Acquisition Of Place Preference Research Articles

Abuse Liability, Anti-Nociceptive, and Discriminative Stimulus Properties of IBNtxA.

IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ-opioid receptor (MOR) agonist which is structurally related to the MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, resulting in anti-nociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants, but further evaluation of its in vivo pharmacological profile is necessary. The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to examine more completely the rewarding properties and discriminative stimulus effects of IBNtxA, allowing broader assessment of IBNtxA as a candidate for further medications development. A dose of 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot-plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and vehicle, the κ-agonist U-50488 fully substituted for IBNtxA. MOR agonist morphine, δ-agonist SNC162, NOP agonist SCH 221510, and MOR/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. A dose of 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Overall, IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent anti-nociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.

Variability in nicotine conditioned place preference and stress-induced reinstatement in mice: Effects of sex, initial chamber preference, and guanfacine.

Relapse to smoking occurs at higher rates in women compared with men, especially when triggered by stress. Studies suggest that sex-specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2-adrenergic receptor agonist, may provide sex-sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress-induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress-induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress-induced reinstatement in both male and female mice, but with different nicotine dose-response patterns. In addition, we explored the variability in nicotine-dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress-induced reinstatement. In groups that showed significant stress-induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala and nucleus accumbens core and shell. Guanfacine induced sex-dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex-dependent relationships between initial chamber preference and stress-induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms.

The Involvement of Intra-Hippocampal Dopamine Receptors in the Conditioned Place Preference Induced By Orexin Administration into the Rat Ventral Tegmental Area.

The activity of dopamine (DA)-containing neurons in the ventral tegmental area (VTA) is a key mechanism in mesolimbic reward processing that has modulatory effects on different diencephalic structures like hippocampus (HIP), and receives inhibitory feedback and excitatory feed forward control. In addition, within the hippocampus, DA receptors are mostly located in the dorsal part (CA1) and dopaminergic innervations are predominant in this sub-region. The current study aimed to examine the effect of intra-hippocampal CA1 administration of SCH23390 and Sulpiride as D1- and D2-like receptor antagonists on the acquisition of orexin-induced conditioned place preference (CPP), respectively. Cannulas were unilaterally implanted into the VTA and HIP of adult male albino Wistar rats weighing 200-250 g. For induction of CPP, orexin A (10 ng/0.3 µL saline) was daily microinjected into the VTA during a three-day conditioning phase. Thereafter, various doses of SCH23390 and Sulpiride (0.25, 1 and 4 µg) were unilaterally injected into the CA1 during this 3-day conditioning phase after intra-VTA administration. The conditioning score was then calculated. Results revealed that intra-CA1 administration of D1- and D2-like receptor antagonists during the 3-day conditioning phase attenuated the acquisition of place preference by orexin A in a dose-dependent manner. It seems the effect of D2-like receptor antagonist within the CA1 region of hippocampus on this phenomenon was found to be more considerable than that of D1-like receptor antagonist. It is concluded that orexin-induced CPP may be mediated, at least in part, by stimulation of DA receptors in the CA1.

The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum

Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.

Decreased anxiety, voluntary ethanol intake and ethanol-induced CPP acquisition following activation of the metabotropic glutamate receptor 8 “mGluR8”

Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory neurotransmission, and have been implicated in addiction to alcohol and anxiety-related behaviors. However, the behavioral consequence and contribution of individual subtypes are not known yet. This study determined the effects of mGluR8 activation on anxiety-like behavior, voluntary ethanol intake and ethanol-induced conditioned reward. To this aim, anxiety and spontaneous behavior were measured in C57BL/6J mice using the elevated plus maze (EPM), open field (OF) and light-dark box (LDB) tests after systemic injection of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG). In addition, the anti-alcohol properties of mGluR8 were studied using a two-bottle choice continuous access drinking paradigm and ethanol-conditioned place preference (CPP). Results have shown that, compared to vehicle, DCPG produced an anxiolytic-like effect in the LDB, and OF tests. Furthermore, DCPG-injected mice displayed significantly lower intake and preference for ethanol [2.5–20% (v/v) escalating over 2weeks] in a two-bottle choice paradigm, with no significant difference observed with saccharin [0.04 & 0.08% (w/v)] nor on quinine [20 & 40μM (w/v)]. Interestingly, DCPG administration attenuated ethanol-induced acquisition, but not expression, of CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the group III mGluR-specific antagonist (S)-2-amino-2-methyl-4- phosphonobutyric (MAP4). These data demonstrate that activation of the mGluR8 reduces voluntary ethanol intake in male mice and eliminates place preference acquisition suggesting that mGluR8 signaling may contribute to the rewarding properties of ethanol. Taken together, these findings demonstrate that mGluR8-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism.

Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2

Early life stress is a major risk factor for cocaine addiction; however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors. We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex. Male BALB/c mice subjected to MS (3h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment. MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS. Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.

Alcohol enhances the psychostimulant and conditioning effects of mephedrone in adolescent mice; postulation of unique roles of D3 receptors and BDNF in place preference acquisition.

The psychostimulant mephedrone is often consumed in combination with alcohol (EtOH). This kind of drug consumption during adolescence is a matter of concern. We studied, in adolescent CD-1 mice, whether EtOH could enhance the psychostimulant (locomotor acivity) and rewarding [conditioned place preference (CPP)] effects of mephedrone. We also determined the transcriptional changes associated with a conditioning treatment with these drugs. Mephedrone (10 mg·kg(-1)) increased locomotor activity, which was further enhanced by 40% when combined with EtOH (1 g·kg(-1)). This enhancement was blocked by haloperidol. Furthermore, mephedrone (25 mg·kg(-1)) induced CPP, which increased by 70% when administered with a dose of EtOH that was not conditioning by itself (0.75 g·kg(-1)). There was enhanced expression of the D3 dopamine receptor mRNA (Drd3) and Arpc5 in all drug-treated groups. The D3 receptor antagonist SB-277011A and the BDNF receptor antagonist ANA-12 completely prevented CPP as well as the increases in Drd3 in all groups. Accordingly, increased expression of BDNF mRNA in medial prefrontal cortex was detected at 2 and 4 h after mephedrone administration. If translated to humans, the enhancement of mephedrone effects by ethanol could result in increased abuse liability. D3 receptors and BDNF play a key role in the establishment of CPP by mephedrone, although an accompanying increase in other synaptic plasticity-related genes may also be necessary.

Inhibition of urokinase plasminogen activator activity alters ethanol consumption and conditioned place preference in mice

Introduction: Urokinase plasminogen activator (uPA) is a serine protease implicated in addiction to drugs of abuse. Using its specific inhibitor B428, the role of uPA in the rewarding properties of psychostimulants, including cocaine and amphetamine, have been characterized but none have examined the role of uPA in ethanol use disorders. Objectives: In the current study, observations on the role of uPA in ethanol consumption and ethanol-induced conditioned place preference have been extended. The general aim of the present series of experiments was to investigate the effects of the administration of B428 on voluntary alcohol intake and ethanol conditioned reward. Materials and methods: A two-bottle choice, unlimited-access paradigm was used to compare ethanol intake between vehicle and 3, 10 and 30mg/kg B428 administered to mice. For this purpose, the mice were presented with an ethanol solution (2.5– 20%) and water, at each concentration for 4 days, and their consumption was measured daily. Consumption of saccharin and quinine solutions was also measured. Results: Systemic administration of B428 dose-dependently decreased ethanol intake and preference. In addition, B428 mice did not differ from vehicle mice in their intake of graded solutions of tastants, suggesting that the uPA inhibition did not alter taste function. Furthermore, ethanol metabolism was not affected following B428 injection. More importantly, 1.5g/kg ethanol-induced conditioned place preference acquisition was blocked following B428 administration. Conclusions: Taken together, our results are the first to implicate uPA inhibition in the regulation of ethanol consumption and preference, and suggest that uPA may be considered as a possible therapeutic drug target for alcoholism and abstinence.

