Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens

The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine enhanced cocaine-induced locomotor activity in a dose-dependent manner; fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. To test the hypothesis that the NAc serves as the locus of action underlying these effects following systemic cocaine administration, fluoxetine (1 and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side) was microinfused into the NAc shell prior to systemic administration of cocaine (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.     

Dopamine receptor regulation of ethanol intake and extracellular dopamine levels in the ventral pallidum of alcohol preferring (P) rats

Sufficient evidence exists for the inclusion of the ventral pallidum (VP) into the category of a dopaminoceptive brain region. The effects of inhibiting dopamine D(1)- or D(2)-like receptors in the VP on (a) ethanol intake and (b) extracellular levels of dopamine, were investigated in the alcohol-preferring (P) rat. The D(1)-like antagonist, SCH-23390, and the D(2)-like antagonist, sulpiride (0.25-2 microg/0.5 microl) were bilaterally injected into the VP and ethanol (15%, v/v) intake was assessed in a 1 h limited access paradigm. The results indicate that microinjections of sulpiride significantly increased ethanol consumption (65% increase at the 2.0 microg dose). Whereas the D(1) antagonists SCH-23390 tended to decrease ethanol intake, the effect was not statistically significant. In a separate group of rats, reverse microdialysis of sulpiride and SCH-23390 (10-200 microM) were conducted in the VP of P rats. Local perfusion of only the 200 microM sulpiride dose significantly increased the extracellular levels of dopamine (maximal increase: 250% of baseline). On the other hand, local perfusion of SCH-23390 (10-200 microM) dose dependently increased the extracellular levels of dopamine 180-640% of baseline. Overall, the results of this study suggest that (a) tonic activation of D(2) postsynaptic receptors in VP imposes a limit on ethanol intake in the P rat; (b) there are few D(2) autoreceptors functioning in the VP; (c) there is tonic D(1)-like receptor mediated inhibitory feedback regulation of VP-dopamine release.     

In alcohol-treated rats, naloxone decreases extracellular dopamine and increases acetylcholine in the nucleus accumbens: evidence of opioid withdrawal

Withdrawal from ethanol is aversive. The question is why. As with the withdrawal from morphine, nicotine, diazepam and sugar, the ethanol withdrawal state may involve an increase in nucleus accumbens (NAc) acetylcholine (ACh) causing an alteration of the dopamine (DA)-ACh balance in favor of ACh. Therefore the effects of acute and chronic alcohol (1 gm/kg/day i.p.) treatment on extracellular concentrations of NAc ACh and DA were determined before and after naloxone-precipitated withdrawal. Ethanol initially increased DA to 119% of baseline as measured by microdialysis. This was still the case on the 21st day of ethanol injection when DA increased to 126%. There was no effect of ethanol on ACh. However, naloxone (3 mg/kg s.c.) injected the next day decreased extracellular DA to 83% of baseline and caused a significant rise in ACh to 119%. This state of high ACh combined with low DA may contribute to the aversive aspects of alcohol withdrawal.     

Induction of brain CYP2E1 changes the effects of ethanol on dopamine release in nucleus accumbens shell

CYP2E1 is an important enzyme involved in the brain metabolism of ethanol that can be induced by chronic consumption of alcohol. Recent works have highlighted the importance of this system in the context of the behavioural effects of ethanol. Unfortunately, the underlying neurochemical events for these behavioural changes, has not been yet explored. In this work, we have started this exploration by analyzing the possible changes in the neurochemical response of the mesolimbic system to ethanol after pharmacological induction of brain CYP2E1. We have used the dopamine extracellular levels in nucleus accumbens (NAc) core and shell, measured by means of microdialysis in vivo, as an index of the effects of ethanol. Acetone 1% in the tap water was used to induce brain CYP2E1. Efficacy of the induction protocol was assessed by immunoblotting. Intravenous administration of 1.5 g/kg of ethanol in control rats provoked a significant increase of the dopamine levels in both the core (up to 127% of baseline) and the shell (up to 122% of baseline) of the NAc. However, the same dose of ethanol in acetone-treated rats only increased the dopamine extracellular levels in the core (up to 142% of baseline) whereas dopamine levels in the shell subregion remain unaltered relative to baseline. The results of this study indicate that induction of CYP2E1 changes the response of the mesolimbic system to ethanol in a region-dependent manner. Two hypotheses are postulated to explain the observed effects.     

