Development Of Conditioned Place Preference Research Articles

Chronic inflammatory pain promotes place preference for fentanyl in male rats but does not change fentanyl self-administration in male and female rats

The current opioid epidemic is a national health crisis marked by skyrocketing reports of opioid misuse and overdose deaths. Despite the risks involved, prescription opioid analgesics are the most powerful and effective medications for treating pain. There is a clear need to investigate the risk of opioid misuse liability in male and female adults experiencing chronic pain. In the present study, we tested the hypothesis that chronic inflammatory pain would increase fentanyl intake, motivation to acquire fentanyl, and drug seeking in the absence of fentanyl in rats. Fentanyl intake, motivation for fentanyl, and drug seeking were tested under limited and extended access conditions using intravenous fentanyl self-administration. Fos activity in ventral tegmental area (VTA) dopamine neurons following intravenous fentanyl challenge (35 μg/kg) was examined using immunohistochemistry. Finally, we tested whether low-dose fentanyl supports development of conditioned place preference under an inflammatory pain state in rats. Contrary to our hypothesis, fentanyl self-administration and VTA Fos activity were unaffected by inflammatory pain status. During acquisition, males exhibited increased fentanyl intake compared to females. Animals given extended access to fentanyl escalated fentanyl intake over time, while animals given limited access did not. Males given extended access to fentanyl demonstrated a greater increase in fentanyl intake over time compared to females. During the dose-response test, females given limited access to fentanyl demonstrated increased motivation to acquire fentanyl compared to males. Both sexes displayed significant increases in responding for fentanyl as unit fentanyl doses were lowered. Following fentanyl challenge, females exhibited higher numbers of Fos-positive non-dopaminergic VTA neurons compared to males. Using conditioned place preference, we found that chronic inflammatory pain promotes fentanyl preference in males, but not females. These findings suggest that established fentanyl self-administration is resistant to change by inflammatory pain manipulation in both sexes, but chronic inflammatory pain increases the rewarding properties of low-dose fentanyl in males.

Ovarian Steroids Mediate Sex Differences in Alcohol Reward After Brain Injury in Mice.

Intoxication is a leading risk factor for injury, and TBI increases the risk for later alcohol misuse, especially when the injury is sustained in childhood. Previously, we modeled this pattern in mice, wherein females injured at postnatal day 21 drank significantly more than uninjured females, while we did not see this effect in males. However, the biological underpinnings of this sex difference have remained elusive. In this study, we utilize this preclinical model and traditional endocrine manipulations to assess the effect of perinatal sex steroids on post-injury ethanol response. We found that perinatal androgen administration and adult ovariectomy prevented the development of conditioned place preference to ethanol in females, while there was not an effect of gonadectomy either developmental time point on the severity of axonal degeneration. Finally, although TBI increased the number of microglia in males, there was no corresponding effect of gonadectomy, which suggests that males exhibit prolonged neuroinflammation after brain injury irrespective of circulating sex steroids. Taken together, our results indicate a potential role for ovarian sex steroids in the development of greater alcohol preference after a juvenile TBI in female mice.

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents.

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

Cannabinoid Receptor Type 1 Regulates Drug Reward Behavior via Glutamate Decarboxylase 67 Transcription.

Interaction of cannabinoid receptor type 1 (CB1) and GABAergic neuronal activity is involved in drug abuse-related behavior. However, its role in drug-dependent Pavlovian conditioning is not well understood. In this study, we aimed to evaluate the effects of a CB1 agonist, JWH-210, on the development of conditioned place preference (CPP)-induced by methamphetamine (METH). Pretreatment with a synthetic cannabinoid, JWH-210 (CB1 agonist), increased METH-induced CPP score and METH-induced dopamine release in acute striatal slices. Interestingly, CB1 was expressed in glutamate decarboxylase 67 (GAD67) positive cells, and overexpression of CB1 increased GAD67 expression, while CB1 knockdown reduced GAD67 expression in vivo and in vitro. GAD67 is known as an enzyme involved in the synthesis of GABA. CB1 knockdown in the mice striatum increased METH-induced CPP. When GAD67 decreased in the mice striatum, mRNA level of CB1 did not change, suggesting that CB1 can regulate GAD67 expression. GAD67 knockdown in the mouse striatum augmented apomorphine (dopamine receptor D2 agonist)–induced climbing behavior and METH-induced CPP score. Moreover, in the human brain, mRNA level of GAD67 was found to be decreased in drug users. Therefore, we suggest that CB1 potentiates METH-induced CPP through inhibitory GABAergic regulation of dopaminergic neuronal activity.

