Inhibition by ginsenosides Rb1 and Rg1 of cocaine-induced hyperactivity, conditioned place preference, and postsynaptic dopamine receptor supersensitivity in mice.

A single or repeated administration of cocaine (15 mg/kg) in mice produced hyperactivity and conditioned place preference (CPP). Ginsenoside Rb1 (Rb1) and ginsenoside Rg1 (Rg1), prior to and during the cocaine treatment in mice, inhibited cocaine-induced hyperactivity and CPP. The development of enhanced postsynaptic dopamine (DA) receptor sensitivity in mice displaying a cocaine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg). Rb1 and Rg1 inhibited the development of postsynaptic DA receptor supersensitivity. However, Rb1 and Rg1 did not show any antidopaminergic activity at the postsynaptic DA receptors, because the apomorphine-induced climbing behavior was not inhibited by Rb1 and Rg1. Therefore, it is presumed that Rb1 and Rg1 modulate DA activity induced by cocaine at the presynaptic DA receptors, and this modulation results in the inhibition of postsynaptic dopaminergic activation. These results suggest that the cocaine-induced CPP may be associated with enhanced DA receptor sensitivity. The inhibition by Rb1 and Rg1 of cocaine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by cocaine at the presynaptic DA receptors.     

Effects of the NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference.

Effects of the novel NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with morphine (5 mg/kg, i.p.) or cocaine (5 mg/kg, i.p.) for 3 conditioning trials, alone or in combination of these drugs with L-701,324 (2.5 mg/kg and 5 mg/kg, p.o.). L-701,324 prevented acquisition of the place preference produced by morphine and cocaine. Administration of L-701,324 on the test day attenuated the expression of morphine-induced CPP, whereas it had no effect on cocaine CPP. When L-701,324 was given alone it did not affect dependent variables (i.e. time spent in non-preferred compartment) suggesting that L-701,324 did not display any reinforcing properties by itself. Our current data suggest that glycine site on the NMDA receptor complex may be involved in the mediation of the rewarding effects of drugs of abuse.     

The effects of the kappa agonist U-50,488 on cocaine-induced conditioned and unconditioned behaviors and Fos immunoreactivity

The ability of kappa opioid agonists to modulate dopamine-mediated behavior and Fos immunore-activity was assessed in adult rats. It was predicted that kappa agonist treatment would block the unconditioned and conditioned behaviors produced by cocaine (an indirect dopamine agonist). In the initial experiments, cocaine-induced locomotor activity was assessed after either acute or chronic injections of the kappa receptor agonist U-50,488 (5 mg/kg, SC). As expected, U-50,488 decreased cocaine-induced activity, while leaving baseline activity levels unaffected. Interestingly, chronic treatment with U-50,488 did not induce behavioral tolerance. The conditioned effects of cocaine (20 mg/kg, IP) were assessed using the conditioned place preference (CPP) paradigm. As expected, rats showed a preference for the cocaine-paired compartment, an effect blocked by U-50,488 (5 mg/kg, SC). One hour after CPP testing, rats were killed and Fos immunoreactivity was assessed. Rats conditioned with cocaine, but not U-50,488, showed increased Fos activity in the anterior cingulate cortex, piriform cortex, lateral septal area, and olfactory tubercles. When considered together, these results suggest that U-50,488 was effective at blocking the unconditioned and conditioned effects of cocaine, as well as cocaine-induced neuronal activity (as measured by Fos induction).     

Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.

Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DAex) and serotonin (5-HT(ex)) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DAex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DAex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DAex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DAex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DAex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT(ex) in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DAex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT(ex) can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.     

mGlu5 and adenosine A2A receptor interactions regulate the conditioned effects of cocaine

Adenosine A2A receptors and metabotropic glutamate type 5 (mGlu5) receptors are co-localized in the striatum and can functionally interact to regulate drug-seeking. We further explored this interaction using antagonism of mGlu5 receptors with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in combination with genetic deletion of A2A receptors. The conditioned rewarding and locomotor-activating properties of cocaine were evaluated via conditioned place preference (CPP). Vehicle-treated mice of both genotypes expressed a CPP to cocaine while MTEP abolished cocaine CPP in wild-type, but not A2A knockout, mice. These results were mirrored when conditioned hyperactivity was assessed. In contrast, MTEP attenuated the acute locomotor-activating properties of cocaine similarly in both genotypes. These data provide evidence for a functional interaction between adenosine A2A and mGlu5 receptors in mediating the conditioned effects of cocaine but not direct cocaine-induced hyperactivity. This functional interaction is supported by modulation of 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([125I]ZM241385) binding to the A2A receptor by MTEP.     