Glycyl-glutamine (β-endorphin30-31) inhibits morphine-induced dopamine efflux in the nucleus accumbens

Glycyl-glutamine (Gly-Gln) is an endogenous dipeptide that is synthesized from β-endorphin post-translationally. Previously, we showed that Gly-Gln prevents acquisition of morphine-conditioned place preference, a behavioral test of morphine reward, but does not interfere with morphine analgesia. In this study, we tested the hypothesis that Gly-Gln inhibits morphine reward by blocking morphine-induced dopamine efflux in the nucleus accumbens (NAc). Extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were sampled by microdialysis and analyzed by high-performance liquid chromatography with electrochemical detection. Guide cannulas were implanted in the right NAc and left lateral ventricle of male Sprague–Dawley rats stereotaxically. Approximately 24 h later, a microdialysis probe was inserted into the NAc and perfused at 1 μl/min. Gly-Gln (1, 3, 30, or 100 nmol/5 μl) or saline was administered intracerebroventricularly, morphine (2.5 mg/kg) was injected intraperitoneally (i.p.) 2 min later, and extracellular dopamine and DOPAC were sampled at 20-min intervals. Morphine administration increased extracellular dopamine concentrations by approximately 600% within 40 min. Gly-Gln pretreatment inhibited the rise in extracellular dopamine in a dose-related manner; the lowest significantly inhibitory dose was 1 nmol. Gly-Gln also inhibited the morphine-induced rise in extracellular DOPAC concentrations but did not affect extracellular dopamine or DOPAC in control animals. Gly-Gln (100 nmol/5 μl) prevented morphine-induced dopamine efflux in rats treated with morphine chronically (10 mg/kg, i.p. twice daily for 6 days), although it did not affect DOPAC concentrations significantly. These data support the hypothesis that Gly-Gln abolishes the rewarding effect of morphine by inhibiting the ability of morphine to stimulate dopamine release in the NAc.     

Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission

Acetaldehyde (ACD) has been postulated to mediate some of the neurobehavioral effects of ethanol (EtOH). In this study we sought to evaluate whether the stimulatory effects of EtOH on mesolimbic dopamine (DA) transmission are affected by the administration of ACD-sequestering agent D-penicillamine (Dp). To this end we studied the effect of EtOH and ACD in the rat mesoaccumbens pathway by in vivo microdialysis in the nucleus accumbens shell (NAccs), and by single cell extracellular recordings from antidromically identified mesoaccumbens DA neurons in the ventral tegmental area (VTA). Both EtOH (1 g/kg) and ACD (20 mg/kg) administration increased DA levels in the NAccs and increased the activity of mesoaccumbens DA neurons. Pretreatment with Dp (50 mg/kg i.p. 1 h before drug challenge) prevented both EtOH- and ACD-induced stimulation of the DA mesolimbic system without affecting morphine stimulatory actions. These observations add further support to the notion that EtOH-derived ACD stimulates the mesolimbic DA system and is essential in EtOH-induced stimulation of the DA mesoaccumbens system. We conclude that modulation of ACD bioavailability may influence the addictive profile of EtOH by decreasing its psychotropic effects and possibly leading the way to new pharmacological treatments of alcoholism.     

Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens

RATIONALE: Prior research suggests that high levels of acetylcholine (ACh) in the nucleus accumbens (NAc) are associated with aversive states such as morphine withdrawal, but this has not been tested for nicotine withdrawal. OBJECTIVES: The goal was to test the hypothesis that acute nicotine decreases extracellular ACh and increases extracellular dopamine (DA) in the NAc, while withdrawal from nicotine causes an opposite neurochemical imbalance with high extracellular ACh and low DA. METHODS: Rats were prepared with a microdialysis probe in the NAc (primarily the shell region). They received one injection of nicotine (0.5 mg/kg, s.c.) or chronic nicotine (9 mg/kg per day via osmotic minipump). RESULTS: Naive animals receiving acute nicotine showed a mild, significant increase in both ACh (122% of baseline) and DA (124%). After chronic nicotine administration for 7 days, the nicotinic antagonist mecamylamine (1.0 mg/kg, s.c.) precipitated withdrawal with the appearance of somatic signs (teeth chattering and shakes/tremors) and a significant increase in extracellular ACh to 125% of baseline, while extracellular DA decreased to 65%. Control groups receiving saline in place of nicotine or mecamylamine did not show these effects. CONCLUSIONS: Earlier work suggests that the observed release of accumbens ACh and DA in response to acute nicotine administration may be a factor in nicotine-induced suppression of appetite. ACh release during withdrawal, coupled with the decrease in extracellular DA may play a role in the aversive aspects of nicotine withdrawal that contribute to dependency.     

Chronic desipramine and fluoxetine differentially affect extracellular dopamine in the rat prefrontal cortex

The effect of chronic administration of desipramine or fluoxetine (10 mg/kg IP once a day for 2 weeks) on extracellular noradrenaline, serotonin and dopamine in the rat prefrontal cortex was studied by transcerebral microdialysis. Chronic desipramine increased extracellular noradrenaline and dopamine by three-fold as compared to saline controls. Acute challenge with 10 mg/kg desipramine increased by more than three-fold extracellular noradrenaline and dopamine in saline controls, but failed further to increase extracellular noradrenaline and dopamine in rats chronically administered desipramine. Chronic fluoxetine more than doubled the extracellular concentrations of serotonin but failed to change the extracellular concentrations of dopamine as compared to saline controls. Challenge with 5 mg/kg fluoxetine while almost doubling extracellular serotonin and dopamine concentrations in saline controls, failed further to increase extracellular serotonin and did not change extracellular dopamine in rats chronically exposed to fluoxetine. In contrast, challenge with 10 mg/kg desipramine normally increased extracellular dopamine in rats chronically exposed to fluoxetine. Therefore, chronic fluoxetine is associated with normal presynaptic dopamine transmission in the prefrontal cortex as a result of tolerance to fluoxetine-induced increase of extracellular dopamine; in contrast, chronic desipramine is associated with an increase of pre-synaptic dopamine transmission in the prefrontal cortex up to a level that cannot be further elevated by acute desipramine challenge. The results suggest that prefrontal cortex dopamine plays a different role in the antidepressant properties, of desipramine and fluoxetine.     

In vivo electrochemical determination of extracellular dopamine in the caudate of freely-moving rats after a low dose of ethanol

Low doses of ethanol (i.e. less than 1 g/kg) elicit behavioral stimulation, control discriminative performance and mediate reinforcement in rats. These effects are thought to be mediated through central dopaminergic neuronal systems. In the present study, dopamine and serotonin/uric acid release from caudate was measured by in vivo voltammetry in freely-moving, unanesthetized rats after administration of a low dose of ethanol (600 mg/kg, IP). Within 15 min after a single ethanol administration, extracellular dopamine levels significantly increased in caudate, peaking at 35 min, and returning to baseline by 75 min. In addition, ethanol caused an attenuation of a second voltammetric signal that correlates with extracellular serotonin/uric acid concentrations, and this effect persisted through the course of the experiments. These neurochemical changes may underlie behavioral responses found after low doses of ethanol.     

