Research Findings - Basic Behavioral Research
"Speedball" Abuse May be Motivated by the Attenuation of Cocaine's Negative Aversive Effects
According to epidemiological observations, "speedballing," the combined use of psychostimulants with opiates, is relatively widespread among drug users. Verbal reports suggest that the combination of cocaine and heroin induces a greater euphoria than experienced with either drug alone. These drug combinations also produce higher break points in preclinical studies using progressive ratio schedules to assess relative reinforcement. Heroin also shifts the cocaine reward dose-effect curve to the left, suggesting that heroin enhances cocaine's rewarding effects. However, cocaine also induces a negative affective state that can be measured using runway procedures to detect approach/avoidance responses when animals are trained to run into a goal box for i.v. cocaine. In this paradigm, the dependent measure of avoidance is the number of "retreats" en route to the goal box. Dr. Aaron Ettenberg, has been studying aversive properties of cocaine and recently found that either a low (.025 mg/kg), or a high (.100 mg/kg), dose of heroin reduces the number of retreats in animals trained to traverse a runway for 1.0 mg/kg i.v. cocaine. Three groups of rats were trained to run the runway for cocaine and were matched prior to testing with heroin on mean number of retreats over 14 days of training. Seven trials were conducted with groups reinforced for running to the goal box, either with cocaine only, or cocaine + one of the heroin doses. While it is also possible that heroin produces its effects by enhancing the reinforcing effects of this dose of cocaine (thus, the "approach" component of responding), the groups showed no difference in latency to leave the runway start box. Also, the low dose of heroin used does not produce a conditioned place preference on its own. The authors argue that these observations support the interpretation that heroin attenuates the ambivalence or conflict experienced over entering the goal box for a cocaine injection. Guzman, D. and Ettenberg, A. Heroin Attenuates the Negative Consequences of Cocaine in a Runway Model of Self-Administration. Pharmacology, Biochemistry and Behavior, 79, pp. 317-324, 2004.
Chronic Cocaine Enhances the Strength of Conditioning to Sexual Stimuli
Repeated psychostimulant administration induces behavioral sensitization to the locomotor activating effects of these drugs, and is associated with greater drug-induced dopamine release than acute drug treatment. This sensitization has been proposed to be responsible for enhanced incentive motivational properties of drug-related stimuli that induce craving in addiction. For example, in animal studies, behavioral sensitization increases drug self-administration and drug seeking after abstinence. Cross-sensitization has also been demonstrated; drug sensitization facilitates responding for other classes of reinforcers, such as natural rewards including sucrose, and for sexual stimuli. Psychostimulant-sensitized animals also form stronger associations in Pavlovian conditioning, and it has been suggested that increased dopamine enhances learning. Dr. Chana Akins and colleagues have been using a well-studied sexual conditioning paradigm in Japanese quail to measure approach behaviors for stimuli previously paired with copulatory experience. In a recent study, cocaine-treated animals received 10mg/kg i.p. daily for six days and were tested for locomotion after each injection. After a 10-day withdrawal period, 10 conditioning trails were conducted with a discrete visual stimulus in the test box introduced 30 sec before availability to interact with a female conspecific. Time spent in proximity of this conditioned stimulus (CS) was recording for drug or saline injected animals that were exposed to this stimulus paired or unpaired with access to a female. On tests of locomotor activity, cocaine injected animals had greater activation, in comparison with saline injected controls, over all six sessions. While both paired groups showed a successive increase in amount of time spent near the CS, this effect was greater for cocaine CS-paired animals than for the other three groups, suggesting enhanced conditioning as a result of the prior cocaine treatments. Cocaine-treated animals conditioned with a paired CS also demonstrated a shorter latency to copulate and had more cloacal contacts with the female than saline-treated animals with the CS conditioned to a female. These findings suggest that prior repeated cocaine exposure may strengthen the ability of sex-related stimuli to acquire incentive motivation properties that can elicit approach behavior, and also may increase unconditioned sexual behaviors. As cocaine use has been associated with high-risk sexual behaviors, these findings may suggest a neurobiological mechanism for cross-sensitization to the vulnerability for sexual behaviors. Levens, N. and Akins, C.K. Chronic Cocaine Pretreatment Facilitates Pavlovian Sexual Conditioning in Male Japanese Quail. Pharmacology, Biochemistry and Behavior, 79, pp. 451-457, 2004.