Serotonin2C receptors (5-HT2C R) control expression of cocaine-induced conditioned hyperactivity

Environmental cues can become classically conditioned to cocaine exposure and are known to contribute to drug craving and relapse in addicts. The 5-HT2C receptor (5-HT2C R) has been shown to control the behavioral effects of acute cocaine administration and, in the present study, we investigated the role of this receptor in the expression of cocaine-induced conditioned hyperactivity. Rats received repeated pairings of a distinct test environment with either saline or cocaine (15 mg/kg, i.p.) for 7 days. In a drug-free test 2 days after the last pairing, expression of conditioned hyperactivity was seen in the rats previously exposed to cocaine in the test environment. The 5-HT2C R agonist MK 212 (0.0625-0.5 mg/kg, i.p., 5 min before test) significantly decreased, while the 5-HT2C R antagonist SB 242084 (0.5-1 mg/kg, i.p. 30 min prior to test) enhanced, expression of cocaine-induced conditioned hyperactivity. The effective doses of MK 212 and SB 242084 did not alter basal activity on the test session. These results suggest that the 5-HT2C R controls expression of cocaine-induced conditioned hyperactivity and suggest that such ligands may be useful in preventing relapse and promoting abstinence in cocaine-dependent individuals.     

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.     

100Hz电针通过激活伏隔核内κ阿片受体抑制可卡因CPP的表达

目的：探讨100Hz电针抑制大鼠可卡因条件位置偏爱（Conditioned Place Preference,CPP）表达的机制。方法：采用可卡因诱导大鼠CPP模型,观察（1）选择性κ阿片受体拮抗剂nor-BNI加100Hz电针对可卡因CPP表达的影响;（2）每次电针前给大鼠双侧伏隔核内注射nor-BNI,能否阻断电针对可卡因CPP的表达;（3）电针处理可卡因CPP大鼠伏核组织中κ阿片受体mRNA表达的变化。结果：（1）10μg／5μl nor—BNI侧脑室给药或0．3μg／1μl nor-BNI伏隔核内微注射预处理给药都能翻转100Hz电针对可卡因CPP的抑制作用;（2）100Hz电针能显著增加可卡因CPP大鼠伏隔核内κ阿片受体mRNA的表达。结论：100Hz电针通过激活伏隔核内κ阿片受体从而抑制可卡因CPP的表达。     

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.     

Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

Rationale

Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation.

Objectives

The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT).

Methods

Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters.

Results

ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT.

Conclusions

Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates.     

100Hz电针对大鼠可卡因CPP重建的影响

目的:探讨100Hz电针对大鼠可卡因条件位置偏爱(Conditioned Place Preference,CPP)重建的影响.方法:采用可卡因诱导大鼠CPP重建模型,观察100 Hz电针对大鼠可卡因CPP重建的作用及选择性κ阿片受体拮抗剂nor-BNI对电针作用的影响.结果:100 Hz电针5次刺激抑制了可卡因(5 mg/kg)引燃CPP重建,nor-BNI(10μg/5μl)翻转了电针对可卡因CPP重建的抑制作用.结论:多次电针可通过κ阿片受体抑制可卡因引燃CPP的重建.     

Scopolamine inhibits cocaine-conditioned but not unconditioned stimulant effects in mice

RATIONALE: In animal models, cocaine cues contribute to the development of conditioned responses to the psychomotor stimulating and rewarding effects of the drug. OBJECTIVES: In the present study we investigated the effect of scopolamine, known to impair learning and memory, on cocaine-induced conditioned and unconditioned responses in Swiss Webster mice. METHODS: In the first experiment, mice were treated with saline/saline, saline/cocaine (20 mg/kg), scopolamine (1.0 mg/kg)/cocaine, or scopolamine/saline for 5 days. The treatments were paired with the locomotor activity test cage twice, on days 1 and 5. This allowed to determine: (a) the induction and expression of place-dependent sensitization (PDS) to the psychomotor-stimulating effect of cocaine and (b) place-dependent hyperlocomotion (PDH; i.e., conditioning) as defined by the response to saline injection in the test cage. In the second experiment, all injections were delivered in animals' home cage in order to induce place-independent sensitization (PIS) to cocaine and to avoid the development of PDH. In the third experiment, the effect of scopolamine (1.0 mg/kg) on the acquisition of cocaine-induced conditioned place preference (CPP) was investigated. RESULTS: Data from the first experiment suggest that pretreatment with scopolamine had no specific effect on the induction and expression of cocaine-induced PIS. However, scopolamine blocked cocaine-induced PDH. Results from the second experiment confirmed that scopolamine had no effect on the induction of PIS to cocaine. Results from the third experiment showed that scopolamine completely blocked cocaine-induced CPP. CONCLUSIONS: The finding that scopolamine blocked the conditioned behaviors, PDH and CPP, that develop after exposure to cocaine supports the hypothesis that cocaine cue reactivity in the paradigms tested is associated with learning and memory.     

