by antidepressant and related agents. Eur J Pharmacol. 1967;7:270–277. doi: 10.1016/0014-2999(67)90084-2. [DOI] [PubMed] [Google Scholar]
  53. Smith JE, Co C, Freeman ME, Sands MP, Lane JD. Neurotransmitter turnover in rat striatum is correlated with morphine self-administration. Nature. 1980;287:152–154. doi: 10.1038/287152a0. [DOI] [PubMed] [Google Scholar]
  54. Smith JE, Co C, Freeman ME, Lane JD. Brain neurotransmitter turnover correlated with morphine-seeking behavior of rats. Pharmacol Biochem Behav. 1982;16:509–519. doi: 10.1016/0091-3057(82)90460-9. [DOI] [PubMed] [Google Scholar]
  55. Smith JE, Co C, Lane JD. Limbic acetylcholine turnover rates correlated with rat morphine-seeking behaviors. Pharmacol Biochem Behav. 1984;20:429–442. doi: 10.1016/0091-3057(84)90282-x. [DOI] [PubMed] [Google Scholar]
  56. Weiss F, Hurd YL, Ungerstedt U, Markou A, Plotsky PM, Koob GF. Neurochemical correlates of cocaine and ethanol self-administration. In: Kalivas PW, Samson HH, editors. The neurobiology of drug and alcohol addiction. Vol. 654. Annals of the New York Academy of Sciences; New York: 1992. pp. 220–241. [DOI] [PubMed] [Google Scholar]
  57. Wilson JM, Nobrega JN, Corrigall WA, Coen KM, Shannak K, Kish SJ. Amygdala dopamine levels are markedly elevated after self- but not passive-administration of cocaine. Brain Res. 1994;668:39–45. doi: 10.1016/0006-8993(94)90508-8. [DOI] [PubMed] [Google Scholar]
  58. Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev. 1987;94:469–492. [PubMed] [Google Scholar]
  59. Wise RA, Newton P, Leeb K, Burnette B, Pocock D, Justice JB., Jr Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology. 1995;120:10–20. doi: 10.1007/BF02246140. [DOI] [PubMed] [Google Scholar]

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