Inhibition of urokinase plasminogen activator “uPA” activity alters ethanol consumption and conditioned place preference in mice

Urokinase plasminogen activator, uPA, is a serine protease implicated in addiction to drugs of abuse. Using its specific inhibitor, B428, we and others have characterized the role of uPA in the rewarding properties of psychostimulants, including cocaine and amphetamine, but none have examined the role of uPA in ethanol use disorders. Therefore, in the current study, we extended our observations to the role of uPA in ethanol consumption and ethanol-induced conditioned place preference. The general aim of the present series of experiments was to investigate the effects of the administration of the B428 on voluntary alcohol intake and ethanol conditioned reward. A two-bottle choice, unlimited-access paradigm was used to compare ethanol intake between vehicle- and 3, 10, and 30 mg/kg B428-administered mice. For this purpose, the mice were presented with an ethanol solution (2.5%–20%) and water, at each concentration for 4 days, and their consumption was measured daily. Consumption of saccharin and quinine solutions was also measured. Systemic administration of B428 dose-dependently decreased ethanol intake and preference. Additionally, B428 mice did not differ from vehicle mice in their intake of graded solutions of tastants, suggesting that the uPA inhibition did not alter taste function. Also, ethanol metabolism was not affected following B428 injection. More importantly, 1.5 g/kg ethanol-induced conditioned place preference acquisition was blocked following B428 administration. Taken together, our results are the first to implicate uPA inhibition in the regulation of ethanol consumption and preference, and suggest that uPA may be considered as a possible therapeutic drug target for alcoholism and abstinence.

Effects of prenatal immune activation and peri-adolescent stress on amphetamine-induced conditioned place preference in the rat

Addiction is a disease of learning and memory, as learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play central roles in addiction. Early developmental stress enhances risk for drug problems in adulthood. Environmental factors influencing learning and memory processes relevant to addiction remain incompletely characterized. To determine effects of prenatal immune activation and developmental stress on conditioned place preference to amphetamine, and reversal learning. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or vehicle on gestational day 14. Half of the male offspring received 2 h of restraint stress at post-natal day 35. Behavioral testing was performed in adulthood. Restraint stress inhibited acquisition of place preference to low-dose amphetamine (0.5 mg/kg), while poly I:C treatment had no measurable effect on place preference acquisition. In contrast, drug-induced reinstatement of preference for drug-paired chamber was enhanced in offspring of poly I:C-treated dams [F(1,25)05.31, p00.03]. Performance on a Morris water maze reversal learning task was impaired in poly I:C offspring. Reversal learning performance was correlated with place preference reinstatement in non-stressed (r200.42, p00.0095), but not stressed rats (r2 00.04, p00.49). Prenatal immune activation enhances drug induced reinstatement of conditioned place preference. These data demonstrate longstanding impact on behaviors with potential influence on risk for drug relapse as a consequence of prenatal immune activation. Further study is needed to determine clinical and epidemiological consequences of similar exposures in human populations.

Irregular morphine administration affects the retention but not acquisition of conditioned place preference in rats

Drug addiction is increasingly viewed as the expression of abnormal associative learning following repeated exposures to the drugs of abuse. Previous studies have demonstrated that the patterns of repetition such as frequency and spacing are important to many kinds of learning and memory retention. We hypothesized that drug repetition pattern might affect the reward-related learning although the total doses of the drug were the same. In the present study, we tested morphine-induced place preference following either regular or irregular pattern of morphine pairing in rats. Regular morphine group received morphine administration daily at a regular time with the same dose. Irregular morphine groups received morphine administration either at the same time but irregular doses, irregular time but same dose, or irregular time and irregular doses. We found that rats, who received irregular morphine pairing, exhibited similar acquisition of place preference but different preference retentions compared with regular morphine-treated rats after the same total dose of morphine. Rats, who received morphine administration at the same time but irregular doses and at irregular time and irregular doses, showed rapid disruption of place preference than the regular morphine group. Rats, who received morphine at irregular time but the same dose, showed similar retention of place preference to regular morphine group. Our results suggest that the pattern of drug pairing plays an important role in the retention of reward-related memory. This study may provide new evidence to broaden our understanding of the development and maintenance of drug craving.