Preexposure to cocaine attenuates aversions induced by both cocaine and fluoxetine: Implications for the basis of cocaine-induced conditioned taste aversions

Although cocaine-induced conditioned taste aversions (CTA) are well documented, little is known about the basis for cocaine's aversive effects. To address the role of serotonin (5-HT) in cocaine-induced aversions, the present experiments used the cross-drug preexposure design in which the effects of exposure to fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) with 5-HT transporter (SERT) inhibitory properties, were examined on aversions induced by cocaine (a nonselective monoamine transport inhibitor) and the effects of cocaine preexposure were examined on fluoxetine-induced aversions. Prior to these assessments, a fluoxetine dose-response function (3.2, 5.6, 10, and 18 mg/kg) was established in male Sprague-Dawley rats to determine a dose of fluoxetine that would induce intermediate aversions that were comparable to those induced by 18 mg/kg cocaine (Experiment 1). Other groups of rats were then exposed to fluoxetine prior to aversion conditioning with cocaine (Experiment 2) and with cocaine prior to aversion conditioning with fluoxetine (Experiment 3). All drugs were administered subcutaneously (cocaine 18 mg/kg; fluoxetine 10 mg/kg). Although there was no effect of fluoxetine preexposure on either cocaine- or fluoxetine-induced aversions, preexposure to cocaine significantly attenuated aversions induced by itself and by fluoxetine. These results were discussed in terms of the possible role 5-HT might play in the mediation of aversions induced by cocaine.     

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.     

Effects of repeated exposure to cocaine on group II metabotropic glutamate receptor function in the rat medial prefrontal cortex: behavioral and neurochemical studies

Rationale  Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Enhanced excitatory output from the medial prefrontal cortex (mPFC), which can be modulated by group II metabotropic glutamate receptors (mGluR), is thought to play a key role in the development of sensitization to cocaine. Objectives  The present studies were designed to determine whether the ability of intra-mPFC injections of the group II mGluR agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit cocaine-induced motor activity and dopamine release in the nucleus accumbens is reduced in sensitized animals. Results  Initial studies demonstrated that injection of APDC (0.015–15 nmol/side) into the mPFC dose dependently reduced cocaine-induced (15 mg/kg, i.p.) motor activity. The lowest dose in the present studies that significantly reduced the acute motor-stimulant response to cocaine was 1.5 nmol/side. The specificity of the effects of APDC was confirmed by demonstrating that intra-mPFC co-injection of LY341495 (1.5 nmol/side), a group II mGluR antagonist, prevented the inhibitory actions of APDC. Finally, it was shown that intra-mPFC injection of APDC was able to prevent the initiation of behavioral and neurochemical sensitization to cocaine. Intra-mPFC APDC was also observed to block the expression of cocaine-induced sensitization after short (1 day), but not prolonged (7 and 30 days), abstinence from cocaine. Conclusions  Taken together, these data suggest that mPFC group II mGluR function is reduced following extended abstinence from repeated cocaine.     

Orphanin FQ/nociceptin but not Ro 65-6570 inhibits the expression of cocaine-induced conditioned place preference

The present study investigated the effect of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like 1 (ORL-1) receptor on the expression of cocaine-induced conditioned place preference (CPP) in rats. To extend this study, the new non-peptidic compound Ro 65-6570 (8-acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one), with agonist activity at ORL-1 receptors, was examined. The influence of both compounds on cocaine-induced hyperactivity was also studied. Our experiments indicated that intracerebroventricular (i.c.v.) injection of OFQ/N, at doses of 10 and 20 microg/rat, significantly suppressed the expression of cocaine-induced place preference. Ro 65-6570 (3 and 6 mg/kg, i.p.) did not change the effect of cocaine, although its acute injection in control rats significantly increased the time spent in the drug-associated compartment of the CPP apparatus. The substances exhibited opposite effects on cocaine-induced hyperactivity (OFQ/N suppressed it but Ro 65-6570 increased it). Our results suggest that the effect of OFQ/N on the expression of cocaine-induced CPP may be a result of its influence on dopamine (DA) neurotransmission in mesolimbic structures. Ro 65-6570 does not share this effect with OFQ/N.     