Analogous Changes in Striatal Gene Expression Follow Sexual Experience or Exposure to Drugs of Abuse
It has been suggested that drugs of abuse "hijack" neural systems that evolved to support natural motivated behaviors. Thus, an understanding of the neural control of natural behaviors can help us understand the specific pathology of drug abuse. Motivated behaviors that exhibit properties such as sensitization — an increase in behavioral response with repeated exposures to motivating stimuli — are of particular interest in this regard. Repeated sexual experiences, like repeated drug use, produce long-term changes including sensitization of dopamine release in the nucleus accumbens and dorsal striatum. Previously, Drs. Katherine Bradley and Robert Meisel showed that amphetamine-stimulated locomotor activity was sensitized by previous sexual experience in female Syrian hamsters. They are now collaborating with Dr. Paul Mermelstein to investigate the molecular mechanisms underlying neuroadaptations produced by sexual experience. In this study, they used DNA microarray techniques to identify genes differentially expressed within the nucleus accumbens and dorsal striatum between sexually experienced and sexually naïve female hamsters. For these experiments, female hamsters were ovariectomized and hormonally primed. Half of them were then exposed to a stimulus male once a week for six weeks, while the other half remained naïve. On week seven, the two groups were subdivided, with one half of each exposed to a stimulus male. In comparison with sexually naïve animals, sexually experienced hamsters that received a stimulus male on week seven exhibited an increase in a large number of genes. Conversely, sexually experienced females that did not receive a stimulus male on week seven exhibited a reduction in the expression of many genes compared to naïve animals. The data for the nucleus accumbens and dorsal striatum were similar in terms of directional changes and the categories of genes regulated by the experimental conditions. However, the specific genes exhibiting changes in expression differed between these two brain areas. The investigators also observed that many of the gene classes and specific genes regulated by sexual experience overlapped with those previously reported to be regulated by chronic administration of drugs of abuse, and that many of these genes are involved in forms of neuronal plasticity such as changes in excitability or dendritic growth. These experiments are among the first to profile genes regulated by sexual behaviors in brain areas (the mesolimbic and nigrostriatal dopamine pathways) involved in long term neuroadaptive changes underlying addiction. And, importantly, studies like this may help us understand why, unlike drug use, natural motivated behaviors do not, in general, progress to an uncontrolled, compulsive state. Bradley, K.C., Boulware, M.B., Jiang, H., Doerge, R.W., Meisel, R.L. and Mermelstein, P.M. Sexual Experience Generates Distinct Patterns of Gene Expression Within the Nucleus Accumbens and Dorsal Striatum of Female Syrian Hamsters. Genes, Brain and Behavior, 4, pp. 31-44, 2005.
Opioid Receptor Activation of the Mesolimbic System by Sexual Behavior and Associated Environmental Cues
The mesolimbic system plays an important role in the regulation of both pathological behaviors such as drug addiction and normal motivated behaviors such as sexual behavior. In this study, Dr. Lique Coolen and her colleagues, investigated the mechanism by which this system is endogenously activated during sexual behavior in male rats. Specifically, they studied the effects of sexual experience and sex-related environmental cues on the activation of several components of the mesolimbic system, which consists of a dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous studies suggest that these neurons are under tonic inhibition by local GABA interneurons, which are in turn modulated by mu opioid receptor (MOR) ligands. To test the hypothesis that opioids are acting in the VTA during sexual behavior, the investigators measured MOR internalization in VTA as a marker for ligand-induced activation of the receptor. They observed significant increases in MOR internalization following copulation or exposure to sex-related environmental cues alone (the test cage). A second experiment was designed to determine if sexual behavior activates dopamine neurons in the VTA, using tyrosine hydroxylase as a marker for dopaminergic neurons and Fos-immunoreactivity as a marker for neuronal activation. They found significant increases in the percentage of activated dopaminergic neurons following copulation or exposure to sex-related environmental cues. In addition, mating and sex-related cues activated a large population of nondopaminergic neurons in VTA and neurons in both the NAc core and shell. This study is the first to provide direct functional neuroanatomical evidence that the mesolimbic system is activated by both sexual behavior and exposure to sex-related environmental cues. Opioid addiction is, at least in part, mediated by activation of these same MORs, which inhibit the firing of GABA neurons in the VTA, releasing the dopamine neurons from inhibition. Studies like this one from Dr. Coolen's laboratory will help us understand how these brain systems are regulated in their normal function and become dysregulated in drug addiction. Balfour, M.E., Yu, L., and Coolen, L.M. Sexual Behavior and Sex-Associated Environmental Cues Activate the Mesolimbic System in Male Rats. Neuropsychopharmacology, 29, pp. 718-730, 2004.
