Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats

Rationale

Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activity, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-h “binge” in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected.

Objective

This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited-access self-administration “binge.”

Methods

Long-Evans rats underwent episodic social defeat and were assessed 10 days later for either (1) behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, i.p.), (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3) intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited-access “binge.”

Results

Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer “binge” in both sexes, females had a significantly longer “binge” duration than males.

Conclusions

These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.     

Differential neurochemical and behavioral adaptation to cocaine after response contingent and noncontingent exposure in the rat

Rationale In naive rats, passive administration of drugs of abuse preferentially increases extracellular dopamine (DA) in the nucleus accumbens (NAc) shell as compared to the core. Repeated exposure to the same drugs results in behavioral and biochemical sensitization characterized by stereotyped activity and reduction of the shell/core DA response ratio. Objectives The aim of this work is to study the neurochemical and behavioral effects of response-contingent vs response-noncontingent drug administration in rats, who were bilaterally implanted with chronic intracerebral guide cannulae and trained to self-administer cocaine by nose poking in daily 1-h sessions for 3 weeks (5 days/week). Nose poking in the active hole by master rats resulted in intravenous injection of cocaine (0.25 mg/kg) in master rats and in rats yoked to them. Dialysate DA was monitored before, during, and for 30 min after cocaine availability on alternate days by inserting the probe into the NAc shell and core. Stereotyped and non-stereotyped behavior was recorded during the sessions. Results In master rats, dialysate DA increased preferentially in the NAc shell during cocaine self-administration throughout the 3 weeks of cocaine exposure. In yoked rats, DA increased preferentially in the shell but to a lesser extent than in master rats. With continued exposure to cocaine, the shell/core ratio of DA changes decreased progressively and, on the third week, was reversed so that DA increased more in the core than in the shell. Yoked rats showed a progressive and faster increase in stereotyped behaviors than master rats. Conclusions Response-noncontingent cocaine administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.     

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

 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 microbore 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. Received: 23 May 1996 / Final version: 11 April 1997     

5-HT3 agonist-induced dopamine overflow during withdrawal from continuous or intermittent cocaine administration

This experiment examined alterations in the ability of the highly selective 5-HT₃ receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to induce dopamine (DA) overflow in caudate brain slices obtained from rats withdrawn from continuous or intermittent cocaine administration. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either subcutaneous injections or osmotic minipumps, and then withdrawn from this regimen for 7 days. Caudate brain slices were obtained, and perfused with artificial cerebrospinal fluid. Following an equilibration period, the slices were then perfused with 25, 50, or 100 µM mCPBG. The samples were assayed for DA content by HPLC with electrochemical detection. The results indicated that the pretreatment with intermittent cocaine did not consistently alter the ability of mCPBG to induce DA overflow, although there was a reduction in the amount of DA released by the highest concentration of mCPBG. In contrast, pretreatment with continuous cocaine administration consistently and significantly attenuated the ability of mCPBG to induce DA overflow. The DA overflow induced by mCPBG was partially dependent on extracellular Ca²⁺ in the perfusion medium for the saline control and intermittent administration subjects: elimination of Ca²⁺ from the medium significantly reduced, but did not eliminate, DA overflow for these two groups. In contrast, elimination of Ca²⁺ from the perfusion medium had a significant enhancing effect on mCPBG-induced DA overflow in the continuous administration rats. These results suggest that distinct temporal patterns of cocaine administration differentially alter the ability of a 5-HT₃ agonist to increase extracellular DA levels, and that this effect may be related to an impairment of Ca²⁺-dependent release. These results further suggest that 5-HT₃ receptor subsensitivity may represent a partial mechanism for the tolerance following continuous cocaine administration.     

6-Hydroxydopamine lesions of the medial prefrontal cortex fail to influence intravenous self-administration of cocaine

It has been suggested that the initiation and maintenance of cocaine self-administration (SA) is critically dependent on the dopaminergic (DA) projection to the medial prefrontal cortex (mPFC). Evidence for this hypothesis has been obtained from intracranial SA of cocaine, but a role of the mPFC in IV cocaine SA has not been established. The present experiment investigated the effect of destruction of DA-containing terminals in the mPFC on the rate and pattern of IV cocaine SA. Rats were trained to self-administer cocaine during daily 3-h sessions. After stable response patterns were obtained, the rats received either bilateral injections of 6-hydroxydopamine (6-OHDA) into the mPFC, or sham operations. The lesions did not affect either the rate or pattern of IV cocaine SA, despite producing substantial DA depletions in the mPFC. Thus, the mPFC does not appear to be a critical substrate for the maintenance of IV cocaine SA. The 6-OHDA lesions of the mPFC resulted in an apparent increase in DA turnover in both the striatum and the nucleus accumbens, suggesting that DA terminals in the mPFC may have an inhibitory influence on the activity of subcortical DA projections. Offprint requests to: C. Szostak     