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.     

Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice.

The abuse of substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) can result in neurotoxicity, manifested as the depletion of dopamine (DA) and 5-hydroxytriptamine (5-HT; serotonin) axon terminal markers in humans and animal models. Human METH and MDMA users exhibit impairments in memory and executive functions, which may be a direct consequence of the neurotoxic potential of amphetamines. The objective of this study was to investigate the influence of amphetamines-induced neurotoxicity on Pavlovian learning. Using mouse models of selective DA neurotoxicity (METH; 5 mg/kg x 3), selective 5-HT neurotoxicity (fenfluramine /FEN; 25 mg/kg x 4) and dual DA and 5-HT neurotoxicity (MDMA; 15 mg/kg x 4), appetitive and aversive conditioning were investigated. Dopaminergic neurotoxicity significantly impaired METH and cocaine conditioned place preference (CPP), but had no effect on LiCl-induced conditioned place aversion (CPA). In contrast, serotonergic neurotoxicity significantly enhanced CPP, and had no effect on CPA. Dual dopaminergic/serotonergic neurotoxicity had no apparent effect on CPP; however, CPA was significantly attenuated. Postmortem analysis revealed that significantly diminished levels of DA and 5-HT markers persisted in the striatum, frontal cortex, hippocampus, and amygdala. These findings suggest that amphetamines-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on the affective state produced by subsequent drug reward, while dual dopaminergic/serotonergic neurotoxicity impairs associative learning of aversive conditioning. Furthermore, results revealed that amphetamines-induced DA and 5-HT neurotoxicity modulates appetitive Pavlovian conditioning similar to other DA and 5-HT neurotoxins. Modulation of Pavlovian conditioning by amphetamines-induced neurotoxicity may be relevant to compulsive drug-seeking behavior in METH and MDMA abusers.     

Dissociating effects of cocaine and <Emphasis Type="Italic">d</Emphasis>-amphetamine on dopamine and serotonin in the perirhinal,entorhinal, and prefrontal cortex of freely moving rats

Rationale Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However, the neurochemical nature of these brain activities is not characterized. Objective The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal cortex (PFC). Materials and methods We conducted in vivo microdialysis experiments in behaving rats measuring DA and 5-HT in the perirhinal cortex (PRC), entorhinal cortex (EC), and PFC, after application of cocaine (0, 5, 10, 20 mg/kg; i.p.) or d-amphetamine (0, 0.5, 1.0, 2.5 mg/kg; i.p.). Results Cocaine and d-amphetamine dose-dependently increased DA and 5-HT levels in the PRC, EC, and PFC. A predominant DA response to d-amphetamine was only found in the PFC, but not in the PRC and EC. Cocaine increased DA and 5-HT to an equal extent in the PFC and PRC but induced a predominant 5-HT response in the EC. When comparing the neurochemical responses between the drugs at an equal level of behavioral activation, cocaine was more potent than d-amphetamine in increasing 5-HT in the PFC, while no differences were found in the PRC or EC or in the DA responses in all three cortical areas. Conclusions We conclude that cocaine and d-amphetamine increase DA and 5-HT levels in PRC and EC largely to the same extent as in the PFC.     

Postconditioning effects of magnesium on cocaine conditioned place preference in mice

Magnesium chloride (MgCl2) has recently been shown to have stimulant-like properties. Because stimulants are known to induce conditioned place preference (CPP), the CPP procedure was used to test the hypothesis that cocaine and MgCl2 share similar stimulus properties. This would be shown if cocaine-induced CPP could be enhanced in a postconditioning preference test by MgCl2 and other stimulants. Mice were conditioned with 5.0 mg/kg cocaine to the nonpreferred end of a three-compartment straight shuttle box. All groups showed significant shifts in preference from the preconditioning test to the postconditioning test. There were no changes in place preference over test days in mice that were injected only with saline and therefore not conditioned. When animals were given acute injections of either saline, 5.0 mg/kg cocaine, 1.0 mg/kg amphetamine, 30 mg/kg MgCl2, 10 mg/kg pentobarbital, or 0.25 mg/kg haloperidol following conditioning with cocaine, amphetamine and MgCl2 elevated the conditioned cocaine effect, and pentobarbital and haloperidol decreased the conditioned cocaine effect compared to saline. In addition, there was a dose-dependent influence of MgCl2, with 30 mg/kg producing the maximum effect on the conditioned cocaine effect.