Sex differences in the development of conditioned place preference induced by intragastric alcohol administration in mice

BackgroundThe present study aimed to identify for the first time sex differences in the development of CPP induced by intragastric alcohol administration in mice. MethodsMale and female adult Swiss mice were submitted to 16 days of conditioning with alcohol (0.5–3.0 g/kg, N = 8/dose/sex), with 2 post-conditioning tests (after 8 and 16 sessions) during the protocol. Results8 days of conditioning (4 alcohol sessions, 4 saline sessions) with intragastric alcohol administration were sufficient to induce CPP in male mice at the doses of 1.0, 1.5 and 2.0 g/kg. However, only higher doses (2.0, 2.5 and 3.0 g/kg) induced CPP in female mice using an 8-day conditioning protocol, while a 16-day conditioning protocol was necessary for the development of intragastric alcohol-induced CPP at the doses of 1.0 and 1.5 g/kg. Regardless of the conditioning protocol, higher doses or alcohol that had rewarding effects in females (2.5 and 3.0 g/kg) did not induce CPP in males, with a significant difference between males and females at those doses. Analysis of the potency (EC50) and efficacy (Emax) of alcohol in inducing CPP when administered intragastrically in male and female mice showed significant sex differences with 8 conditioning sessions. ConclusionsOur data show a clear protocol (8 vs 16 days) and dose difference between male and female Swiss mice regarding the development of CPP induced by intragastric alcohol administration. Intragastric alcohol administration is closer to human drinking, and our protocol provides a more translational approach to studying the rewarding effects of alcohol in mice.

Cocaine reward and memory after chemogenetic inhibition of distinct serotonin neuron subtypes in mice.

We probed serotonin neurons, those denoted by their developmental gene expression as r2Hoxa2-Pet1 (experiment 1) and Drd1a-Pet1 (experiment 2), for differential modulation of cocaine reward and memory as revealed by the expression and development of conditioned place preference (CPP) in transgenic mice. To query roles in CPP, we inhibited neurons cell autonomously in vivo by activating the transgenically expressed, synthetic DREADD receptor hM4Di (Di) with the exogenous ligand clozapine-N-oxide (CNO). To examine CPP expression, mice were conditioned using behaviorally active doses of cocaine (10.0 or 17.8 mg/kg) vs. saline followed by CPP assessment, first without neuron inhibition (post-conditioning session 1), and then with CNO-mediated neuron inhibition (post-conditioning session 2), followed by 4 more post-conditioning sessions. To examine CPP development, we administered CNO during conditioning sessions and then assayed CPP across 6 post-conditioning sessions. In r2Hoxa2-Pet1-Di mice, post-conditioning CNO administration did not impact cocaine CPP expression, but after CNO administration during conditioning, cocaine CPP (17.8 mg/kg) persisted across post-conditioning sessions compared with that in controls, suggesting a deficit in extinguishing cocaine memory. Drd1a-Pet1-Di mice, prior to CNO-Di-triggered neuronal inhibition, unexpectedly expressed heightened cocaine CPP (10.0 and 17.8 mg/kg) compared with controls, and this basal phenotype was transiently blocked by acute post-conditioning CNO administration and persistently blocked by repeated CNO administration during conditioning. Cocaine reward and memory likely map to distinct serotonergic Pet1 neuron subtypes. r2Hoxa2-Pet1 neurons normally may limit the durability of cocaine memory, without impacting initial cocaine reward magnitude. Drd1a-Pet1 neurons normally may help to promote cocaine reward.

