Extracellular Dopamine In Nucleus Accumbens Research Articles

Self-Administered Heroin and Cocaine Combinations in the Rat: Additive Reinforcing Effects—Supra-Additive Effects on Nucleus Accumbens Extracellular Dopamine

The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose-effect curves for rat self-administration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose-effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA](e)) in rats self-administering low doses of cocaine, heroin, or cocaine/heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA](e), while heroin alone did not. The ratio of the % baseline of [DA](e) (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during self-administration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA](e) may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the self-administration of this drug combination.

Increased extracellular dopamine in nucleus accumbens in response to unconditioned and conditioned aversive stimuli: studies using 1 min microdialysis in rats

Previous microdialysis studies measuring extracellular dopamine levels in response to unconditioned and conditioned aversive stimuli have used relatively long (e.g. 10 min) sample durations, such that more than one stimulus event occurred within a single dialysis sample. The present study used 1 min dialysate sampling to measure changes in dopamine levels in response to individual stimulus presentations. The changes evoked by mild footshock showed an initial enhancement from the first to the second presentation, after which there was a steady decline in the response over subsequent presentations. Compared to the responses to footshock alone, when the footshock was paired with an unfamiliar tone, there was no change in the response to the first stimulus presentation, but a significant augmentation of responses during subsequent presentations, giving weight to the view that dopamine is not involved in the learning per se, but rather in the processing of learned information. Whilst an unfamiliar tone had no measurable effect on extracellular dopamine levels, the same tone which had previously been paired with footshock evoked a significant increase in dopamine during the tone presentation, indicating that it is the aversive nature of the stimulus onset rather than the ‘rewarding’ nature of its offset which increases extracellular dopamine.

Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

Recently, we have shown that acamprosate is able to modulate extracellular dopamine (DA) levels in the nucleus accumbens (NAc) and may act as an antagonist of N-methyl-D-aspartate (NMDA) receptors. Neurochemical studies show that chemical stimulation (using NMDA) of the ventral subiculum (vSub) of the hippocampus produces robust and sustained increases in extracellular DA levels in the NAc, an effect mediated through ionotropic glutamate (iGlu) receptors. The present study examines whether acamprosate locally infused in the NAc of rats could block or attenuate the increase in NAc extracellular DA elicited by chemical stimulation (with 5 mM NMDA) of the ventral subiculum of the hippocampus. The stimulation of the vSub during perfusion of artificial cerebrospinal fluid in NAc induced a significant and persistent increase in NAc DA levels. Reverse dialysis of 0.05 mM acamprosate in NAc blocked the increase in DA evoked by the chemical stimulation of the vSub. These data support the possibility that the antagonism at the NMDA receptors in NAc can explain, at least in part, the mechanism of action of this drug.

Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study.

The effects of acamprosate on the in vivo dopamine extracellular levels in the nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in these effects were investigated. Microdialysis in freely moving rats was used to assess dopamine levels before and during simultaneous perfusion of acamprosate and/or different agonists or antagonists of NMDA receptors. Perfusion with acamprosate at concentrations of 0.5 and 5 mM provoked a concentration-dependent increase in extracellular dopamine in nucleus accumbens. The lowest concentration of acamprosate assayed (0.05 mM) had no effect on dopamine levels. Infusion of NMDA (25 and 500 microM) and the glutamate uptake blocker, L-trans-pyrrolidine-2,4-dicarboxilic acid (PDC) (0.5 mM) into the NAc caused a significant increase in DA, whereas acamprosate (0.05 mM) co-infusion with these compounds blocked or attenuated the NMDA and PDC-induced increases in DA levels. Co-infusion of the selective antagonist of NMDA receptors, DL-2-amino-5-phosphonopentanoic acid (AP5) (400 microM) with acamprosate (0.5 mM), did not reduce the increase of DA levels induced by acamprosate. These results demonstrate that acamprosate is able to modulate DA extracellular levels in NAc via NMDA receptors and suggest that acamprosate acts as an antagonist of NMDA receptors.

Repeated ventral tegmental area amphetamine administration alters dopamine D1 receptor signaling in the nucleus accumbens.

Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.

