Adolescent exposure to methylphenidate has no effect on the aversive properties of cocaine in adulthood

Methylphenidate is the most widely prescribed pharmacotherapeutic treatment of AD/HD in children and teens and has actions that are also involved in drug reward and reinforcement. Its clinical use has often raised concerns over the possibility that it could potentiate the risk for later drug-related problems. Animals exposed to methylphenidate during adolescence exhibit attenuated cocaine-induced conditioned place preference, but tend to self-administer cocaine more quickly than controls. A drug's abuse potential, as reflected by self-administration, is thought to be the product of a balance between its rewarding and aversive properties, thus the present research assessed the effects of adolescent exposure to methylphenidate on conditioned taste aversions induced by cocaine in adulthood in 132 male Sprague Dawley rats. Although cocaine induced robust dose-dependent taste aversions in accordance with previous research, there were no effects of adolescent exposure to methylphenidate in spite of evidence that it was behaviorally active. The present results indicate that changes in adult cocaine self-administration are not likely mediated by changes in the aversive response. The possibility that such changes are a function of reductions in reward threshold is discussed.     

Absence of cocaine-induced place conditioning in serotonin 1B receptor knock-out mice

A large body of evidence suggests that genetic factors may affect the reinforcing properties of drugs of abuse. This study investigated the involvement of the serotonin 1B (5-HT1B) receptor in modulating cocaine-induced place conditioning by comparing the response of 5-HT1B receptor gene knock-out mice with wild type 129/Sv-ter mice. The rewarding effects of various doses of cocaine (0, 2.5, 5, 10, 20, and 40 mg/kg) were examined in both strains. Results clearly show that 5-HT1B receptor knock-out mice failed to display a conditioned place preference for stimuli paired with cocaine while wild type mice exhibited a conditioned place preference for the compartment paired with cocaine (5 and 20 mg/kg). As other studies showed that 5-HT1B knock-out mice self-administer cocaine, these results suggest a dissociation between the psychologic state linked to self-administration and the one measured in conditioned place preference.     

Differential ability of D1 and D2 dopamine receptor agonists to induce and modulate expression and reinstatement of cocaine place preference in rats

Rationale D1-Like agonists are self-administered by drug-naive animals, whereas D2-like agonists reinstate cocaine-seeking behavior, but the rewarding and reinstating effects of D1- and D2-like agonists in pavlovian-based conditioned place preference are equivocal. Objective To compare the ability of D1 and D2 agonists to produce conditioned place preference with their modulation of expression and reinstatement of an established cocaine place preference. Methods Using an unbiased procedure, we measured the place preference induced by the D1 receptor agonist SKF 81297 and the D2/D3 receptor agonist quinpirole in drug-naive or cocaine-exposed rats. The rewarding effects of the D1 agonists SKF 82958, ABT-431, A-77636, and the D2/D3 receptor agonist 7-OH-DPAT were also tested. Additionally, we tested the ability of SKF 81297 and quinpirole to modulate expression and reinstatement of an established cocaine place preference. Results The D1 receptor agonists SKF 81297, SKF 82958, and ABT-431 produced dose-dependent conditioned place preferences, whereas A-77636 produced only place aversion, and the D2/D3 agonists quinpirole and 7-OH-DPAT were without effect in drug naive rats. In cocaine-treated rats, SKF-81297-induced place preference was reduced, whereas quinpirole-induced place preference was revealed. Pretreatment using either D1 or D2/D3 agonists blocked expression of an established cocaine place preference, but only the D1 agonist SKF 81297 and cocaine dose-dependently reinstated an extinguished cocaine place preference, whereas the D2/D3 agonist quinpirole induced place aversion but failed to alter cocaine-induced reinstatement. Conclusions D1, but not D2/D3, agonists mediate rewarding effects and reinstatement of cocaine place preference, but the reinstating effects differ markedly from self-administration paradigms.     