Inhibition of TrkB at the nucleus accumbens, using ANA-12, regulates basal and stress-induced orexin A expression within the mesolimbic system and affects anxiety, sociability and motivation

Repeated stress exposure can lead to the development of anxiety and mood disorders. An emerging biological substrate of depression and associated pathology is the nucleus accumbens (NAc), which through interactions with limbic, cognitive and motor circuits can regulate a variety of stress responses. Within these circuits, orexin neurons are involved in arousal and stress adaptability, effects proposed mediated via brain-derived neurotrophic factor signaling. This study tested the hypotheses that 1) repeated exposure to heterotypic stress alters social ability and preference and passive avoidant behaviors, 2) TrkB receptors at the NAc shell regulates stress-induced behavioral responses and orexin expression within the mesocorticolimbic system. Our findings indicate that ANA-12 (0.25 μg/0.5 μl) enhanced sociability during the social interaction test, although treatment had no effect on social preference. The development of conditioned place preference, and fear retention in the passive avoidance test were also facilitated by ANA-12. Biochemical assessments on brain tissues collected within 2 h of a forced swim exposure revealed that ANA-12 increased orexin A immunoreactivity (ir) in the hypothalamic perifornical area, while expression was reduced in the ventral portion of the hippocampal CA1 layer, irrespective of the stress condition. This contrasts changes at the VTA characterized by elevated versus reduced orexin A-ir in ANA-12-treated stress and non-stress rats, respectively. Colocalized orexin A- and tyrosine hydroxylase (TH)-ir at the VTA supports a different temporal expression post stress, TH-ir being unaffected 9 days post stress. These findings support a role for TrkB receptors in regulating basal and stress-induced social, cognitive and motivational behavior, and modulatory actions of BDNF, via TrkB signaling, on orexin A signaling upon stress exposure.

PolyMorphine provides extended analgesic-like effects in mice with spared nerve injury

Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties of a new polymer form of morphine known as PolyMorphine. This polymer has monomeric units of morphine incorporated into a poly(anhydride-ester) backbone that has been shown to hydrolyze into free morphine in vitro. Using an animal model of chronic pain, the spared nerve injury surgery, we showed that PolyMorphine is able to block spared nerve injury-induced hypersensitivity in mice for up to 24-h post-administration. Free morphine was shown to only block spared nerve injury-induced hypersensitivity for up to 2-h post-injection. PolyMorphine was also shown to act through the mu opioid receptor due to the ability of naloxone (a mu opioid receptor antagonist) to block PolyMorphine-induced analgesia in spared nerve injury animals pretreated with PolyMorphine. Additionally, we observed that PolyMorphine causes similar locomotor and constipation side effects as free morphine. Finally, we investigated if PolyMorphine had any effects in a non-evoked pain assay, conditioned place preference. Pretreatment of spared nerve injury mice with PolyMorphine blocked the development of conditioned place preference for 2-methyl-6-(phenylethynyl)pyridine (MPEP), a short-lasting mGluR5 antagonist with analgesic-like properties. Free morphine does not block the development of preference for MPEP, suggesting that PolyMorphine has longer lasting analgesic effects compared to free morphine. Together, these data show that PolyMorphine has the potential to provide analgesia for significantly longer than free morphine while likely working through the same receptor.