Endogenous Opioids in Dopaminergic Cell Body Regions Modulate Amphetamine-Induced Increases in Extracellular Dopamine Levels in the Terminal Regions

Opioid antagonists attenuate behavioral effects of amphetamine and amphetamine-induced increases in extracellular dopamine levels in nucleus accumbens and striatum of rats but do not alter those effects of cocaine. This study was performed to determine 1) if the effect of opioid antagonists on the dopamine response to amphetamine is mediated in either the terminal or cell body region of the nigrostriatal and mesolimbic pathways, and 2) if the enkephalinase inhibitor thiorphan, which slows degradation of endogenous opioid peptides, increases the dopamine response to amphetamine but not to cocaine. Microdialysis probes were placed either into a dopaminergic terminal region or into both a terminal and cell body region of rats. Naloxone methiodide (1.0 microM), a lipophobic opioid antagonist, was administered into either the terminal or cell body region by reverse dialysis, whereas extracellular dopamine was collected in the terminal region. Increases in extracellular dopamine in nucleus accumbens and striatum caused by amphetamine (0.1-6.4 mg/kg, s.c.) were reduced significantly (28-39%) by naloxone methiodide administered into either substantia nigra or ventral tegmentum but not into terminal regions. Thiorphan (10 microM) administered into substantia nigra increased significantly the dopamine response to amphetamine in the ipsilateral striatum by as much as 42% but did not affect the dopamine response to cocaine (3.0-56 mg/kg, i.p.). These results suggest that amphetamine promotes release of endogenous opioids, which, through actions in the ventral tegmentum and substantia nigra, contribute to amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and striatum.

Caudate-putamen and nucleus accumbens extracellular acetylcholine responses to methamphetamine binges

Exposure of experimental animals to an escalating dose, multiple binge pattern of methamphetamine administration results in the progressive emergence of a unique behavioral profile, which includes a significant decrease in the duration of the stereotypy phase as well as a profound increase and qualitative change in the locomotor activation. This behavioral profile is associated with a selective decrease in the caudate-putamen but not nucleus accumbens extracellular dopamine response. Since the acetylcholine interneurons in these regions are partly under the control of the mesostriatal and mesoaccumbens dopamine inputs, changes in the activation of these interneurons should parallel the regionally differential dopamine responses during multiple binge treatment. Therefore, we characterized the caudate-putamen and nucleus accumbens extracellular acetylcholine responses to escalating-dose, multiple binge methamphetamine administration. An acute methamphetamine binge decreased acetylcholine levels in caudate-putamen, but had no effect on levels in nucleus accumbens. Furthermore, corresponding to the selective decrease in the dopamine response, the caudate-putamen but not nucleus accumbens extracellular acetylcholine response exhibited tolerance with repeated binge exposures; i.e. the decrease in acetylcholine associated with the acute methamphetamine binge was attenuated with multiple binge exposure. These results are consistent with our hypothesis and suggest that the regionally differential acetylcholine responses reflect one functional consequence of the escalating-dose, multiple binge stimulant treatment.

L-tryptophan attenuation of the dopaminergic and behavioral responses to cocaine

This study assessed the effects of acute intravenous L-tryptophan (neutral amino acid precursor for serotonin) administration on cocaine-induced dopaminergic responses. Male Sprague-Dawley rats were surgically implanted with guide cannulas in the nucleus accumbens 5 days prior to the study and with vascular catheters (carotid artery and jugular vein) on the day prior to the study. Using microdialysis, extracellular nucleus accumbens dopamine levels were measured in freely moving rats. Following a 2 h equilibration period, animals were randomized (n=7–8 per group) to receive either a constant intravenous (IV) infusion of L-tryptophan (200 mg/kg/h) or an equal volume (2 ml/h) of saline. Ninety minutes into the infusion, cocaine (20 mg/kg) was injected intra-peritoneally. Cocaine increased nucleus accumbens microdialysate dopamine levels (500% at 30 min). This was associated with marked hyperactivity. Tryptophan infusion elevated plasma tryptophan (8-fold), and blunted the cocaine-induced increase in nucleus accumbens microdialysate dopamine levels by ∼60%. Furthermore, tryptophan attenuated the cocaine-induced locomotor activity. These neurochemical and behavioral effects of tryptophan were associated with a marked increase in brain tissue serotonin content. The results of these studies demonstrate the feasibility of acute dietary manipulation of neurochemical and behavioral responses to cocaine. The duration, adaptation and tolerance to these effects remain to be elucidated.

Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats.

Orphanin FQ (OFQ; also known as nociceptin), the endogenous ligand of the opioid receptor-like receptor, injected intracerebroventricularly (i.c.v.) decreases basal motor activity and basal extracellular levels of dopamine (DA) in the nucleus accumbens (Nuc Acc) in rats. The present study was designed to determine if OFQ similarly attenuates cocaine-induced motor stimulation and to determine if this effect is dependent on attenuation of the increase in extracellular DA. After a 1-h adaptation period, rats were injected with either artificial cerebrospinal fluid or OFQ (3-30 nmol, i.c.v.) 5 min prior to cocaine (10 mg/kg, i.p.) or apomorphine (3 mg/kg, i.p.) administration and the total distance traveled was measured for a further 1 h. In a separate experiment, changes in extracellular DA were monitored by microdialysis following cocaine and OFQ treatment in anesthetized rats. OFQ dose-dependently attenuated both basal and cocaine-induced motor stimulation. OFQ (30 nmol, i.c.v.) also attenuated both the basal and the cocaine-induced increase in extracellular DA in the Nuc Acc. OFQ, at the highest dose, also decreased the motor stimulation induced by apomorphine. Our results suggest that the modulatory effect of OFQ on locomotor activity is not solely due to its inhibitory action on extracellular DA in the Nuc Acc.