Resistance to ethanol sensitization is associated with increased NMDA receptor binding in specific brain areas

The purpose of the present study was to determine the acute effects of the anticraving compound acamprosate (calcium acetylhomotaurinate) and the closely related compound homotaurine on ethanol intake and ethanol-stimulated dopamine release in the nucleus accumbens. Male rats were treated with acamprosate (200 or 400 mg/kg intraperitoneally, i.p.) or homotaurine (10, 50, or 100 mg/kg i.p.) 15 min prior to access to 10% ethanol and water for 1 h in a two-bottle choice restricted access paradigm. A separate group of rats was implanted with microdialysis probes in the nucleus accumbens and given an acute injection of ethanol (1.5 g/kg i.p.) that was preceded by saline, acamprosate, or homotaurine. Acamprosate and homotaurine dose-dependently reduced ethanol intake and preference. These compounds also delayed or suppressed ethanol-stimulated increases in nucleus accumbens dopamine release, suggesting that acamprosate and homotaurine may reduce ethanol intake by interfering with the ability of ethanol to activate the mesolimbic dopamine reward system.     

Repeated d-amphetamine enhances stimulated mesoamygdaloid dopamine transmission

The mesoaccumbens dopamine pathway exhibits an enhanced dopaminergic response to a challenge injection of d-amphetamine or cocaine after repeated intermittent exposure to that drug. Much research has focused on the potential role of this sensitised response in the enhanced propensity of drug-associated stimuli to elicit relapse. However, the amygdala is acknowledged to play a critical role in stimulus-reward learning, and recent work suggests that the mesoamygdaloid dopamine pathway exerts a significant influence upon amygdala function. In the present study, rats were administered d-amphetamine (1 mg/kg, IP) or vehicle once per day, for 14 days. After 11 untreated days, a locomotor assay showed that prior repeated administration of d-amphetamine led to a markedly enhanced locomotor response to 0.5 mg/kg d-amphetamine. There was no effect of d-amphetamine pretreatment upon the response to a novel environment, or to injection with vehicle. Following a total of 14 days in the home cage, subjects were implanted with microdialysis probes within the amygdala, and for comparison also within the nucleus accumbens. Baseline and d-amphetamine-stimulated (0.5 mg/kg) levels of extracellular dopamine were assessed for each brain region. Results showed that baseline levels of dopamine were very similar in sensitised and control animals. By contrast, prior treatment with d-amphetamine enhanced dopamine overflow in response to a challenge with d-amphetamine both in the nucleus accumbens and amygdala. These results indicate that changes in the pattern of dopamine transmission both in the nucleus accumbens, and the amygdala, accompany the behavioural sensitisation observed after repeated exposure to d-amphetamine. Hence, an enhanced propensity of drug-associated stimuli to elicit relapse may not depend solely upon changes relating to the mesoaccumbens dopamine projection. Received: 24 October 1996/Final version: 28 February 1997     

Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine.

Stimulation of central serotonin2C receptor (5-HT(2C)R) inhibits dopamine (DA)-dependent neurochemical and behavioral effects of cocaine, while 5-HT(2C)Rs locally expressed into the ventral tegmental area (VTA) and the nucleus accumbens (NAc) exert opposite functional control over cocaine-induced behavioral effects. Using in vivo microdialysis in halothane-anesthetized rats, we tested the hypothesis that this functionally opposite regulation of the mesoaccumbens DA pathway relies on the ability of 5-HT(2C)Rs in the VTA and the NAc to inhibit and enhance respectively cocaine-induced accumbal DA outflow. Intra-VTA injection of the 5-HT(2C)R agonist Ro 60-0175 at 5 microg/0.2 microl, but not 1 microg/0.2 microl, attenuated the increase in accumbal DA outflow induced by the systemic administration of 10 mg/kg of cocaine. Intra-VTA injection of the 5-HT(2C)R antagonist SB 242084 at either dose (0.1 or 0.5 microg/0.2 microl) did not modify the effects of cocaine. Intra-NAc application of Ro 60-0175 dose-dependently excited (0.1 microM) and inhibited (1 microM) cocaine-induced DA outflow. In contrast, intra-NAc application of SB 242084 resulted in diametrically opposite effects when applied at these concentrations. These results further support the idea that the overall action of central 5-HT(2C)Rs on accumbal DA output is dependent, at least in part, on the functional balance between different 5-HT(2C)R populations within the NAc and within the mesoaccumbens DA pathway (VTA vs NAc).     