Early Life Stress Enhances Relapse in an Animal Model
Observations from clinical studies on cocaine abusers show that both psychological and physical stress elicit drug craving. Moreover, risk for drug use has been associated with adverse life events and chronic stress. Thus, stress may contribute to the vulnerability for drug abuse behavior and to the propensity to maintain this behavior or to relapse. A vast preclinical literature has modeled deleterious effects of physical and social stressors on acquisition, maintenance and reinstatement of drug seeking. Animal models of early life stress employ neonatal isolation procedures that involve prolonged separation from the mother for one hour per day over post-natal days 2 through 12. Neonatal stress has previously been shown to enhance vulnerability for acquisition of cocaine self-administration, but subsequent effects on relapse after self-administration has been extinguished are unknown. In the present study, the investigators compared male and female rats that were subjected to neonatal isolation with controls that were only handled and returned to the litter. All animals were trained for cocaine i.v. self-administration at 90 days of age, under a fixed ratio 1 schedule of reinforcement. They were then subjected to seven consecutive sessions of a 24-hr discrete trial procedure that provides extended access to drug and has been used to develop excessive, uncontrollable intake. This was followed by 10 days of extinction during which time animals did not receive drug infusion for operant responses in the chamber. After the tenth session, rats were tested in a single one-hour reinstatement session in the presence of cues previously paired with i.v. drug delivery. Group comparisons revealed that during acquisition, female rats took more cocaine than males, replicating findings of many prior preclinical studies on gender differences in cocaine intake. During extinction responding, females also tended to respond at higher levels during initial extinction sessions than males, and isolated rats responded at much higher levels than handled controls. Similarly, neonatally isolated rats responded at much higher levels during cue-induced reinstatement testing — making approximately 48% more responses in the presence of drug-associated cues. The findings of this study indicate that early stress may enhance the vulnerability for relapse to cocaine-seeking behavior in adulthood, when cues previously associated with drug reinforcement are encountered. Lynch,W.J., Mangini, L.D., and Taylor, J.R. Neonatal Isolation Stress Potentiates Cocaine-Seeking Behavior in Adult Male and Female Rats. Neuropsychopharmacology, 30, pp. 322-329, 2005.
Sucrose Intake Enhances Behavioral Sensitization Produced by Cocaine
Prior research has revealed interactions between an animal's history with sweet solutions and psychostimulant drug self-administration. For example, access to a sweet solution can prevent acquisition, and decrease the continued maintenance of cocaine self-administration. Dr. Blake Gosnell from the Neuropsychiatric Research Institute has now shown that experience with sucrose can sensitize animals to the locomotor-activating effects of cocaine. For 38 days, three groups of rats had daily 1-hr access either to sucrose, ground rat chow, or alternating daily access to either chow or sucrose. On the following two days, respectively, rats were given an i.p cocaine injection and an i.p saline injection. In response to the cocaine injection, rats pre-exposed to sucrose exhibited an elevated, although non-significant, locomotor response compared to the other two groups. Next, for five days, rats were given an injection of cocaine and immediately returned to their home cage. Then one and 15 days after the final cocaine injection they were tested for their locomotor response to cocaine. On the first day, all rats exhibited a sensitized locomotor response to cocaine with the sucrose group exhibiting the greatest sensitization. When tested 15 days after the last cocaine injection, sensitization was still present and was greater in the previously exposed sucrose group than the other two. These outcomes indicate that repeated, intermittent intake of a palatable food can potentiate the effect of cocaine on locomotor behavior, and are consistent with other studies showing that food reward and drug reward are subserved by overlapping neural circuits. This area of investigation may contribute to understanding high rates of comorbidity between eating disorders and substance abuse, especially in females. Gosnell, B.A. Sucrose Intake Enhances Behavioral Sensitization Produced by Cocaine. Brain Research, 1031, pp. 194-201, 2005.
Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys
Numerous rodent studies have demonstrated that cocaine sensitivity is greater in females than in males and that this sensitivity varies with the estrus cycle. Laboratory-based studies in humans have also documented sex differences and menstrual cycle differences in the subjective effects of cocaine thus raising questions about possible fluctuations in cocaine pharmacokinetics during the menstrual cycle. Drs. Suzette Evans and Richard Foltin addressed this issue by studying the rhesus monkey, which has a menstrual cycle similar in length and hormonal fluctuations to that in humans. They examined cocaine pharmacokinetics in five female rhesus monkeys given acute i.v. doses of 0, 0.25, 0.50 and 1.0 mg/kg cocaine during four phases of the menstrual cycle: menses, midfollicular, periovulatory and midluteal. Plasma levels of cocaine and cocaine metabolites benzoylecgonine (BZE) and ecgonine methyl ester (EME) were measured at multiple time points during 90 min following each cocaine injection. The researchers found that peak plasma levels of cocaine increased as a function of dose, but did not vary with the menstrual cycle. There were also no menstrual cycle differences in either the time to achieve peak plasma levels of cocaine or the half-life of cocaine. On the other hand, levels of cocaine metabolites did vary with the menstrual cycle. Plasma levels of BZE and EME were greatest during the luteal phase particularly following the highest cocaine dose. In an analysis of their data from a prior study in which plasma cocaine metabolite levels were collected in women who received repeated doses of 12 mg smoked cocaine during the follicular and luteal phases (Evans et al., 2002), Drs. Evans and Foltin also found that BZE plasma levels were higher in the luteal phase than in the follicular. The present findings, along with the similarity of the menstrual cycle in rhesus monkey and in humans, point to the feasibility of the rhesus monkey model to further our understanding of the role of the menstrual cycle in acute and chronic effects of cocaine. Evans, S.M., and Foltin, R.W. Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys. Neuropsychopharmacology, 29, pp. 1889-1900, 2004.
Impulsivity (Delay Discounting) as a Predictor of Acquisition of IV Cocaine Self-Administration
Studies in humans have shown a relationship between drug abuse and impulsivity as measured by delayed discounting. Cigarette smokers, crack/cocaine abusers, and opioid dependent individuals, for example, discount delayed rewards more than non-drug users, although it is not clear whether the impulsivity precedes the development of drug abuse or is a consequence. This question was addressed by researchers at the University of Minnesota and University of Wisconsin-Eau Claire using an animal model in which they compared acquisition of cocaine self-administration in female rats that differed in baseline level of impulsivity, as measured by choice for an immediate small reinforcer (one 45 mg food pellet) over a delayed larger reinforcer (three 45 mg food pellets). The researchers found that acquisition of cocaine self-administration occurred in a greater percentage of the rats that exhibited high levels of baseline impulsivity compared to those that exhibited low levels of baseline impulsivity. These data are consistent with and extend prior research showing that rats that exhibited high impulsive choices consumed more ethanol than those that exhibited medium or low impulsive choices (Poulos et al., 1995) and therefore point to impulsivity as a factor that may predispose one to drug abuse. The authors caution, however, that the relationship between impulsivity and drug use may not be unidirectional, citing findings from an earlier study (Richards et al., 1999) in which rats receiving chronic methamphetamine showed increased delay discounting. Perry, J.L., Larson, E.B., German, J.P., Madden, G.J., and Carroll, M.E. Impulsivity (Delay Discounting) as a Predictor of Acquisition of IV Cocaine Self-Administration in Female Rats. Psychopharmacology, 178, pp. 193-201, 2005.
Binge Self-Administration and Deprivation Produces Sensitization to the Reinforcing Effects of Cocaine
Recently there has been heightened interest in using animal behavioral paradigms of drug self-administration to model compulsive drug use in humans. One such model has been described by Dr. David Roberts and colleagues at Wake Forest University (Roberts et al., 2002). These investigators use a procedure in which rats receive access to cocaine for 24 hr per day in 4 discrete trials (DT4) per hour, (thus permitting a maximum of four infusions per hour), for 10 days followed by 7-days of cocaine deprivation. This procedure results in an enhanced reinforcing efficacy of cocaine as measured by breakpoints (BP) on a progressive ratio schedule (PR). [In a PR schedule, the number of responses required for reinforcement progressively increases after each reinforcer until a "breakpoint" is reached where responding ceases]. In the present study, these researchers sought to identify features of the DT4 procedure that are critical for producing an enhancement of cocaine's reinforcing efficacy. Four separate groups of rats were tested under the DT4 procedure for 10 days with cocaine self-administered doses of 0.38, 0.75, 1.5, or 3.0 mg/kg per infusion. A fifth group, the Matched FR group, self-administered 1.5 mg/kg per infusion according to a fixed ratio one (FR 1) schedule and received the average number of daily cocaine infusions that was self-administered by the DT4 1.5 mg/kg group. A sixth group also self-administered 1. 5-mg/kg but received a 1-day drug-free period before PR assessment instead of a 7-day period. Responding on an FR1 schedule and on a PR schedule was measured prior to the 10 days of cocaine self-administration, and then again following the 7 days, or one day, of drug abstinence. Results indicated that following the DT4 procedure and 7 drug-free days, there was not an increase in BP for all four dose groups; but instead, BPs were increased for groups receiving 1.5 and 3.0 mg/kg per per infusion, but not for groups receiving the lower doses. By contrast, experience with the DT4 procedure followed by 7 drug-free days did not alter responding on a FR1 schedule. The Matched FR group failed to show any change in BP following the DT4 procedure, indicating that the daily pattern of self-administration is an important determinant in development of enhanced reinforcing efficacy. Although these groups were matched on the absolute amount of drug received over 24 hours, it is significant that self-administration in the Matched FR group occurred largely in the first eight hours of cocaine availability and at a high frequency, thus permitting high blood levels of cocaine, whereas in the DT4 groups self-administration could not occur at similarly high rates and was spaced over far more hours per day. Thus, the pattern of drug intake may be an important variable in the changing efficacy of cocaine produced by the DT4 schedule. Also, as the group receiving only one drug-free day failed to exhibit an increase in BP following the DT4 procedure, exposure to an extended drug-free deprivation period may be another variable that is important in the development of enhanced drug reinforcement efficacy. The results of this study illustrate the utility of this protocol for identifying factors that may contribute to a shift from casual to compulsive use of abused drugs. Morgan, D., Smith, M.A. and Roberts, D.C.S. Binge Self-Administration and Deprivation Produces Sensitization to the Reinforcing Effects of Cocaine in Rats. Psychopharmacology, 178, pp. 309-316, 2005.
Effects of D-amphetamine on Cognition and Response Inhibition
Stimulant drugs such as d-amphetamine and methylphenidate (RitalinTM) are often used to improve performance in humans and, in fact, are prescribed to treat behavioral and cognitive impairments associated with ADHD and disorders of self-control. Moreover, illicit use of stimulants, such as d-amphetamine and cocaine, might be motivated by self-medication of behavioral and/or cognitive deficits. Research by NIDA grantee Mark Fillmore and his colleagues tested the effects of d-amphetamine on working memory and inhibitory control in a group of healthy adults with no reported history of illicit stimulant use or drug dependence. The study used well-documented and reliable measures of working memory (the rapid information processing task, RIP) and inhibitory control (the stop signal task). Three doses of oral d-amphetamine (0, 7.5 and 15 mg/70kg) were administered double blind in a randomized, within-subject design. In addition to the two dependent variables of primary interest, the study also measured subjective (12-item, visual analogue scale) and physiological (HR and BP) effects of this drug. Results indicated that RIP rates increased 2 hr following the two active doses and the increase was maintained at 3 hr. By contrast, d-amphetamine had no effect on response inhibition. Active doses of the drug increased BP and HR up to 3 hr after drug administration and subjective effects of the drug were seen at 2 and 3 hrs. These findings indicate that a stimulant drug can enhance aspects of cognitive functioning without producing a concomitant improvement in inhibitory control of behavior. Failure to observe a stimulant-induced enhancement of inhibitory control in healthy adults might appear at odds with previous reports that d-amphetamine improved inhibitory control in this population. However, the facilitating effects in those studies were confined to individuals who displayed poor levels of response inhibition at baseline. Poor inhibition was determined in those studies by a median split of subjects into high and low baseline inhibition levels. That evidence, along with findings of stimulant-induced inhibitory facilitation in children with ADHD, could suggest that stimulant-induced enhancement of response inhibition might be selectively induced in individuals with poor basal levels of inhibitory control. The present findings contribute to a growing understanding of how stimulant drugs affect behavioral control in humans. The findings also highlight the complex nature of stimulant effects on human behavior and the utility of performance tasks as models of complex behavioral and cognitive functions. Fillmore, M.T., Kelly, T.H., and Martin, C.A. Effects of D-amphetamine in Human Models of Information Processing and Inhibitory Control. Drug and Alcohol Dependence, 77, pp. 151-159, 2005.