Gamma-hydroxybutyric acid affects the acquisition and reinstatement of cocaine-induced conditioned place preference in mice

Cocaine addicts very often use different combinations of cocaine and other drugs of abuse such as gamma-hydroxybutyric acid. The objective of the present work was to evaluate the impact of gamma-hydroxybutyric acid administration on the rewarding actions of cocaine, using the conditioned place preference procedure. Cocaine-induced conditioned place preference (50 mg/kg) was studied after pairing this drug with different gamma-hydroxybutyric acid doses (6.25, 12.5, 25, 50 and 100 mg/kg) during either the acquisition or the expression phase of the procedure. After conditioned place preference had been established, and the preference was extinguished, a reinstatement was induced by a dose of cocaine half of that used to produce conditioning, or by gamma-hydroxybutyric acid alone or by both drugs together. The doses of 12.5 and 100 mg/kg of gamma-hydroxybutyric acid blocked the acquisition of cocaine-induced conditioned place preference, and no dose affected the expression of this conditioning. Reinstatement was abolished only with the dose of 25 mg/kg gamma-hydroxybutyric acid, which did not reinstate the preference by itself. This is the first study evaluating the effects of gamma-hydroxybutyric acid on the rewarding properties of cocaine using the conditioned place preference procedure. The principal conclusion of the study is that gamma-hydroxybutyric acid does not enhance the rewarding effect of cocaine, and within a narrow margin of effective doses, blocks the acquisition and reinstatement of cocaine-induced preference.     

Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats

 Food-deprivation increases the reinforcing efficacy of cocaine and other drugs within self-administration experiments. In this study, the effects of food-deprivation on cocaine-induced conditioned place preference were investigated. Male Sprague-Dawley rats were assigned to one of two feeding conditions: satiated (with ad libitum food) or deprived (maintained at 80% of free-feeding body weights). During conditioning trials, on alternate days, rats received IP injections of cocaine (0.0, 2.5, 5.0, or 10.0 mg/kg; n=12 per dose group) and were confined for 30 min in one of two distinct environments. On intervening days, the same rats were injected with saline and confined for 30 min in the opposite environment. After four cocaine and four saline trials, a 15-min choice test (with no injections) was given. During this time, the rats were able to move freely through a passageway between both environments. Relative to the food-satiated rats, the food-deprived rats showed a greater conditioned preference for the cocaine-paired environment during the choice test, greater cocaine-induced locomotor activity during conditioning trials, and a greater degree of sensitization to the activating effects of cocaine across conditioning trials. This study extends the general findings of food deprivation-induced increases in the reinforcing efficacy of cocaine to include the conditioned place preference paradigm. Received: 23 January 1996 / Final version: 4 December 1996     

Conditioned Contribution of Peripheral Cocaine Actions to Cocaine Reward and Cocaine-Seeking

Cocaine has actions in the peripheral nervous system that reliably precede—and thus predict—its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood–brain barrier, to isolate the peripheral actions of cocaine and determine their central and behavioral effects in animals first trained to lever-press for cocaine hydrochloride (the centrally acting and abused form of the drug). We first confirmed with fast-scan cyclic voltammetry that cocaine methiodide causes rapid dopamine release from dopamine terminals in cocaine hydrochloride-trained rats. We then compared the ability of cocaine hydrochloride and cocaine methiodide to establish conditioned place preferences in rats with self-administration experience. While cocaine hydrochloride established stronger place preferences, cocaine methiodide was also effective and its effectiveness increased (incubated) over weeks of cocaine abstinence. Cocaine self-administration was extinguished when cocaine methiodide or saline was substituted for cocaine hydrochloride in the intravenous self-administration paradigm, but cocaine hydrochloride and cocaine methiodide each reinstated non-rewarded lever-pressing after extinction. Rats extinguished by cocaine methiodide substitution showed weaker cocaine-induced reinstatement than rats extinguished by saline substitution. These findings suggest that the conditioned peripheral effects of cocaine can contribute significantly to cocaine-induced (but not stress-induced) cocaine craving, and also suggest the cocaine cue as an important target for cue-exposure therapies for cocaine addiction.     

Gene - environment interactions determine the individual variability in cocaine self-administration

Research into factors that determine the propensity to self-administer cocaine has shown that stressors can determine the amount of cocaine self-administered as well as the rate of acquisition. However, the interaction between the genetic make-up of the animal and stress is unknown. This study investigated this interaction by using the genetic animal model consisting of apomorphine susceptible (APO-SUS) and unsusceptible (APO-UNSUS) rats. Animals were allowed to self-administer 0.25 mg/kg cocaine under stressful and habituated conditions. This study revealed that the amount of cocaine consumed was highly dependent on the genetic make-up of the animal as well as the amount of stress during self-administration. Under habituated circumstances the APO-UNSUS rats took far more cocaine than the APO-SUS rats. Under stressful circumstances, however, the APO-SUS rats took far more cocaine than the APO-UNSUS rats. This difference in the amount consumed by APO-SUS and APO-UNSUS rats is likely to be due to the specific neurobiological features of their dopaminergic and, possibly, noradrenergic system as well as the reactivity of their HPA-axis. It is suggested that the amount of a drug consumed and, accordingly, its addictive potential and ‘drug-vulnerability’ are determined by the interaction between the genetic make-up of the animals and stress, and not by either component alone.     

Chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine

The purpose of this study was to determine whether chronic exercise alters sensitivity to the conditioned rewarding effects of cocaine. Female rats were obtained at weaning and randomly assigned to either sedentary or exercise conditions. After 6 weeks under these conditions, the effects of cocaine were examined in the conditioned place preference procedure. Cocaine produced a dose-dependent conditioned place preference in both groups of rats. Exercising rats were more sensitive than sedentary rats to cocaine in this procedure, and this effect was most pronounced at the highest dose of cocaine. These data suggest that chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.     

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

RATIONALE: We previously demonstrated that the prototypical kappa-opioid receptor agonist U-50,488H did not affect the discriminative stimulus effects of cocaine, and the dose of U-50,488H which significantly induced aversive effects attenuated the rewarding effects of cocaine. OBJECTIVES: In the present study, the effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine were examined in rats. METHODS: In the drug discrimination procedure, the effects of TRK-820 on the discriminative stimulus effects of cocaine were examined in rats that had been trained to discriminate between 10 mg/kg cocaine and saline. TRK-820-induced place preference or place aversion and the effects of TRK-820 on the cocaine (4 mg/kg)-induced place preference were examined using a conditioned place preference procedure in rats. RESULTS: TRK-820 did not engender cocaine-like responding in rats trained to discriminate between 10 mg/kg cocaine and saline. In combination tests, low doses of TRK-820, which did not affect the response rate, significantly attenuated the discriminative stimulus effects of cocaine, and these effects of TRK-820 were reversed by a kappa-opioid receptor antagonist, nor-BNI. In the conditioned place preference procedure, low doses of TRK-820, which did not affect the response rate in the drug discrimination, did not produce either place preference or place aversion, whereas, higher dose (80 microg/kg) of TRK-820 slightly but significantly induced a place aversion. Under these conditions, the cocaine-induced place preference was completely attenuated by low doses of TRK-820. These results may prompt further investigation of the effectiveness of the new kappa-opioid receptor agonist TRK-820 as a novel pharmacotherapeutic compound for the treatment of cocaine addiction.     

Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice

No medication is approved to treat cocaine addiction, but mounting evidence suggests that glutamate-directed approaches may reduce cocaine dependence and relapse. We tested the hypotheses that the glutamate transporter subtype 1 activator, ceftriaxone, disrupts acquisition of cocaine self-administration, motivation to self-administer cocaine, and conditioned place preference in mice. Repeated ceftriaxone (200 mg/kg) reduced the ability of mice to acquire cocaine and the motivation to self-administer cocaine after successful acquisition without affecting acquisition of or motivation for sweet food. Repeated ceftriaxone had no effect on cocaine-conditioned place preference. These results suggest that a β-lactam antibiotic reduces the direct reinforcing strength of cocaine without producing nonspecific deficits in conditioned learning processes.     

A role for mu opioid receptors in cocaine-induced activity, sensitization, and reward in the rat

Rational Considerable evidence suggests that the endogenous opioid system plays a role in mediating the behavioral effects of psychostimulants. Opioidergic drugs have been shown to have profound effects on cocaine-induced behavioral sensitization and conditioned reward. However, the role specifically of the mu opioid receptor in this regard is unclear as most previous pharmacological studies have used nonselective opioid receptor ligands. Objectives The objective of this series of experiments was to elucidate the role of mu opioid receptors in the behavioral effects of cocaine in the rat. Materials and methods Adult male rats were used to assess the effects of the selective mu opioid receptor antagonist d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr (CTAP) on acute hyperactivity, locomotor sensitization, and conditioned place preference induced by cocaine. Intracerebroventricular administration of CTAP, 4 μg, was paired with peripheral injections of cocaine, 10–15 mg/kg. Results Mu receptor blockade significantly attenuated cocaine-induced hyperactivity, as well as the development of behavioral sensitization. Pretreatment with CTAP also prevented the development of conditioned place preference to cocaine. Administration of CTAP alone had neither effect on locomotor activity nor did it demonstrate aversive or rewarding properties. Conclusions These results suggest that activation of mu opioid receptors by endogenous opioids is an important contributor to cocaine-induced hyperactivity and the development of behavioral sensitization and conditioned reward.     