Effects of SCH23390 and spiperone administered into medial striatum and intermediate medial mesopallium on rewarding effects of morphine in day-old chicks

In the avian forebrain, the medial striatum and the intermediate medial mesopallium are thought to be important structures for associative learning in chicks, where the role of dopaminergic systems in learning processes has been verified in various behavioral paradigms, such as one-trial passive avoidance learning. However, it is not yet clear whether the dopaminergic system of these regions is responsible for associative learning underlying cue-elicited drug reward. In this study, a 6-day conditioning schedule in day-old chicks with i.p. morphine (2 mg/kg) was used to compare the effects of intracerebrally injected dopamine D 1 receptor antagonist, SCH23390, and D 2 antagonist, spiperone. The antagonists were injected bilaterally (3 µg/site) into either the medial striatum or the intermediate medial mesopallium, and tests were conducted on morphine-induced conditioned place preference or locomotor activity. The acquisition of place preference was significantly inhibited by SCH23390 in either the medial striatum or the intermediate medial mesopallium, but not by spiperone. However, in the medial striatum, but not in the intermediate medial mesopallium, the locomotor activity was blocked by both SCH23390 and spiperone. These data suggest that the medial striatum and the intermediate medial mesopallium in birds are differentially involved in the rewarding effects of morphine, and similarly to mammals, the dopamine D 1 system may play an important role in the development of opiate reward.

The Role of Tissue-Type Plasminogen Activator System in Amphetamine-Induced Conditional Place Preference Extinction and Reinstatement

Extracellular serine proteases of the plasminogen activator family (tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) may modulate synaptic adhesion and associate with learning behavior. Psychostimulants strongly induce their expression in the mesolimbic dopaminergic pathway, but cocaine preferentially induces uPA, whereas morphine and amphetamine preferentially induce tPA. tPA-expressing animals displayed enhanced conditional place preference (CPP) for amphetamine compared with uPA-overexpressing animals. Thus, modulation of the plasminogen system in the brain might be a potential target against drugs of abuse. In the present study, we aim to identify whether tPA is involved in the acquisition/learning phase or in the expression/retrieval phase of conditioned drug preference. For this purpose, animals were injected with lentiviruses expressing or silencing tPA in the NAc and place preference was assessed. We found that tPA expression is associated with acquisition of place preference and animals overexpressing tPA spend >87% of the time in the drug-associated compartment, compared with 60% for control animals. When ectopic expression of tPA has been inhibited by doxycycline during acquisition, animals do no more associate the environment with the drug. Suppression of endogenous tPA expression in animals treated with LV-siRNA fully suppresses place preference, and these animals appear to avoid the drug-associated box. tPA overexpression delays extinction, but priming with low doses of amphetamine reinstates place preference even after full extinction. Together, these data clearly indicate that tPA plays an important role in acquisition of amphetamine-induced CPP, but its role in CPP expression does not seem important.

The effects of nitric oxide on the acquisition and expression of nicotine-induced conditioned place preference in mice

In the present study, the possible role of nitric oxide on the conditioned place preference (CPP) induced by nicotine in mice was investigated. Intraperitoneal (i.p.) injections of nicotine (1 mg/kg) and the nitric oxide (NO) precursor, l-arginine (200 and 500 mg/kg), produced significant place preference. However, injection of mecamylamine (0.05 and 0.1 mg/kg; i.p.) or the NO synthase (NOS) inhibitor, l-Nitro-amino-methyl-ester, l-NAME (5–20 mg/kg; i.p.), had no effect. Ineffective doses of nicotine in combination with ineffective doses of l-arginine produced significant place preference. Administration of l-arginine (50, 100 and 150 mg/kg; i.p.) on the test day reduced the expression of nicotine-induced place preference. Nicotine injection (0.25, 0.5 and 0.75 mg/kg) on the test day reduced the expression of place preference induced by l-arginine, while both mecamylamine (0.05 and 0.1 mg/kg) and l-NAME (5, 10 and 20 mg/kg) inhibited the acquisition of place preference induced by nicotine (1 mg/kg) and l-arginine (200 mg/kg). Moreover, neither of the antagonists reduced the expression of nicotine- or l-arginine-induced place preference. It is suggested that nitric oxide may play an important role in nicotine-induced place preference.

5-HT3 receptor antagonist MDL 72222 attenuates cocaine- and mazindol-, but not methylphenidate-induced neurochemical and behavioral effects in the rat.