Withdrawal from continuous cocaine administration: time dependent changes in accumbens 5-HT3 receptor function and behavioral tolerance

We have previously reported that continuous cocaine administration functionally down regulates 5-HT₃ receptors in the nucleus accumbens. The current experiments evaluated the duration of behavioral tolerance to cocaine and whether the duration of behavioral tolerance and 5-HT₃ receptor down-regulation co-varied. Rats were withdrawn from a pretreatment regimen (40 mg/kg/per day cocaine or 0.9% saline for 14 days) for 1, 7 or 14 days. The rats were either sacrificed, and slices from the nucleus accumbens obtained, or were exposed to behavioral rating procedures. The results indicated that continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K⁺-stimulated DA release on days 1 and 7, but not day 14, of withdrawal. Furthermore, continuous cocaine administration induced behavioral tolerance to a cocaine challenge on days 1 and 7, but not day 14, of withdrawal. These results suggest that continuous cocaine administration functionally down-regulates 5-HT₃ receptors in the nucleus accumbens, and this functional down-regulation co-varies with the behavioral tolerance induced by continuous cocaine administration. Hence, a functional down-regulation of accumbens 5-HT₃ receptors may represent a partial mechanism for the tolerance following continuous cocaine administration. Received: 15 April 1998/Final version: 11 September 1998     

Altered cocaine potency in the nucleus accumbens following 7-day withdrawal from intermittent but not continuous treatment: voltammetric assessment of dopamine uptake in the rat

Using in vitro fast scan cyclic voltammetry, we measured cocaine potency for inhibiting dopamine uptake/clearance in accumbens slices 7 days after withdrawal from chronic cocaine pretreatments. Rats were pretreated with 40 mg/kg per day for 14 days, either via continuous osmotic minipumps or by once-daily injections. The cocaine potency was subsequently assessed for endogenous and exogenous dopamine applied via single-pulse electrical stimulation and caged-dopamine photolysis, respectively. Under baseline conditions, no differences in either endogenous or exogenous dopamine kinetics were observed in the two cocaine pretreatment groups. In contrast, the potency of bath-applied cocaine for inhibiting endogenous dopamine uptake was enhanced in the intermittent injection group with no change in the continuous infusion group. The selective increase in the cocaine potency following injections was also demonstrable for clearance of photo-applied DA. The enhanced cocaine potency in the accumbens slices following 7 days of withdrawal is consistent with the residual sensitization to cocaine-induced locomotion following daily cocaine injections. Behavioral tolerance following continuous infusion, on the other hand, may be mediated via a mechanism distinct from altered dopamine uptake. Received: 3 September 1997/Final version: 12 November 1997     

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D₂ autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D₁ receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D₁ class receptor agonist SKF 38393, the DA D₂ class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D₁ receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D₁ responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D₁ receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization. Received: 23 February 1998/Final version: 2 April 1998     

Iptkalim inhibits cocaine challenge—induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up—regulating Kir6.1 and Kir6.2 mRNA expression

目的:研究钾通道开放剂埃他卡林对急慢性可卡因应用引起的伏隔核、纹状体和额叶皮层的多巴胺和谷氨酸水平变化的影响及其机制。方法:采用高效液相色谱与电化学检测、荧光检测联用的方法测定各脑区谷氨酸和多巴胺的含量;采用半定量逆转录聚合酶链反应(RT-PCR)研究ATP敏感性钾通道亚单位Kir6.1、Kir6.2、SUR1和SUR2 mRNA表达的变化。结果:埃他卡林不影响急性可卡因应用引起纹状体和伏隔核中多巴胺和谷氨酸水平的增高(P>0.05),能够逆转激发剂量可卡因诱导的慢性成瘾大鼠纹状体和伏隔核的多巴胺含量增高(P<0.05),对激发后皮层和伏隔核谷氨酸水平增高有降低趋势但差异无显著性(P>0.05)。激发剂量可卡因能提高可卡因预处理组和埃他卡林预处理组纹状体和伏隔核的Kir6.1和Kir6.2 mRNA表达以及皮层的Kir6.2 mRNA表达,而且IPT预处理组的升高幅度显著高显著高于可卡因慢性处 理组。结论:埃他卡林通过上调Kir6.1和Kir6.2 mRNA表达抑制可卡因激发引起的纹状体和伏隔核的多巴胺水平的增高。     

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

Rationale Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear.Objectives To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration.Methods In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0).Results Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions.Conclusions Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.     