Action of Pitolisant on the stimulant and rewarding effects of cocaine in mice

Previous studies have demonstrated that the histamine H3 receptor inverse agonist thioperamide potentiates the stimulant and rewarding effects of cocaine. However, these potentiating effects of thioperamide do not necessarily result from H3 receptor blockade since thioperamide is an imidazole-based compound capable of enhancing plasma cocaine concentrations by blocking cytochrome P450 activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist that has already been tested in clinical trials but it remains to be determined whether this compound also potentiates the behavioral effects of cocaine. The present study tested the effects of Pitolisant on locomotion, on cocaine-induced hyperactivity and on the development of conditioned place preference induced by cocaine (2 and 8mg/kg, i.p.) in male C57BL/6J mice. Pitolisant was injected 30min before each cocaine-pairing session. Locomotion recorded on the first cocaine-pairing session was used to test the effects of Pitolisant on the locomotor effects of cocaine. Our results show that doses of Pitolisant higher than 10mg/kg depressed locomotion. When injected alone at doses that did not affect locomotion, Pitolisant (2.5–10mg/kg, i.p.) had no rewarding properties in the place conditioning technique. Additionally, Pitolisant did not significantly alter cocaine-induced hyperactivity and cocaine-induced conditioned place preference. Taken together, our study indicates that Pitolisant has no addictive properties alone. Moreover, this compound does not significantly affect the stimulant and rewarding effects of cocaine. These results add further evidence to support the hypothesis that a pharmacokinetic interaction is involved in the ability of thioperamide to potentiate cocaine's psychomotor effects.

Basal forebrain projections to the lateral habenula modulate aggression reward.

Maladaptive aggressive behavior is associated with a number of neuropsychiatric disorders1 and is thought to partly result from inappropriate activation of brain reward systems in response to aggressive or violent social stimuli2. Nuclei within the ventromedial hypothalamus3–5, extended amygdala6 and limbic7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behavior8. To address this, we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors (AGG) develop a CPP, while non-aggressors (NON) develop a conditioned place aversion (CPA), to the intruder-paired context. Further, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of AGG with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of NON with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Lastly, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behavior. These results demonstrate that the BF-lHb circuit plays a critical role in regulating the valence of inter-male aggressive behavior and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

Initial D2 Dopamine Receptor Sensitivity Predicts Cocaine Sensitivity and Reward in Rats

The activation of dopamine receptors within the mesolimbic dopamine system is known to be involved in the initiation and maintenance of cocaine use. Expression of the D2 dopamine receptor subtype has been implicated as both a predisposing factor and consequence of chronic cocaine use. It is unclear whether there is a predictive relationship between D2 dopamine receptor function and cocaine sensitivity that would enable cocaine abuse. Therefore, we exploited individual differences in behavioral responses to D2 dopamine receptor stimulation to test its relationship with cocaine-mediated behaviors. Outbred, male Sprague-Dawley rats were initially characterized by their locomotor responsiveness to the D2 dopamine receptor agonist, quinpirole, in a within-session ascending dose-response regimen (0, 0.1, 0.3 & 1.0 mg/kg, sc). Rats were classified as high or low quinpirole responders (HD2 and LD2, respectively) by a median split of their quinpirole-induced locomotor activity. Rats were subsequently tested for differences in the psychostimulant effects of cocaine by measuring changes in cocaine-induced locomotor activity (5 and 15 mg/kg, ip). Rats were also tested for differences in the development of conditioned place preference to a low dose of cocaine (7.5 mg/kg, ip) that does not reliably produce a cocaine conditioned place preference. Finally, rats were tested for acquisition of cocaine self-administration and maintenance responding on fixed ratio 1 and 5 schedules of reinforcement, respectively. Results demonstrate that HD2 rats have enhanced sensitivity to the locomotor stimulating properties of cocaine, display greater cocaine conditioned place preference, and self-administer more cocaine compared to LD2 animals. These findings suggest that individual differences in D2 dopamine receptor sensitivity may be predictive of cocaine sensitivity and reward.

The Metabotropic Glutamate 5 Receptor Modulates Extinction and Reinstatement of Methamphetamine-Seeking in Mice