It has previously been demonstrated that the 5-HT(3) receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including cocaine (COC). The present experiments investigated the role of 5-HT(3) receptors in the actions of selected monoamine uptake inhibitors. The ability of the 5-HT(3) receptor antagonist MDL 72222 (MDL; 0.1 and 1.0 mg/kg) to modify the neurochemical and behavioral changes induced by COC (20 mg/kg), mazindol (MAZ; 10 mg/kg), and methylphenidate (MP; 5.0 or 10, and 20 mg/kg) was assessed with an in vivo microdialysis technique, a conditioned place preference method, and motor activity measurements. MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference, and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT. In contrast, expression of COC-induced place preference was not attenuated by MDL. These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated in development of conditioned reward, are modified by the 5-HT(3) blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite for effective antagonism by 5-HT(3) receptor blockers.

Modulation of Corticosterone Does Not Affect the Acquisition or Expression of Ethanol-Induced Conditioned Place Preference in DBA/2J Mice

Several recent studies have implicated the stress hormone corticosterone in modulating the rewarding properties of abused drugs, including amphetamine and ethanol. The present experiments examined a role for corticosterone in modulating the rewarding effects of ethanol in the place conditioning paradigm. Male DBA/2J mice were subjected to a Pavlovian conditioning procedure in which a distinctive floor stimulus (CS+) was paired four times with ethanol (2 g/kg). On intervening days, a different floor stimulus was paired with saline (CS−). In the first experiment, the steroid synthesis inhibitor, aminoglutethimide (AMG), administered prior to conditioning trials with ethanol, did not alter the acquisition of place preference. However, during conditioning trials, ethanol-stimulated locomotor activity in the AMG-treated group was significantly higher relative to the vehicle-treated group, suggesting that corticosterone may normally inhibit ethanol-stimulated activity. Plasma corticosterone levels in AMG-treated mice were significantly lower than in vehicle-treated mice, showing that AMG effectively suppressed corticosterone release on CS+ trials. The second experiment examined the effect of AMG on the expression of conditioned ethanol place preference. AMG administration prior to the preference test did not alter the magnitude of ethanol place preference. Corticosterone levels in the AMG-treated groups were significantly reduced relative to vehicle-treated groups, which showed a higher level of corticosterone during the preference test. These findings show that manipulation of corticosterone levels in a physiological range does not alter the acquisition or expression of ethanol-induced conditioned place preference in DBA/2J mice.

O-1-6 - The influence of selected quinolones on central action of ethyl alcohol in laboratory animals

Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory neurotransmission, and have been implicated in addiction to alcohol and anxiety-related behaviors. However, the behavioral consequence and contribution of individual subtypes are not known yet. This study determined the effects of mGluR8 activation on anxiety-like behavior, voluntary ethanol intake and ethanol-induced conditioned reward. To this aim, anxiety and spontaneous behavior were measured in C57BL/6J mice using the elevated plus maze (EPM), open field (OF) and light-dark box (LDB) tests after systemic injection of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG). In addition, the anti-alcohol properties of mGluR8 were studied using a two-bottle choice continuous access drinking paradigm and ethanol-conditioned place preference (CPP). Results have shown that, compared to vehicle, DCPG produced an anxiolytic-like effect in the LDB, and OF tests. Furthermore, DCPG-injected mice displayed significantly lower intake and preference for ethanol [2.5–20% (v/v) escalating over 2 weeks] in a two-bottle choice paradigm, with no significant difference observed with saccharin [0.04 & 0.08% (w/v)] nor on quinine [20 & 40 μM (w/v)]. Interestingly, DCPG administration attenuated ethanol-induced acquisition, but not expression, of CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the group III mGluR-specific antagonist (S)-2-amino-2-methyl-4- phosphonobutyric (MAP4). These data demonstrate that activation of the mGluR8 reduces voluntary ethanol intake in male mice and eliminates place preference acquisition suggesting that mGluR8 signaling may contribute to the rewarding properties of ethanol. Taken together, these findings demonstrate that mGluR8-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism.