Effects of withdrawal from chronic escalating-dose binge cocaine on conditioned place preference to cocaine and striatal preproenkephalin mRNA in C57BL/6J mice

Relapse is a serious problem for the effective treatment of cocaine addiction.RationaleExamining cocaine re-exposure-induced behavioral and neurobiological alterations following chronic escalating-dose binge cocaine administration and withdrawal may provide insight into the neurobiological basis of cocaine relapse.ObjectivesOur goal was to determine how exposure to chronic escalating-dose cocaine affects development of subsequent cocaine-induced conditioned place preference (CPP) and changes in endogenous opioid systems.MethodsMice were injected with either escalating-dose binge cocaine (15–30 mg/kg/injection × 3/day) or saline for 14-days and conditioned with 15 mg/kg of cocaine or saline (once per day for 10-days), starting either 1 or 14-days after the last day of binge injections.ResultsMice exposed to chronic escalating cocaine did not develop CPP to cocaine when conditioning commenced on the first day of withdrawal (CPP test on day 10 of withdrawal). By contrast, mice did develop CPP to cocaine when conditioning started on the 14th day of withdrawal (CPP test on day 24 of withdrawal). Furthermore, preproenkephalin (Penk) mRNA levels in caudate putamen were significantly higher in mice that received 14-day withdrawal from escalating-dose binge cocaine before the CPP procedure (tested 24 days post-binge) than those that received 1-day withdrawal (tested 10 days post-binge).ConclusionsThe rewarding effect of cocaine was blunted in early withdrawal from chronic escalating exposure, but recovered in more prolonged withdrawal. Time-dependent elevations in Penk mRNA levels may be part of the underlying mechanisms of this effect.     

Dopamine efflux during withdrawal from continuous or intermittent cocaine

Daily, intermittent, subcutaneous cocaine injections produce sensitization, while the continuous administration of cocaine produces tolerance to the behavioral effects of subsequent cocaine injections. The present experiments examined whether these behavioral differences are related to differences in the ability of cocaine to increase extracellular dopamine. Increases in perfusate DA, in response to different concentrations of cocaine, were measured in caudate-putamen slices obtained from rats withdrawn for 7 days from a 14-day treatment of either continuous or daily subcutaneous cocaine injections. Compared to saline controls, cocaine-induced DA efflux was increased in subjects receiving daily injections and markedly decreased in subjects receiving continuous cocaine. Thus, different temporal patterns of cocaine administration produce dramatically different alterations in DA neurotransmission. Such changes in dopamine release may be related to the withdrawal symptoms experienced by human cocaine abusers.     

5-HT3 receptor mediated dopamine release in the nucleus accumbens during withdrawal from continuous cocaine

The present experiment examined changes in the ability of the selective 5-HT₃ receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to facilitate K⁺-induced dopamine (DA) release during withdrawal from continuous cocaine administration. Rats were withdrawn from continuous cocaine administration (40 mg/kg per day cocaine for 14 days) for 7 days, and then slices from the nucleus accumbens obtained. Following an equilibration period, the slices were perfused with 0, 12.5, 25, or 50 μM mCPBG in the absence and presence of 25 mM K⁺. The samples were assayed for DA content by HPLC with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K⁺-induced DA overflow compared to saline control rats. These results suggest that continuous cocaine administration functionally down-regulates 5-HT₃ receptors in the nucleus accumbens. These results further suggest that 5-HT₃ receptor subsensitivity may represent a partial mechanism for the tolerance induced by continuous cocaine administration. Received: 19 June 1996 / Final version: 25 October 1996     

Subregion-specific down-regulation of 5-HT3 immunoreactivity in the nucleus accumbens shell during the induction of cocaine sensitization