Systemic sulpiride increases dopamine metabolites in the lateral hypothalamus.

In rats with microdialysis probes in the perifornical lateral hypothalamus (PFH) a single injection of the D2 receptor blocker 1-sulpiride (20 mg/kg IP) significantly increased extracellular dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), but not 5-hydroxyindoleacetic acid (5-HIAA). This suggests that sulpiride crosses the blood-brain barrier and blocks D2 dopamine receptors in the PFH leading to increased dopamine turnover reflected in increased extracellular DOPAC and HVA. We conclude that D2 blockade in the hypothalamus could play a role in the hyperphagia and body weight gain observed in female rats under chronic administration of the antipsychotic drug, sulpiride.     

Dopamine D2 and serotonin 5-HT1A receptors mediate the actions of aripiprazole in mesocortical and mesoaccumbens transmission

The antipsychotic agent aripiprazole acts as a partial agonist of dopamine D2 and serotonin 5-HT1A receptors. However, the detailed actions of aripiprazole in mesolimbic and mesocortical transmission remain to be clarified. To address this, we examined the effects of systemic and local administrations of aripiprazole on extracellular levels of dopamine and GABA in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and anterior (aVTA) and posterior (pVTA) ventral tegmental areas. Intraperitoneal injection of aripiprazole (0.5mg/kg) increased dopamine release in mPFC without affecting those in aVTA, pVTA, or NAc, whereas 10mg/kg decreased the release in all four regions. Local sulpiride administration in aVTA increased concentration-dependently dopamine release in both aVTA and NAc without affecting that in mPFC, whereas local aripiprazole administration in aVTA concentration-dependently decreased dopamine release in aVTA and mPFC without affecting that in NAc. Blockade of 5-HT1A receptor in aVTA produced aripiprazole-induced dopamine release in aVTA and prevented the aripiprazole-induced reduction of dopamine release in mPFC. Local administration of aripiprazole in mPFC increased dopamine and decreased GABA releases, whereas local administration of sulpiride had no effect on dopamine or GABA. In mPFC, blockade of 5-HT1A receptor prevented the aripiprazole-induced dopamine elevation and GABA reduction; however, under the activation of GABA(A) receptor, local perfusion with aripiprazole in mPFC decreased GABA release without affecting dopamine release. The results suggested that the combination of 5-HT1A and D2 partial agonistic actions of aripiprazole against mesocortical and mesoaccumbens transmission, explains, at least in part, the atypical antipsychotic properties of aripiprazole. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

The associative type of sensitization to d-amphetamine is expressed as an NO-dependent dramatic increase in extracellular dopamine in the nucleus accumbens

After repeated administration of psychomotor-stimulant drugs such as d-amphetamine, a sensitization to its stimulant effects such as locomotor activity and stereotyped behaviour can be observed depending on the treatment schedule. It was the aim of the present study to test whether (1) associative (conditioning) and non-associative (pseudoconditioning) types of sensitization differ in the corresponding alterations in extracellular dopamine in the nucleus accumbens, and (2) the inhibitor of nitric oxide synthase (NOS), N(G)-nitro-L-arginine methyl ester (L-NAME), influences the two types of sensitization in a different way. Rats were treated with d-amphetamine (1 mg/kg i.p.) on days 1, 3, 5 and 7 and alternatively with saline on days 2, 4 and 6 under associative or non-associative conditions, respectively. A third (saline control) group was treated with saline daily for 7 days. Subsequently, probes for microdialysis were implanted into the nucleus accumbens. After a drug-free period of 10 days, on day 17, the increase in extracellular dopamine produced by 1 mg/kg d-amphetamine was much more pronounced in associative (conditioned) than in non-associative (pseudoconditioned) or naive rats. Pretreatment with L-NAME (100 mg/kg i.p.) on day 17 did not significantly alter the baseline concentrations of dopamine, but it inhibited the dopamine increase much more in associative than in naive rats and did not significantly affect it in non-associative rats. The results suggest that (1) associative sensitization to d-amphetamine leads to the most pronounced increase in extracellular dopamine in the nucleus accumbens, and (2) NO is very much involved in the expression of the associative increase in extracellular dopamine in the nucleus accumbens.     