Methamphetamine (METH) is a highly addictive psychostimulant with no therapeutics registered to assist addicts in discontinuing use. Glutamatergic dysfunction has been implicated in the development and maintenance of addiction. We sought to assess the involvement of the metabotropic glutamate 5 receptor (mGlu5) in behaviours relevant to METH addiction because this receptor has been implicated in the actions of other drugs of abuse, including alcohol, cocaine and opiates. mGlu5 knockout (KO) mice were tested in intravenous self-administration, conditioned place preference and locomotor sensitization. Self-administration of sucrose was used to assess the response of KO mice to a natural reward. Acquisition and maintenance of self-administration, as well as the motivation to self-administer METH was intact in mGlu5 KO mice. Importantly, mGlu5 KO mice required more extinction sessions to extinguish the operant response for METH, and exhibited an enhanced propensity to reinstate operant responding following exposure to drug-associated cues. This phenotype was not present when KO mice were tested in an equivalent paradigm assessing operant responding for sucrose. Development of conditioned place preference and locomotor sensitization were intact in KO mice; however, conditioned hyperactivity to the context previously paired with drug was elevated in KO mice. These data demonstrate a role for mGlu5 in the extinction and reinstatement of METH-seeking, and suggests a role for mGlu5 in regulating contextual salience.

Estradiol enhances conditioned place preference to cocaine in male rats

Gender differences are reported in the subjective effects of cocaine, as well as in the response to treatment. Animal studies show that in ovariectomized rats, estradiol enhances sensitization, as well as conditioned place preference to cocaine. Furthermore, blocking estrogen receptors with ICI 182,780, in gonadally intact females blocks cocaine‐induced behavioral sensitization and conditioned place preference. We observed a similar situation in males. Gonadectomized males that receive estradiol, but not DHT, become sensitized to cocaine after repeated administration. Administration of ICI 182,780 curtails the development of conditioned place preference to repeated cocaine injections in gonadally intact males. These results indicate that estrogen receptors are essential for conditioning to the rewarding effects of cocaine. We are currently exploring the mechanism involved. This work was supported by the NINDS Specialized Neuroscience Research Program of the U54NS39405 and the NIGMS RISE Program R25Gm061838.

Place conditioning and neurochemical responses elicited by the aftereffect of acute stressor exposure involving an elevated stand

Acute exposure to an elevated stand has been used as an inescapable mild stressor for rats. The present study examined the effects of this stressor using a place conditioning behavioral test and neurochemical assays of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex and nucleus accumbens. The behavioral data showed that a conditioned place preference was formed as an aftereffect of the elevated stand stressor. In a separate experiment, neurochemical assay showed an immediate increase of dopamine in the nucleus accumbens after 30min exposure to the elevated stand stressor. In addition, the DOPAC content in the nucleus accumbens was significantly increased at 30min after this stressor. No significant change in dopamine or DOPAC levels in the medial prefrontal cortex was detected for up to 60min after stressor manipulation. These results suggest that an increase in dopamine activity in the nucleus accumbens is involved in the development of conditioned place preference elicited by the aftereffects of the elevated stand stressor.

Rhynchophylline down-regulates NR2B expression in cortex and hippocampal CA1 area of amphetamine-induced conditioned place preference rat

N-methyl-D-aspartate receptor 2B subunit (NR2B) has an important role in the development of conditioned place preference (CPP) and psychostimulant abuse. Rhynchophylline is presently used to treat central nervous systems diseases and has a non-competitive antagonistic effect on NMDA receptors. In this study, amphetamine was administered in rats (2 mg/kg, s.c., once each day for 4 consecutive days), during which they were treated with rhynchophylline (60 mg/kg, i.p., once each day for the next 3 days). NR2B mRNA and protein expression were examined by in situ hybridization and immunohistochemistry. CPP was induced by amphetamine (2 mg/kg, s.c.) by 4th day in rats. Rhynchophylline effectively reversed the expression of amphetamine-induced CPP and itself did not produce a CPP. Amphetamine-CPP rats showed a significantly increased NR2B mRNA and protein expression in medial prefrontal cortex and hippocampal CA1 areas as compared to the control group. Rhynchophylline reversed NR2B mRNA and protein levels induced by amphetamine but rhynchophylline by itself had no effect on NR2B expression in control rats. These results indicate that rhynchophylline inhibits the expression of amphetamine-induced rewarding effect, and this action might be related to down-regulation of NR2B expression in medial prefrontal cortex and hippocampal CA1 area.