Repeated exposure to psychostimulants such as cocaine and amphetamine can result in behavioral sensitization, which is believed to model the onset of drug addiction, as well as neural adaptations that occur after repeated drug abuse that lead to addictive behaviors. Dopamine (DA) in the nucleus accumbens (NAc) has been shown to play an integral role in this phenomenon. However, cocaine also acts on the serotonin (5-HT) system, which has been shown to modulate psychostimulant-induced increases in motor behavior and DA release in the NAc. Recently, it has been demonstrated that the shell portion of the NAc can no longer be considered a homogeneous structure and can be subdivided into at least five separate regions. The present study examines 5-HT(3) receptors in the subdivisions of the NAc in cocaine-sensitized rats. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg ip for five consecutive days). Two or 14 days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg ip) and sacrificed 2 h later. Sections of the NAc were processed for 5-HT(3) immunoreactivity (5-HT(3)-IR), and the number of puncta was quantified in each of the subregions of the shell, as well as the core of the accumbens. Repeated cocaine administration resulted in robust sensitization that correlated with a transient decrease in the density of 5-HT(3) immunoreactive puncta in the intermediate zone of the accumbens shell. After a 2-week withdrawal period, sensitized animals no longer showed any differences in any of the areas examined. These data suggest a possible role for 5-HT(3) receptors in the intermediate zone during the induction of cocaine sensitization.     

Self-administered heroin and cocaine combinations in the rat: additive reinforcing effects-supra-additive effects on nucleus accumbens extracellular dopamine.

The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose-effect curves for rat self-administration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose-effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA](e)) in rats self-administering low doses of cocaine, heroin, or cocaine/heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA](e), while heroin alone did not. The ratio of the % baseline of [DA](e) (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during self-administration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA](e) may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the self-administration of this drug combination.     

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

Time-dependent changes in mesolimbic dopamine (DA) function are believed to play a role in behavioral sensitization and drug craving experienced during withdrawal from chronic cocaine administration. The present study utilized intravenous (IV) cocaine self-administration coupled with intracranial microdialysis in rats to investigate time dependent changes during withdrawal from chronic cocaine exposure. Following 2 weeks of IV cocaine self-administration, rats were allowed contingent access to cocaine at 1 and 7 days of withdrawal while extracellular levels of DA were measured from the ventral striatum. A second group of animals received yoked, noncontingent cocaine for 2 weeks and were then administered noncontingent cocaine on days 1 and 7 of withdrawal. In addition, a third group of animals received 2 weeks of yoked saline followed by noncontingent cocaine 1 day after withdrawal. There were no significant differences between groups for the overall cocaine dosage or temporal pattern of infusions on days 1 and 7 of withdrawal. Basal extracellular DA concentrations did not differ between any treatment groups at either withdrawal time. Extracellular DA levels were increased throughout the session on both days; however, the increases at day 7 were significantly less than day 1 for both contingent and noncontingent conditions. DA overflow on day 1 did not differ between animals receiving chronic yoked cocaine or saline. These results suggest that tolerance-like attenuation to the DA-elevating effects of cocaine is not apparent early in withdrawal, but does develop by later time points. DA release in the ventral striatum may not be directly related to cocaine self-administration following withdrawal, since DA levels were attenuated after 7 days of withdrawal while responding for cocaine was unaltered.     

Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats

Rationale Animal models that identify the effects of self-administration histories on subsequent patterns, levels of intake, and other aspects of reinforcement will help clarify the controlling variables of human drug use.Objective Identify the effects of extended-access to cocaine and 1 or 7 days of deprivation on cocaine-maintained breakpoints on a progressive ratio (PR) schedule of reinforcement.Methods Male, Sprague–Dawley rats were trained to self-administer intravenous cocaine (expt 1: 1.5 mg/kg per infusion; expt 2: 0.75 mg/kg per infusion), and then given various histories of self-administration and deprivation. Breakpoints, the number of infusions self-administered on a PR schedule, were assessed following the deprivation period.Results Rates of cocaine intake increased when access to cocaine was extended to 6 h/day. From day 1 to day 14, daily intake increased from 92 (±2.5) to 101 (±2.8) mg/kg in expt 1, and from 55 (±4) to 78 (±2.2) mg/kg in expt 2. Total intake across this 2-week period was approximately 1260 and 970 mg/kg in expts 1 and 2. Breakpoints were not different following this escalation period. The introduction of a 7-day deprivation period failed to alter breakpoints.Conclusions There is dissociation between changes in rate of cocaine intake (or consumption) and breakpoints maintained on a PR schedule. Extended-access to cocaine produced increases in rate of intake without altering breakpoints. Depending on the experimental question, extended-access conditions may prove useful for studying changes in certain aspects of reinforcement, such as consumption, but not others, such as the strength of a drug as a reinforcer.     