DNQX in the nucleus accumbens inhibits cocaine-induced conditioned place preference

Several lines of evidence suggest that activation of both AMPA/kainate receptors and dopaminergic receptors in the nucleus accumbens may be required for psychostimulant drug induced reward. However, it has been reported that dopaminergic antagonists fail to block acquisition of conditioned place preference to cocaine. The goal of these experiments was to determine whether AMPA receptor antagonists injected into the nucleus accumbens could block conditioned place preference elicited by cocaine under conditions where dopaminergic antagonists do not inhibit acquisition of place preference. DNQX (1 μg0.5 μl), injected into the nucleus accumbens just before systemic injections of cocaine (20 mg/kg i.p.) during the training sessions, attenuated the acquisition of place preference. This suggests that AMPA receptors are involved in acquisition of place preference to cocaine. By contrast, fluphenazine (2.5 μg0.5 μl), injected into the nucleus accumbens during training, did not alter cocaine-induced place preference. Analysis of locomotor activity showed that the ability of flyphenazine to inhibit cocaine-induced hyperactivity progressively decreased with each training session. These observations suggest that the failure of dopaminergic antagonists to block cocaine-induced place preference may be related to adaptations occurring following repeated exposure to these drugs. Both DNQX and fluphenazine blocked the expression of conditioned place preference in rats that had been previously trained with cocaine alone. This result suggests that both AMPA and dopaminergic receptors are involved in the expression of a conditioned place preference to cocaine.

Effects of the AMPA/kainate receptor antagonist DNQX in the nucleus accumbens on drug-induced conditioned place preference

Activation of AMPA/kainate glutamatergic receptors in the nucleus accumbens may be a component of the mechanism of drug induced reward. To test this hypothesis, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate glutamatergic receptor antagonist, was injected into the nucleus accumbens before the administration of amphetamine or morphine during the training phase (acquisition) of a conditioned place preference paradigm. Rats were then tested for place preference in the absence of drugs. In other experiments, DNQX was given before testing for place preference (expression) but not during the training phase. Bilateral injection of DNQX (1 μg/0.5 μl/side) inhibited acquisition of place preference to amphetamine (1 mg/kg) but not morphine (10 mg/kg). During acquisition, DNQX marginally attenuated the locomotor stimulation elicited by amphetamine during the first but not subsequent training sessions, while the combination of morphine plus DNQX produced marked akinesia during each training session. When given prior to testing, DNQX inhibited the expression of place preference induced by amphetamine and morphine but did not affect locomotor activity. The results suggest that activation of AMPA/kainate receptors is involved in the primary reward stimulation (acquisition of place preference) of amphetamine but not morphine and in behaviors elicited by memory of primary reward stimulation (expression of place preference) for both drugs. Furthermore, locomotor activity during conditioning is not necessary for acquisition of place preference.

Effects of medial dorsal thalamic and ventral pallidal lesions on the acquisition of a conditioned place preference: Further evidence for the involvement of the ventral striatopallidal system in reward-related processes

In our previous work, it has been established that the basolateral amygdala and ventral striatum are part of a neural system that is involved in reward-related processes. However, it is unclear how information processed in this limbic-motor interface may come to affect incentive motivational responses. The present experiments have investigated the involvement of post-striatal elements of the ventral striatopallidal system in the rat. Lesions of the anterior or posterior domains of the ventral pallidum, which receives the major outflow from the ventral striatum, or the nucleus medialis dorsalis of the thalamus, which receives projections from both the ventral pallidum and also the basolateral amygdala, were made by infusing the excitotoxin, ibotenic acid. The effects of the lesions on the acquisition of a place preference conditioned by exposure of hungry rats to sucrose were then measured. Lesions of either the anterior or posterior ventral pallidum significantly attenuated, whereas lesions of the medial dorsal thalamus completely abolished, the acquisition of a conditioned place preference, provided that the latter lesions included the medial-lateral extent of the nucleus. Medial dorsal thalamic lesions did not damage the stria medullaris or medial habenula. Ingestion of sucrose following 23 h deprivation was unaffected by either ventral pallidal or medial dorsal thalamus lesions and thus disruption of place preference acquisition was not secondary to changes in primary motivation. The results indicate that reward-related processes, as measured in the place preference conditioning paradigm, may depend upon ventral striatopallidal outflow that engages medial dorsal thalamus frontal cortex mechanisms, in addition to the previously highlighted direct outflow to brainstem elements of the motor system.