The lack of A2A adenosine receptors diminishes the reinforcing efficacy of cocaine.

Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system. A2A adenosine and D2 dopamine receptors are colocalized in the same neurons in discrete brain areas, and the dopaminergic transmission plays a crucial role in the addictive properties of drugs of abuse, such as cocaine. In the present study, we have investigated the specific role of A2A adenosine receptors in cocaine-induced behavioral responses related to its addictive properties. For this purpose, we have evaluated the acute locomotor effects produced by cocaine and the development of locomotor sensitization by repeated cocaine administration. In addition, we have also examined cocaine acute rewarding properties using the conditioned place preference. Finally, we used the intravenous drug self-administration paradigm to investigate the acquisition of an operant response maintained by cocaine self-administration and the reinforcing efficacy of the drug in these knockout animals. Acute cocaine induced a similar increase of locomotor activity in mice lacking A2A adenosine receptors and wild-type littermates. Cocaine-induced locomotor sensitization and conditioned place preference were also maintained in A2A knockout mice. Nevertheless, these knockout mice showed a lower rate of cocaine self-administration than wild-type mice in both fixed ratio 1 and 3 schedules of reinforcement. Moreover, a reduction in the maximal effort to obtain a cocaine infusion was found in A2A knockout mice under a progressive ratio schedule. In addition, a vertical shift of the cocaine dose-response curve was observed in mice lacking A2A adenosine receptors in comparison with wild-type littermates. Our study demonstrates that A2A adenosine receptors play an important role in cocaine addictive properties, and these receptors seem to be required to develop the addictive effects of this drug.     

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats

It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D1 and D2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1-3 mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.     

Enhanced ethanol-, but not cocaine-induced, conditioned place preference in Apoe(-/-) mice

Apolipoprotein (apo) E is a glycoprotein that is most commonly associated with cardiovascular and Alzheimer's disease risk. Recent data showing that apoE mRNA expression is reduced in the frontal cortex of alcoholics raise the possibility that apoE may also be related to the rewarding properties of ethanol. In this study, we examined whether Apoe deletion affects the rewarding properties of ethanol in mice. Male and female wild-type (WT; C57BL/6J) and apoE knockout (Apoe(-/-); C57BL/6J-Apoe(tm1Unc)) mice underwent an unbiased place conditioning procedure with ethanol (2 g/kg) or cocaine (5 mg/kg). Female mice were also tested for ethanol intake in a two-bottle choice procedure. Apoe(-/-) mice showed greater ethanol-induced conditioned place preference (CPP). In contrast, cocaine-induced CPP and ethanol intake were similar between the genotypes. These findings suggest that apoE normally reduces the conditioned rewarding properties of ethanol but not of cocaine. While the exact mechanisms underlying these effects of apoE are unknown, these data support a possible role for apoE in modulating the conditioned rewarding properties of ethanol.     

Individual differences in initial low-dose cocaine-induced locomotor activity and locomotor sensitization in adult outbred female Sprague-Dawley rats

Sex and individual differences are important considerations when studying cocaine responsiveness. We have previously shown that male Sprague-Dawley (S-D) rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following a single dose of cocaine (10 mg/kg, i.p.). Further, this distinction was found to predict dopamine transporter function, cocaine-induced locomotor sensitization, cocaine conditioned place preference and motivation to self-administer cocaine. Here we investigated whether or not individual differences in cocaine-induced locomotor activity and locomotor sensitization exist in female S-D rats. Female rats exhibited a broad range of locomotor activation following either a 5 or 10 mg/kg cocaine injection, allowing for classification as LCRs or HCRs. When administered over 7 days, both doses induced locomotor sensitization in female LCRs/HCRs. However, the magnitude of effects produced by 5 mg/kg cocaine in female LCRs/HCRs was more comparable to that produced by 10 mg/kg in male LCRs/HCRs, both of which, interestingly, developed sensitization in this study. These findings suggest that female S-D rats, like male S-D rats, can be classified as LCRs/HCRs and highlight the importance of accounting for dose when studying sex and individual differences to the effects of cocaine.     