Pharmacological reactivity to cocaine in adult rats undernourished at perinatal age: behavioral and neurochemical correlates

The influence of neuronal alterations induced by early undernutrition on the stimulant effect of cocaine was assessed in adult rats submitted to a protein deprivation schedule at perinatal age. To evaluate the sensitization phenomenon induced by repeated cocaine administration, different groups of control (C) and deprived (D) rats received a daily injection of cocaine (5, 10 or 15 mg/kg, i.p.) for 16 days. Behavioral parameters were assessed every two days in an open-field. Dose-response curves obtained with different doses of cocaine used revealed a shift to the left in the locomotor activity curves of D rats compared to controls. Thus, D animals showed a clear behavioral sensitization to the lower dose of cocaine, whereas this phenomenon was only observed in C rats for the higher dose used. To correlate this differential development of sensitization with neurochemical parameters, we assessed extracellular dopamine (DA) levels in nucleus accumbens (core and shell) and in the dorsal caudate-putamen, using a microdialysis technique. A challenge with cocaine in cocaine pre-exposed animals produced a different increase in DA output only in nucleus accumbens "core" of D animals. Comparable DA levels were observed in nucleus accumbens shell and in dorsal caudate-putamen of both groups. These results demonstrate that D rats had a lower threshold developing a progressive behavioral sensitization following repeated cocaine administration, as well as higher responsiveness of the nucleus accumbens (core) expressed by increased DA release.     

Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine.

Stimulation of central serotonin2C receptor (5-HT(2C)R) inhibits dopamine (DA)-dependent neurochemical and behavioral effects of cocaine, while 5-HT(2C)Rs locally expressed into the ventral tegmental area (VTA) and the nucleus accumbens (NAc) exert opposite functional control over cocaine-induced behavioral effects. Using in vivo microdialysis in halothane-anesthetized rats, we tested the hypothesis that this functionally opposite regulation of the mesoaccumbens DA pathway relies on the ability of 5-HT(2C)Rs in the VTA and the NAc to inhibit and enhance respectively cocaine-induced accumbal DA outflow. Intra-VTA injection of the 5-HT(2C)R agonist Ro 60-0175 at 5 microg/0.2 microl, but not 1 microg/0.2 microl, attenuated the increase in accumbal DA outflow induced by the systemic administration of 10 mg/kg of cocaine. Intra-VTA injection of the 5-HT(2C)R antagonist SB 242084 at either dose (0.1 or 0.5 microg/0.2 microl) did not modify the effects of cocaine. Intra-NAc application of Ro 60-0175 dose-dependently excited (0.1 microM) and inhibited (1 microM) cocaine-induced DA outflow. In contrast, intra-NAc application of SB 242084 resulted in diametrically opposite effects when applied at these concentrations. These results further support the idea that the overall action of central 5-HT(2C)Rs on accumbal DA output is dependent, at least in part, on the functional balance between different 5-HT(2C)R populations within the NAc and within the mesoaccumbens DA pathway (VTA vs NAc).     

The effects of continuous cocaine dose, treatment, and withdrawal duration on the induction of behavioral tolerance and dopamine autoreceptor function

The present experiment evaluated the interactions between continuous cocaine dose, duration of administration, and duration of withdrawal on the induction of behavioral tolerance and changes in dopamine autoreceptor (DA) function. In the current experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 0, 5, or 20 mg/kg/day cocaine for either 3 or 7 days. All subjects were then withdrawn from the pretreatment regimen for 1 or 7 days. For the experiments examining behavioral tolerance, the subjects received 15.0 mg/kg ip cocaine. For the experiments examining alterations in DA function, the subjects received a 0.063 mg/kg ip quinpirole injection, followed 5 min later by a 15.0 mg/kg ip cocaine injection. For all experiments, the subjects were placed in activity monitors, and ambulation was measured for 60 min. The results indicated that all continuous cocaine durations induced significant changes in cocaine-induced behavior at the 1-day withdrawal period. However, for tolerance to be exhibited on the 7-day withdrawal period, either high-dose or long-duration continuous cocaine had to be administered. This tolerance was associated with an increase in DA sensitivity. However, the change in DAs was dose- or duration-dependently related to tolerance. Overall, the literature suggests that behavioral tolerance following continuous cocaine administration may be mediated by multiple, time-dependent mechanisms that operate in an all-or-none manner.