Changes in the amygdala amino acid microdialysate after conditioning with a cue associated with ethanol

 Excitatory amino acid neurotransmission within the amygdala has been implicated in learning associations between external stimuli and intrinsic reward values, such that it may play a key role in conditioned drug effects. In the present studies, the responses of the excitatory amino acids, aspartate and glutamate, together with the neuromodulatory sulphonated amino acid, taurine, within the basolateral amygdala, to an odor cue repeatedly associated with acute ethanol injections (2 g/kg, IP) have been investigated by a microdialysis technique combined with HPLC-EC analysis. After presentation of the ethanol-conditioned stimulus, a single IP saline injection induced an immediate and significant increase in the taurine microdialysate content which could be related to the neuromodulatory action of taurine. Furthermore, when the conditioned stimulus was combined with the ethanol injection (2 g/kg, IP), significant increases in both taurine and glutamate microdialysate content were observed and indicated a learned compensatory response to counteract the acute effects of ethanol. These results demonstrate that changes in amygdala extracellular glutamate and taurine concentrations can be conditioned to ethanol-associated stimuli and are therefore probably implicated in the phenomenon of environmental-dependent tolerance to ethanol. Received: 4 December 1997 / Final version: 13 May 1998     

Ethanol-stimulated serotonin release in the ventral hippocampus: an absence of rapid tolerance for the alcohol-preferring P rat and insensitivity in the alcohol-nonpreferring NP rat.

This study examined the acute effects of intraperitoneal administration of ethanol on the extracellular levels of serotonin (5-HT) in the ventral hippocampus (vHIP) of adult, male alcohol-preferring P and -nonpreferring NP rats. Using in vivo microdialysis coupled with HPLC and electrochemical detection, the effects of acute administration of saline or 1.0, 1.75, or 2.5 g/kg ethanol on the extracellular levels of 5-HT in the vHIP were examined. Saline and 1.0 g/kg ethanol did not alter the extracellular levels of 5-HT. However, the 1.75-g/kg dose resulted in a transient increase in 5-HT levels in the vHIP of P rats only. Administration of 2.5 g/kg ethanol increased 5-HT levels to 180% of baseline in P rats (P<.05), but was without effect on NP rats. The 2.5-g/kg dose also significantly increased the extracellular levels of 5-HT in the vHIP of P rats, which had been pretreated with the same dose of ethanol 18-24 h earlier (P<.05). Comparison of the response of ethanol pretreated P rats with animals that had been pretreated with saline 24 h earlier did not reveal any significant differences in ethanol-stimulated increases in 5-HT levels between the groups. These data suggest that ethanol may activate terminals of the median raphe 5-HT system in P rats because the vHIP receives its 5-HT inputs primarily from the median raphe nucleus (MRN). Rapid tolerance does not develop to this activation of the system in the vHIP of P rats. In addition, the data suggest that the 5-HT system in the vHIP of NP rats may be relatively insensitive to the stimulating effect of acute ethanol of 5-HT release.     

Dopamine in the medial prefrontal cortex controls genotype-dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion.