Repeated Maternal Separation in Mice: Sex Differences in Cocaine-Induced Behavioral Sensitization in Adulthood
Experimental protocols in rats have documented that repeated maternal separation (MS) of the neonate can produce changes in the dopamine system and in the hypothalamic-pituitary-adrenal axis (HPA axis), including enhancement of cocaine-induced increases in ventral striatal dopamine levels and elevated basal levels of circulating glucocorticoids and glucocorticoid response to mild stress. Dr. Klaus Miczek and colleagues now report the effects of MS on cocaine-induced sensitization, on glucocorticoid receptors in the hippocampus, and on the dopamine transporter in the nucleus accumbens in male and female neonatal mice. MS occurred for 1 hour per day on postnatal days (PD)1-13. Induction of sensitization occurred during PD 50-59 with mice receiving daily i.p. injections of 10-mg/kg cocaine. The development of locomotor sensitization was assessed on PD 50, 54, and 59. Expression of sensitization was assessed on PD 69 or 71 and on PD 99 by measuring the locomotor response to 7.5 mg/kg i.p. cocaine injections. On PD 50, the locomotor response to cocaine was greater in MS females than in non-MS females, MS males, and non-MS males. On PD 54 and 59, all MS mice exhibited enhancement of cocaine-induced locomotion. Assessment of the expression of cocaine locomotor sensitization on PD 69 or 71 and on PD 99 indicated an enhancement of sensitization in MS males, but not in females. This study is the first to report a relationship between MS and cocaine reactivity in mice. Whereas prior studies of MS rats have shown down-regulation of hippocampal glucocorticoid receptor expression and increased accumbal dopamine transporter binding, in the present study neither of these measures were affected by MS; however, but both measures were greater in females than males. Possible explanations for these discrepancies between MS rats and MS mice include differences in maternal care in rats and mice and differences in the daily length of MS used in this study and prior studies with rats. Kikusui, T., Faccidomo, S., and Miczek, K.A. Repeated Maternal Separation: Differences in Cocaine-Induced Behavioral Sensitization in Adult Male and Female Mice. Psychopharmacology, 178, pp. 202-210, 2005.
Activation of Metabotropic Glutamate Receptors Blocks Enhanced Amphetamine Self-Administration
Central glutamatergic (GLU) systems participate in the development and expression of psychostimulant sensitization. Sensitization is observed when repeated amphetamine or cocaine administration produces enhanced behavioral activation, (i.e., greater hyperactivity than seen with acute drug administration), paralleled by increases in dopamine (DA) and GLU release from subcortical mesolimbic regions. Sensitized animals also take more drug when available in i.v. self-administration paradigms. Ionotropic GLU receptors have been demonstrated to contribute importantly to the development and expression of sensitization. However, metabotropic group II GLU receptors negatively regulate GLU release and therefore may be in a position to "gate" sensitization by controlling transmitter available at the synapse for activating ionotropic receptors. Dr. Paul Vezina and colleagues at the University of Chicago have tested a recently developed GLU agonist, with high potency for metabotropic GLU receptors, in tests of behavioral sensitization, DA and GLU release, and self-administration for the psychostimulant, amphetamine. Rats were sensitized with five injections of either saline or 1mg/kg amphetamine (AMPH), with injections given every 2-3 days. Two weeks later they were tested for locomotor stimulation with i.p. saline, AMPH, the GLU agonist LY379268 (LY), or AMPH + LY. Animals receiving prior amphetamine injections showed the expected sensitized response to AMPH and also had enhanced DA and GLU release from the nucleus accumbens core. However, co-administration of LY greatly attenuated this behavioral sensitization, and the increase of AMPH-induced neurotransmitter release. Animals were also implanted with jugular catheters and trained for i.v. self-administration of AMPH after the sensitization procedure. After training on fixed ratio schedules of reinforcement, all rats were tested on a progressive ratio schedule to determine "how hard" animals were "willing to work" to receive the drug. Animals previously sensitized with AMPH made more operant responses to receive drug on the PR schedule than those with a history of repeated saline injections, but when LY was present in the i.v. solution, this increase in AMPH's reinforcing efficacy was blunted. Together these observations support the hypothesis that activation of II mGluRs can "gate" the neurochemical and behavioral expression of psychostimulant sensitization, including the escalation of drug seeking and drug-taking seen under progressive ratio requirements. Thus, these receptors may be a potential target for pharmacotherapeutic intervention in cocaine addiction. Kim, J-H., Austin, J.D., Tanabe, L., Creekmore, E. and Vezina, P. Activation of Group II mGlu Receptors Blocks the Enhanced Drug Taking Induced by Previous Exposure to Amphetamine. European Journal of Neuroscience, 21, pp. 295-300, 2005.