Memantine and ACPC affect conditioned place preference induced by cocaine in rats

The influence of uncompetitive NMDA receptor antagonist, 1-amino-3,5--dimethyl-adamantane (memantine) and partial glycineB site agonist, 1-amino-cyclopropanecarboxylic acid (ACPC) on cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with cocaine (5 mg/kg, ip) for 3 conditioning trials, alone or in combination with memantine (7.5 mg/kg, ip) or ACPC (50.0 mg/kg, ip). Memantine prevented acquisition and expression of the place preference produced by cocaine, while ACPC prevented only acquisition effect. Neither of the NMDA antagonists displayed any reinforcing properties by itself. Our current data suggest that the NMDA receptor complex may be involved in the rewarding effect of cocaine.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

Regulation of intravenous cocaine self-administration in rats selectively bred for high (HiS) and low (LoS) saccharin intake

Rationale Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (i.v.) cocaine self-administration more rapidly than their low saccharin (LoS)-consuming counterparts. The present experiment was designed to determine whether HiS and LoS rats differed in other aspects of drug abuse. Objective The purpose of the present experiment was to use a two-lever dose self-selection procedure to investigate the regulation/dysregulation of i.v. cocaine self-administration in female HiS and LoS rats. Materials and methods HiS and LoS rats were trained to self-administer eight different doses of cocaine during daily 5-h sessions, with the cocaine doses ranging from 0.2 to 1.6 mg/kg in steps of 0.2 mg/kg. The dose size increased after a response on one lever (infusion duration lengthened by 3 s) and decreased after a response on the other lever (infusion duration shortened by 3 s), with a lower limit of 0 s and with an upper limit of 24 s (a corresponding range of 0 to 1.6 mg/kg); the animals increased or decreased their self-administered dose in nine discrete steps. Results The HiS rats showed less precise regulation of their postinfusion interval (PII) than LoS rats based on the size of the previously self-administered cocaine dose. Correlations between these variables were lower for HiS than for LoS rats during the acquisition and maintenance phases, and HiS rats had lower PIIs than LoS rats after many of the cocaine doses. The HiS rats also self-administered significantly more cocaine infusions during the maintenance phase than the LoS rats, especially at the highest dose. Conclusions These data indicate that HiS rats are more likely to self-administer more cocaine infusions, at higher doses, and with less precise dose-time regulation than LoS rats. Thus, rats selectively bred for HiS showed less inhibitory control over their cocaine intake than LoS rats, suggesting that a genetic predisposition for saccharin preference is related to the rewarding effects of i.v. cocaine.     

Assessing learned associations between conditioned cocaine reward and environmental stimuli in the Wistar Kyoto rat

Clinical studies demonstrate that anxiety disorders increase the risk of substance use disorder. However, few studies have directly assessed anxiety as a vulnerability factor in processing of rewarding stimuli. The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability because it exhibits extreme behavioral inhibition in novel and social environments; yet, it displays paradoxical rapid active avoidance learning that is resistant to extinction. The present study was designed to characterize the acquisition and persistence of cocaine conditioned place preference (CPP) in WKY rats. In the first of a series of three experiments, adult male WKY and Sprague Dawley (SD) rats were given six pairings of cocaine (3, 5, 10, 15 mg/kg) or saline on alternating days. SD rats developed cocaine-induced CPP to each of the four doses of cocaine tested. In contrast, WKY rats demonstrated CPP when conditioned with 3, 5, and 10 mg/kg, but displayed no preference to the 15 mg/kg dose. Next, separate groups of rats were subject to an extended CPP paradigm, which included acquisition, extinction and reinstatement phases. Rats were conditioned with cocaine and saline on alternating days using either a 6/6 (as above) or 4/4 conditioning regimen. Both SD and WKY rats acquired a lasting CPP with the 6/6 conditioning regimen. Results from the 4/4 conditioning regimen show that SD, but not WKY, rats acquired CPP. Preference scores for SD rats during the cocaine primed reinstatement test were significantly different from pretest scores indicating reinstatement of CPP in this group. Paradoxically, WKY rats demonstrated a latent sensitization to the conditioned rewarding effects of cocaine during the drug-primed reinstatement test. Taken together, WKY rats appear to be more sensitive to high doses of cocaine and need more experience with the drug to acquire a preference than SD rats.     

Early methylphenidate exposure enhances cocaine self-administration but not cocaine-induced conditioned place preference in young adult rats

Rationale  

Previous studies in rodents show that early exposure to methylphenidate alters later responsiveness to drugs of abuse. An interesting feature of these studies is that early methylphenidate treatment decreases the rewarding value of cocaine when measured by conditioned place preference (CPP), but the same treatment increases cocaine self-administration.