Mice of background DBA/2J are hyporesponsive to the behavioral effects of D-amphetamine in comparison with the widely exploited murine background C57BL/6J. In view of the important role of dopamine (DA) release in the nucleus accumbens (NAc) regarding the behavioral effects of psychostimulants, we tested the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning in the two backgrounds. Systemic D-amphetamine induces a sustained increase in DA release in the medial prefrontal cortex (mpFC) accompanied by a poor increase in the NAc in mice of the low-responsive DBA/2J background, as shown by intracerebral microdialysis in freely moving animals. The opposite occurs in C57BL/6J mice, which show low prefrontal cortical DA outflow accompanied by high accumbal extracellular DA. Moreover, the DBA/2J background showed lower locomotor activity than C57BL/6J mice following D-amphetamine challenge. Selective DA depletion in the mpFC of DBA/2J mice produced a clear-cut increase in D-amphetamine-induced DA outflow in the NAc as well as locomotor activity that reached levels similar to those observed in C57BL/6J mice. Finally, local infusion of D-amphetamine by reverse microdialysis produced a similar increase in extracellular DA in both the mpFC and the NAc of DBA/2J mice. This finding points to similar transporter-related mechanisms in the two brain areas and supports the hypothesis that low accumbal DA release induced by systemic D-amphetamine in the DBA/2J background is determined by the inhibitory action of prefrontal cortical DA. The present results indicate that genotype-dependent susceptibility to addictive properties of D-amphetamine involves unbalanced DA transmission in the mesocorticolimbic system.     

Yawning and suppression of exploration in amphetamine-treated rats,incompatibility with the autoreceptor hypothesis

The hypothesis that yawning and suppression of exploration, induced by low doses of dopamine agonists, are mediated by stimulation of dopamine autoreceptors was tested by studying the influence of amphetamine on these behavioural models and on extracellular levels of dopamine sampled by microdialysis. Behaviour was measured in a holeboard apparatus. A low dose of amphetamine (0.2 mg/kg) caused slight activation of habituated rats. The same dose of amphetamine completely counteracted the decrease in extracellular dopamine levels caused by pergolide (0.02 mg/kg) and, instead, elevated the dopamine levels to 300% above baseline. The same or higher doses of amphetamine (0.5–1.0 mg/kg) did not completely antagonise suppression of exploration or yawning induced by apomorphine (0.05 mg/kg) or pergolide (0.02 mg/kg). The results suggest that both yawning and suppression of exploration induced by low doses of dopamine agonists are not mediated by dopamine autoreceptors, since these behaviours could be elicited when the extracellular levels of dopamine were elevated above baseline. The alternative hypothesis that these behaviours are mediated by sensitive post-synaptic receptors is suggested. It was also found that combined treatment with SCH 23390 (0.05 mg/kg) and amphetamine (2 mg/kg) induced yawning, which further supports the new hypothesis.     

Effects of chronic buprenorphine treatment on levels of nucleus accumbens glutamate and on the expression of cocaine-induced behavioral sensitization in rats

Rationale

Chronic treatment with the mu-opioid receptor agonist, buprenorphine, reduces cocaine-induced behaviors in rats with a history of cocaine self-administration. The mechanisms underlying these actions of buprenorphine remain unclear.

Objectives

The objective of this study is to investigate the effects of chronic buprenorphine treatment on cocaine-induced activity and levels of glutamate and dopamine (DA) in the nucleus accumbens (NAc) in rats that were preexposed to cocaine or drug-naïve.

Materials and methods

In experiment 1, basal levels of NAc glutamate were assessed using in vivo microdialysis in cocaine-naïve rats that were treated chronically with buprenorphine (3.0 mg/kg per day) via osmotic minipumps or that underwent sham surgery. In experiment 2, rats were preexposed to seven daily injections of cocaine or saline. After a 12–16-day drug-free period, extracellular levels of NAc glutamate and DA and locomotor activity were assessed simultaneously, before and after an acute injection of cocaine (15 mg/kg, intraperitoneal), in rats under sham and chronic buprenorphine (3.0 mg/kg per day) treatment.

Results

Chronic buprenorphine treatment increased basal levels of glutamate in drug-naïve and cocaine-preexposed rats, blocked the expression of locomotor sensitization to cocaine, and potentiated the NAc DA response to acute cocaine in cocaine-preexposed rats.

Conclusions

These findings suggest that buprenorphine may block the expression of cocaine sensitization and other cocaine-related behaviors by increasing basal levels of glutamate in the NAc, which would serve to decrease the effectiveness of cocaine or cocaine-associated cues.