Levo-tetrahydropalmatine attenuates oxycodone-induced conditioned place preference in rats

Levo-tetrahydropalmatine ( l-THP) is an alkaloid purified from the Chinese herb corydalis and stephania and is contained in many traditional Chinese herbal preparations. Our previous studies demonstrated the ability of l-THP to inhibit locomotor stimulation and physical dependence induced by oxycodone in mice and rats. The present study was designed to evaluate effects of l-THP on reward of oxycodone using conditioned place preference assay. Oxycodone (0.32–5.0 mg/kg) induced the development of conditioned place preference in rats. Furthermore, oxycodone (2.5 mg/kg) induced the increased phosphorylation of CREB and ERK in nucleus accumbens and hippocampus, but not in prefrontal cortex. l-THP (6.25–18.50 mg/kg) per se was not able to induce conditioned place preference or conditioned place aversion. l-THP co-administered with oxycodone during the conditioning sessions partly abolished the development of oxycodone-induced conditioned place preference in rats. Furthermore, l-THP inhibited the increased phosphorylation of ERK and CREB in nucleus accumbens and hippocampus of rats. All these results suggest that l-THP can inhibit oxycodone-induced psychological dependence by affecting phosphorylation of CREB and ERK in nucleus accumbens and hippocampus of rats. Together, the present data, combined with previous finding, support the potential use of l-THP for treatment of oxycodone addiction.

Reversal of cocaine addiction by environmental enrichment

Environmental conditions can dramatically influence the behavioral and neurochemical effects of drugs of abuse. For example, stress increases the reinforcing effects of drugs and plays an important role in determining the vulnerability to develop drug addiction. On the other hand, positive conditions, such as environmental enrichment, can reduce the reinforcing effects of psychostimulants and may provide protection against the development of drug addiction. However, whether environmental enrichment can be used to "treat" drug addiction has not been investigated. In this study, we first exposed mice to drugs and induced addiction-related behaviors and only afterward exposed them to enriched environments. We found that 30 days of environmental enrichment completely eliminates behavioral sensitization and conditioned place preference to cocaine. In addition, housing mice in enriched environments after the development of conditioned place preference prevents cocaine-induced reinstatement of conditioned place preference and reduces activation of the brain circuitry involved in cocaine-induced reinstatement. Altogether, these results demonstrate that environmental enrichment can eliminate already established addiction-related behaviors in mice and suggest that environmental stimulation may be a fundamental factor in facilitating abstinence and preventing relapse to cocaine addiction.

Development of conditioned place preference induced by intra-accumbens infusion of amphetamine is attenuated by co-infusion of dopamine D1 and D2 receptor antagonists

The present study investigated the role of dopamine receptors within the nucleus accumbens in place conditioning induced by d-amphetamine. Previous work has shown that conditioned place preference can be established by intra-accumbens infusion of amphetamine. The present study further examined whether bilateral co-infusion of the selective dopamine receptor antagonists with d-amphetamine into this region would disrupt the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Bilateral infusions of d-amphetamine into the nucleus accumbens at the dose of 10 μg per side significantly induced conditioned place preference. At the tested doses of 1 μg and 10 μg, either the selective D1 dopamine receptor antagonist (SCH23390) or the selective D2 dopamine receptor antagonist (raclopride) infused with the high dose into the nucleus accumbens significantly blocked the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Furthermore, the sole infusion of SCH23390 or raclopride into the nucleus accumbens produced little or no place conditioning effect. It is concluded that the dopamine D1 and D2 receptors in the nucleus accumbens are critically involved in the development of amphetamine induced conditioned place preference.

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

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. 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. 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 microg, was paired with peripheral injections of cocaine, 10-15 mg/kg. 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. 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.

NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference

In the present study, involvement of the N-methyl- d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5–10 mg/kg) induced conditioned place preference in rat. NMDA (0.1–1 μg/rat) or MK-801 (1–4 μg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1–1 μg/rat) increased, while MK-801 (1–4 μg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference.