Cocaine Response Research Articles

Diazepam alters cocaine self-administration, but not cocaine-stimulated locomotion or nucleus accumbens dopamine

Cocaine is known to enhance nucleus accumbens dopamine (NAcc DA), to serve as a positive reinforcer and to produce negative effects, such as anxiety. The influence of diazepam on cocaine intake, cocaine-stimulated behavioral activity and NAcc DA was investigated using self-administration and experimenter-administered intravenous (i.v.) cocaine. In Experiment 1, rats were pretreated with diazepam (0.25 mg/kg) or saline (0.1 ml) 30 min prior to 20 daily 1-hour cocaine (0.75 mg/kg/injection) self-administration sessions. Cocaine intake increased for all animals across sessions, but was highest in diazepam-pretreated animals. Diazepam rats also self-administered their first cocaine injection of each session faster than controls. Experiment 2 utilized in vivo microdialysis to assess NAcc DA levels before and after experimenter-administered i.v. cocaine injections (0.75 mg/kg/injection × 2; 10-min interval) in diazepam- and saline-pretreated rats. Group differences were not revealed across basal and cocaine-stimulated NAcc DA assessments, indicating that diazepam did not decrease NAcc DA during cocaine self-administration. Findings that diazepam enhances cocaine self-administration and decreases cocaine response latency support the notion that cocaine-induced anxiety limits voluntary cocaine intake. It is further suggested that individual variations in cocaine-induced aversive effects may determine whether cocaine use is avoided or repeated.

Disparate cocaine-induced locomotion as a predictor of choice behavior in rats trained in a delay-discounting task

Heightened impulsivity and differential sensitivity to a drug's behavioral effects are traits that, individually, have been associated with chronic drug use and dependence. Here, we used an animal model to test whether individual differences in cocaine-induced activity are predictive of impulsive choice behavior. Adult, male Sprague-Dawley rats were given cocaine (10 mg/kg, i.p.) and classified into low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor response in an open-field arena. Rats were then trained in a delay-discounting task that offers a choice between immediately delivered, but smaller reinforcements, or larger reinforcements that are delivered after a delay. We also examined the effects of amphetamine (AMPH; 0.3–1.0 mg/kg) and the 5-HT 1A agonist 8-OH-DPAT (0.3–1.0 mg/kg) on delay-discounting. Lastly, all rats were retested in the open-field to determine if phenotypes were stable. We observed baseline differences in choice behavior between the groups, with HCRs behaving more impulsively (i.e., choosing the small reinforcement) compared to LCRs. AMPH decreased choice of the large reinforcement in LCRs, but did not alter choice in HCRs. Impulsive choice was increased in both phenotypes following 8-OH-DPAT, with LCRs exhibiting changes across a wider range of delays. When cocaine-induced open-field behavior was retested, responses in LCRs were similar whereas HCRs showed evidence of tolerance. Our results suggest that differential sensitivity to cocaine-induced locomotion is predictive of impulsivity and the potential neurobiological differences in LCRs and HCRs may provide insight into mechanisms contributing to vulnerability for chronic drug use and/or dependence.

Simultaneous expression of cocaine-induced behavioral sensitization and conditioned place preference in individual rats

Conditioned place preference and locomotor sensitization are rodent behavioral models commonly used to investigate the actions of drugs of abuse. However, few studies have examined both paradigms in the same group of animals. We were interested in developing a combined protocol which successfully induced both conditioned place preference and sensitization simultaneously in cocaine-treated Sprague–Dawley rats in order to test the hypothesis that the magnitude of these two phenomena would be positively correlated. We used an open-field with a removable place preference insert to assess these measures independently. Cocaine-conditioned animals demonstrated a significant shift in preference for the drug-paired compartment and a sensitized locomotor response which was not observed in saline-conditioned animals challenged with cocaine. There was no significant relationship between locomotor sensitization and conditioned place preference in individual animals. We further examined these results with respect to each rat's initial response to cocaine, response to a novel environment and central zone entries in an open-field. Locomotor sensitization demonstrated an inverse correlation with the initial cocaine response. In contrast, conditioned place preference demonstrated an inverse correlation with the centre response. These results demonstrate that the combination of the acute cocaine response and the centre response in a novel open-field environment can be used to indicate the propensity of a given rat to exhibit either behavioral sensitization or conditioned place preference; however, it seems that sensitization and place preference are not necessarily co-expressed to a similar extent in the same individual animal.

Individual differences to cocaine activation and self‐administration in rats: role of the brain dopamine transporter

Individuals differ in their responsiveness to psychostimulants like cocaine, which produce their activating effects largely by inhibiting the dopamine transporter (DAT). This differential responsiveness may impact subsequent drug abuse and addiction. Adult outbred Sprague‐Dawley rats also differ in their responsiveness to cocaine and can be classified as either low or high cocaine responders (LCRs or HCRs), based on the magnitude of each rat's locomotor activity resulting from its first exposure to low dose cocaine. Initially, cocaine inhibits striatal DAT activity only in HCRs; and LCR/HCR differences in rapid cocaine‐induced regulation of DATs parallel their behavioral differences. With repeated daily cocaine administration, however, cocaine begins to inhibit striatal DAT activity in LCRs. Also with repeated cocaine, LCRs more readily develop behaviors associated with enhanced drug responsiveness and reward than HCRs: viz. cocaine‐induced locomotor sensitization, conditioned place preference and greater motivation to self‐administer cocaine. Together, our findings suggest that the initial responsiveness of striatal DATs to cocaine helps to explain the variable locomotor activation to cocaine and may also contribute to the differential reinforcing effectiveness of cocaine in individuals. Supported by NIH grants DA004216, DA015050, DA023343.

Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

Evidence from both human studies and animal models indicates that cocaine elicits more behavioral stimulation in females than males. The present study sought to determine whether sex-specific responses to cocaine emerge during adolescence and to determine if gonadal steroid action during puberty affects adult responsiveness to cocaine. We administered cocaine using an escalating dose model in male and female rats at ages postnatal (PN) 28, 42, and 65 days. To assess the effects of pubertal gonadal steroid action, we compared the effects of binge cocaine administration on intact and prepubertally gonadectomized male and female rats in adulthood. Cocaine responses changed in opposite directions in males and females as they progressed through adolescence. At most doses, adolescent males were more responsive than adult males whereas adult females were more responsive than adolescent females. Ambulatory activity was age-dependent in males whereas non-ambulatory activity was age-dependent in females. Prepubertal gonadectomy increased behavioral responsiveness to the highest dose of cocaine in males whereas it decreased behavioral responsiveness to lower doses of cocaine in females. We conclude that sex differences in behavioral responses to cocaine arise during adolescence from a concurrent decrease in male responsiveness and increase in female responsiveness. Our results suggest that gonadal steroids exert lasting and opposing effects on the sensitivity of males and females to psychostimulants during development.

Chronic valproate normalizes behavior in mice overexpressing calcineurin

Calcineurin (PP2B) is a Ca 2+-dependent protein phosphatase enriched in the brain that takes part in intracellular signaling pathways regulating synaptic plasticity and complex brain functions. We report here that when these pathways are activated by transgenic expression of calcineurin, locomotor activity of mice in response to novelty is increased, as well as the behavioral and molecular responses of the psychostimulant cocaine. We also observed that the anxious-like behavior is altered. These behavioral changes are indicative of a generally increased behavioral responsiveness and could be normalized by chronic treatment with the mood stabilizer valproate. These results provide proof of concept that calcineurin-dependent dephosphorylation plays an important role in behavioral reactivity and in the effects of mood regulators. Mice overexpressing calcineurin represent a novel tool to study affective responses related to psychiatric disorders.

Effects of perceived cocaine availability on subjective and objective responses to the drug

RationaleSeveral lines of evidence suggest that cocaine expectancy and craving are two related phenomena. The present study assessed this potential link by contrasting reactions to varying degrees of the drug's perceived availability.MethodNon-treatment seeking individuals with cocaine dependence were administered an intravenous bolus of cocaine (0.2 mg/kg) under 100% ('unblinded'; N = 33) and 33% ('blinded'; N = 12) probability conditions for the delivery of drug. Subjective ratings of craving, high, rush and low along with heart rate and blood pressure measurements were collected at baseline and every minute for 20 minutes following the infusions.ResultsCompared to the 'blinded' subjects, their 'unblinded' counterparts had similar craving scores on a multidimensional assessment several hours before the infusion, but reported higher craving levels on a more proximal evaluation, immediately prior to the receipt of cocaine. Furthermore, the 'unblinded' subjects displayed a more rapid onset of high and rush cocaine responses along with significantly higher cocaine-induced heart rate elevations.ConclusionThese results support the hypothesis that cocaine expectancy modulates subjective and objective responses to the drug. Provided the important public health policy implications of heavy cocaine use, health policy makers and clinicians alike may favor cocaine craving assessments performed in the settings with access to the drug rather than in more neutral environments as a more meaningful marker of disease staging and assignment to the proper level of care.

Trace amines differentially regulate adult locomotor activity, cocaine sensitivity, and female fertility in Drosophila melanogaster

The trace biogenic amines tyramine and octopamine are found in the nervous systems of animals ranging in complexity from nematodes to mammals. In insects such as Drosophila melanogaster, the trace amine octopamine is a well-established neuromodulator that mediates a diverse range of physiological processes, but an independent role for tyramine is less clear. Tyramine is synthesized from tyrosine by the enzyme tyrosine decarboxylase (TDC). We previously reported the identification of two Tdc genes in Drosophila: the peripherally-expressed Tdc1 and the neurally-expressed Tdc2. To further clarify the neural functions of the trace amines in Drosophila, we examined normal and cocaine-induced locomotor activity in flies that lack both neural tyramine and octopamine because of mutation in Tdc2 (Tdc2(RO54)). Tdc2(RO54) flies have dramatically reduced basal locomotor activity levels and are hypersensitive to an initial dose of cocaine. Tdc2-targeted expression of the constitutively active inward rectifying potassium channel Kir2.1 replicates these phenotypes, and Tdc2-driven expression of Tdc1 rescues the phenotypes. However, flies that contain no measurable neural octopamine and an excess of tyramine due to a null mutation in the tyramine beta-hydroxylase gene (TbetaH(nM18)) exhibit normal locomotor activity and cocaine responses in spite of showing female sterility due to loss of octopamine. The ability of elevated levels of neural tyramine in TbetaH(nM18) flies to supplant the role of octopamine in adult locomotor and cocaine-induced behaviors, but not in functions related to female fertility, indicates mechanistic differences in the roles of trace amines in these processes.

Individual differences in novelty- and cocaine-induced locomotor activity as predictors of food-reinforced operant behavior in two outbred rat strains

A goal of the current study was to determine if individual differences in cocaine-induced locomotion, which has been shown in outbred Sprague–Dawley (SD) rats to be correlated with differential function of dopamine transporters, were also evident in Long–Evans (LE) rats. Another objective was to determine if differences in locomotion following exposure to novelty or cocaine predicted food-reinforced behavior. Between-strain comparisons of open-field activity revealed similar effects of 10 mg/kg cocaine, although increases in rearing were prominent in LE rats. Both strains exhibited robust individual differences in cocaine-induced locomotion, with nearly identical ambulatory behavior observed in low and high cocaine responders (LCRs and HCRs, respectively) from the two strains. In a cued-discrimination operant task, LE rats learned the contingency in fewer sessions, whereas SD rats obtained more food pellets at fixed ratio 10 and maintained higher progressive ratio (PR) breakpoints. HCRs from both strains also tended to maintain higher PR breakpoints; low and high responders to novelty (LR and HR, respectively) had no consistent differences in food-reinforced behavior. Overall, these studies suggest that wide individual differences in cocaine-induced behavior are common to SD and LE strains and certain differences in food-reinforced behavior are associated with HCRs compared to LCRs.

Adolescent Maturation of Cocaine-Sensitive Neural Mechanisms

Both clinical and animal studies have shown that adolescents undergo a late maturation of the central nervous system, which may underlie adolescent typical behaviors. In particular, decreased behavioral response to cocaine has been found in adolescents as compared to adults. In the present study, cocaine was used as a tool to explore adolescent brain maturation. Juvenile (postnatal day (P) 27), adolescent (P37), and adult (P90) male Sprague-Dawley rats were treated acutely with cocaine (750 microg/kg/injection x 2, i.v.), and c-fos mRNA expression, a marker of neuronal activation, was evaluated by in situ hybridization. Cocaine-induced c-fos mRNA was similar across ages in the dorsal caudate putamen (CPu), nucleus accumbens, and lateral bed nucleus of the stria terminalis. In contrast, there was a diminished response in juvenile/adolescent ventral CPu and in juvenile central nucleus of the amygdala, and an increased response in juvenile/adolescent cortex. Further studies evaluated the mechanism of the late maturation of cocaine response in ventral CPu. No significant age differences were observed in regional dopamine (DA) transporter binding. Although striatal DA content was significantly reduced at P27 as compared to adult, there was no difference between dorsal and ventral subregions. In contrast, basal- and cocaine-induced extracellular DA overflow, as measured by in vivo microdialysis, was lower in juvenile ventral CPu than in the adults. This age difference was not observed in dorsal CPu. These findings suggest that impulse activity in DA afferents to ventral CPu is immature in adolescents. In conclusion, the present study showed that cocaine-sensitive neuronal circuits continue to mature during adolescence.

Acute Cocaine Responses Following Cocaethylene Infusion

We report results of a randomized, double-blind, placebo-controlled, within-subject study (n = 8) to determine the ability of cocaethylene to modulate acute responses to cocaine and identify significant pharmacokinetic interactions between cocaine and cocaethylene. Stable plasma cocaethylene concentrations (0, 50, or 200 ng/ml) were maintained for 840 minutes. Cocaine (0, 0.25, or 0.5 mg/kg) was injected over 1 minute after 240 minutes of cocaethylene. Blood samples, subjective, and physiological measures were collected. No differences over baseline responses were observed following 240 minutes of a steady state cocaethylene infusion for cardiovascular or subjective responses. “Rush” duration following a cocaine challenge (0.5 mg/kg) declined when administered during the course of a 200 ng/mL cocaethylene infusion. (p = 0.01). No pharmacokinetic interaction occurred when cocaine was administered in conjunction with cocaethylene. Findings indicate that continuous 8-hour exposure to cocaethylene is safe, produces acute tolerance to itself, and reduces some behavioral effects of coadministered cocaine. Agonist substitution therapy may have potential as an alternative treatment for cocaine dependence.

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague–Dawley rats

Outbred, male Sprague–Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague–Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.

Cocaine Esterase: Interactions with Cocaine and Immune Responses in Mice

Cocaine esterase (CocE) is the most efficient protein catalyst for the hydrolysis of cocaine characterized to date. The aim of this study was to investigate the in vivo potency of CocE in blocking cocaine-induced toxicity in the mouse and to assess CocE's potential immunogenicity. Cocaine toxicity was quantified by measuring the occurrence of convulsions and lethality. Intravenous administration of CocE (0.1-1 mg) 1 min before cocaine administration produced dose-dependent rightward shifts of the dose-response curve for cocaine toxicity. More important, i.v. CocE (0.1-1 mg), given 1 min after the occurrence of cocaine-induced convulsions, shortened the recovery time after the convulsions and saved the mice from subsequent death. Effects of repeated exposures to CocE were evaluated by measuring anti-CocE antibody titers and the protective effects of i.v. CocE (0.32 mg) against toxicity elicited by i.p. cocaine (320 mg/kg) (i.e., 0-17% occurrence of convulsions and lethality). CocE retained its potency against cocaine toxicity in mice after a single prior CocE exposure (0.1-1 mg), and these mice did not show an immune response. CocE retained similar effectiveness in mice after three prior CocE exposures (0.1-1 mg/week for 3 weeks), although these mice displayed 10-fold higher antibody titers. CocE partially lost effectiveness (i.e., 33-50% occurrence of convulsions and lethality) in mice with four prior exposures to CocE (0.1-1 mg/2 week for four times), and these mice displayed approximately 100-fold higher antibody titers. These results suggest that CocE produces robust protection and reversal of cocaine toxicity, indicating CocE's therapeutic potential for acute cocaine toxicity. Repeated CocE exposures may increase its immunogenicity and partially reduce its protective ability.

Mice lacking the melanin-concentrating hormone receptor-1 exhibit an atypical psychomotor susceptibility to cocaine and no conditioned cocaine response

The present study aimed at characterizing the acute and intermittent psychomotor responsiveness to cocaine in mice lacking the MCHR1 receptor, which is thought to modulate the mesocorticolimbic sytem functioning [Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, et al. Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor deficient mice. J Neurosci 2005;25:914–22]. On a first free-drug session, MCHR1-deficient mice exhibited significantly higher levels of locomotor activity elicited by the novelty of the test chambers than their wild-type counterparts. On the following day session, a first injection of 6 or 12 mg/kg cocaine induced comparable dose-related psychomotor activations in both genotypes, without significant difference in the relative increase in locomotion. Over the following eight once-daily test sessions, the slight psychomotor increase induced by 6 mg/kg was equivalent in both genotypes and constant over the sessions. At 12 mg/kg, cocaine induced a clear-cut incremental responsiveness to cocaine in both genotypes on the three first sessions; on the following sessions, only the wild-types displayed an incremental responsiveness until the last session, a sensitized effect that was confirmed for the wild-types but not for the knockouts on a subsequent sensitization test (cocaine challenge). Finally, the knockouts did not exhibit any sign of cocaine-conditioning (saline challenge), contrarily to the wild-types. It is speculated that MCHR1 may contribute to the neurobiological mechanisms of conditioned cocaine-induced psychomotor effects, possibly to those underpinning sensitization, and to a lesser extent to those sub-serving acute pharmacological cocaine action.

Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice

Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.

Isradipine Decreases the Hemodynamic Response of Cocaine and Methamphetamine: Results From Two Human Laboratory Studies

Massive hypertensive crises relating to cerebrovascular accidents such as strokes or ruptured aneurysms, or cardiovascular dysfunction and toxicity, are an important cause of morbidity and mortality associated with cocaine or methamphetamine use. Experimentally administered, pharmacologically effective doses of cocaine and methamphetamine may serve as a model for studying the effects of these drugs on hemodynamic response and for examining the potential utility of the antihypertensive and dihydropyridine-class calcium channel antagonist isradipine to block these effects. We therefore examined, in two separate experiments of similar design conducted contemporaneously, the hemodynamic effects of cocaine or methamphetamine in the presence and absence of isradipine.In both experiments (total N = 31), isradipine pretreatment was provided to cocaine- or methamphetamine-dependent male and female subjects before intravenous administration of low and high doses of cocaine (0.325 or 0.650 mg/kg) or methamphetamine (15 or 30 mg), respectively, on separate test days.Both cocaine and methamphetamine administration produced predicted elevations in blood pressure (with peak response between 1 and 3 min after infusion). Apart from tachycardia, no arrhythmias were reported. Isradipine significantly reduced stimulant-associated increases in all measures of blood pressure except pulse pressure, but tended to enhance the effects of these drugs on heart rate.Clinical studies are needed to determine whether isradipine is therapeutically efficacious in preventing hypertensive crises and the associated cerebrovascular and cardiovascular sequelae in cocaine- or methamphetamine-dependent individuals. As there is no established pharmacotherapy for treating cocaine or methamphetamine dependence, identification of a medication that reduces the harmful medical consequences of these drugs would be scientifically and clinically important.

Desipramine treatment of cocaine-dependent patients with depression: A placebo-controlled trial

Objective: The aim of this study was to test the hypothesis that desipramine would be an effective treatment in cocaine abusers with current depressive disorders. Method: This was a randomized, 12-week, double-blind, ‘placebo-controlled trial of outpatients ( N = 111) meeting DSM-III-R criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with desipramine, up to 300 mg per day, or matching placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included the Clinical Global Impression Scale, self-reported cocaine use and craving, urine toxicology, and the Hamilton Depression Scale (biweekly). Summary measures of mood and cocaine use outcome were compared between treatment groups with χ 2- or t-tests. Dichotomous summary measures of depression response and cocaine response were the primary outcomes. Mixed effect models were also fit to explore the relationship of cocaine use to mood improvement and treatment over weeks in the trial. Results: Desipramine was associated with a higher rate of depression response (51%, 28/55) than placebo (32%, 18/56) ( p < 0.05), but treatment groups did not differ in rate of cocaine response. Depression improvement was associated with improvement in cocaine use. Desipramine was associated with more dropouts due to side effects and medical adverse events, while placebo was associated with more dropouts due to psychiatric worsening. Conclusions : Desipramine was an effective treatment for depression among cocaine-dependent patients. Improvement in mood was associated with improvement in cocaine abuse, but a direct effect of medication on cocaine outcome was not clearly established and rates of sustained abstinence were low. Future research should examine newer antidepressant medications with more benign side effect profiles and combinations of behavioral and pharmacological treatments to maximize effects on cocaine use.

Extinction of Cocaine Self-Administration Reveals Functionally and Temporally Distinct Dopaminergic Signals in the Nucleus Accumbens

While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and post-response dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Pre-response transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, post-response dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic--differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.

Repeated administration of methylphenidate in young, adolescent, and mature rats affects the response to cocaine later in adulthood

Previous studies have shown that the expression of behavioral sensitization to psychostimulants depends on the age and gender of the animal. This study was conducted to determine the pattern of behavioral sensitization to repeated administration of methylphenidate (MPD) at three different developmental ages and to assess the response to a cocaine challenge in adulthood. We gave five daily i.p. injections of 10 or 20 mg kg(-1) of MPD (10 MPD, 20 MPD) or saline to male and female rats beginning on postnatal days (PND) 21, 45, or 60. When all groups reached PND 90, rats were challenged with 10 mg kg(-1) cocaine. For both MPD administration and cocaine challenge, locomotion and stereotyped behaviors were assessed for 1 h. The 10 MPD dose produced increased locomotion over the other two treatments at all ages. Rats that received 20 MPD showed a decline in locomotion across days with an increase in the time spent in high intensity stereotypy by day 5. Animals treated with 10 MPD showed diverse behavioral responses with adolescents showing somewhat dampened stereotypy than the other two age groups. In response to cocaine, pretreatment with MPD at all ages enhanced the cocaine response and produced qualitatively different patterns of stereotyped behavior for each gender and pretreatment age group. MPD produced clear age-specific sensitization of behavior in rats. Furthermore, exposure to MPD cross-sensitized with cocaine regardless of the age at which MPD exposure occurred with each pretreatment age group showing a unique pattern of responses.

Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice

Extensive pharmacological studies have recently emerged indicating that group 2 metabotropic glutamate receptors (mGluRs) comprising mGluR2 and mGluR3 subtypes are associated with several neurological and psychiatric disorders. mGluR2 is widely distributed both presynaptically and postsynaptically in a variety of neuronal cells, but the physiological role of mGluR2 in brain function is poorly understood. This investigation involves a comprehensive behavioral analysis of mGluR2-/- knockout (KO) mice to explore the physiological role of mGluR2 in brain function. Although, under general observation, mGluR2-/- KO mice appeared to have no behavioral abnormalities, they exhibited several lines of behavioral alterations in the enforcing and defined behavioral tests. They showed a significant increase in locomotor sensitization and conditioned place preference in association with repeated cocaine administration, indicating that mGluR2 contributes to behavioral responses implicated in reinforcement and addiction of cocaine. Upon in vivo microdialysis analysis after cocaine administration, not only did extracellular levels of dopamine increase but also the response pattern of glutamate release markedly changed in the nucleus accumbens of mGluR2-/- KO mice. The mGluR2-/- KO mice also showed significant impairment in motor coordination in the accelerating rota-rod test and exhibited hyperlocomotion in novel environmental and stressful conditions, when assessed by the open-field and forced-swim tests. These results indicate that the inhibitory mGluR2 plays a pivotal role in synaptic regulation of glutamatergic transmission in the neural network.