Reverse Microdialysis of a Dopamine Uptake Inhibitor in the Nucleus Accumbens of Alcohol‐Preferring Rats: Effects on Dialysate Dopamine Levels and Ethanol Intake

The mesolimbic dopamine (DA) system has been implicated in mediating the reinforcing actions of ethanol (EtOH). This study examines the effects of local perfusion of the DA uptake inhibitor GBR12909 (GBR) on (1) DA levels in the nucleus accumbens (NAc) and (2) EtOH drinking in alcohol-preferring rats. Stable drinking of a 15% (v/v) EtOH solution (minimum of 0.75 g/kg body weight) was established in daily 1 hr limited access sessions. Rats were then implanted with bilateral guide cannulae aimed 4 mm above the NAc. After recovery from surgery, concentric microdialysis probes (2 mm dialysis membrane surface) were inserted into the NAc. Most placements were in the shell or overlapping both shell and core. Two days later, the probes were perfused at 1.0 microl/min with artificial cerebral spinal fluid (aCSF) for at least a 90 min washout period followed by collection of five basal samples over 150 min. Rats were then perfused with either aCSF alone or 10, 25, 100, or 200 microM of GBR for 240 min on the first day of microdialysis. During the last 60 min of the drug treatment phase, rats were given their scheduled access to 15% EtOH. All rats were then perfused with aCSF for the last 90 min of the experiment. The following day, the procedure was repeated, but animals that received aCSF on the first day were given a dose of GBR and rats given GBR on the first day received only aCSF. GBR perfusion increased extracellular NAc DA levels dose dependently to more than 800% of basal levels at 100 to 200 microM but failed to alter EtOH intake (p > 0.05, paired t test) at any concentration tested. Moreover, after 100 microM of GBR perfusion had terminated, the extracellular levels of DA in the NAc remained elevated for approximately 24 hr (790% of day 1 basal; p < 0.05). The increase in dialysate DA levels observed during GBR perfusion with 100 microM was significantly greater for EtOH-experienced rats than for EtOH-naïve rats [F(7,59) = 14.85, p < 0.0001, analysis of variance, Student-Newman-Keuls post hoc test]. The results suggest (1) that EtOH drinking experience induces neuroadaptations that increase DA release in the NAc, and (2) that additional elevation in synaptic levels of DA in the NAc does not influence the maintenance of ongoing alcohol drinking under scheduled access conditions in alcohol-preferring animals.

Reverse Microdialysis of a Dopamine Uptake Inhibitor in the Nucleus Accumbens of Alcohol-Preferring Rats: Effects on Dialysate Dopamine Levels and Ethanol Intake

Background: The mesolimbic dopamine (DA) system has been implicated in mediating the reinforcing actions of ethanol (EtOH). This study examines the effects of local perfusion of the DA uptake inhibitor GBR12909 (GBR) on (1) DA levels in the nucleus accumbens (NAc) and (2) EtOH drinking in alcohol-preferring rats. Methods: Stable drinking of a 15% (v/v) EtOH solution (minimum of 0.75 g/kg body weight) was established in daily 1 hr limited access sessions. Rats were then implanted with bilateral guide cannulae aimed 4 mm above the NAc. After recovery from surgery, concentric microdialysis probes (2 mm dialysis membrane surface) were inserted into the NAc. Most placements were in the shell or overlapping both shell and core. Two days later, the probes were perfused at 1.0 μl/min with artificial cerebral spinal fluid (aCSF) for at least a 90 min washout period followed by collection of five basal samples over 150 min. Rats were then perfused with either aCSF alone or 10, 25, 100, or 200 μM of GBR for 240 min on the first day of microdialysis. During the last 60 min of the drug treatment phase, rats were given their scheduled access to 15% EtOH. All rats were then perfused with aCSF for the last 90 min of the experiment. The following day, the procedure was repeated, but animals that received aCSF on the first day were given a dose of GBR and rats given GBR on the first day received only aCSF. Results: GBR perfusion increased extracellular NAc DA levels dose dependently to more than 800% of basal levels at 100 to 200 μM but failed to alter EtOH intake (p > 0.05, paired t test) at any concentration tested. Moreover, after 100 μM of GBR perfusion had terminated, the extracellular levels of DA in the NAc remained elevated for approximately 24 hr (790% of day 1 basal;p < 0.05). The increase in dialysate DA levels observed during GBR perfusion with 100 μM was significantly greater for EtOH-experienced rats than for EtOH-naïve rats [F (7,59) = 14.85, p < 0.0001, analysis of variance, Student-Newman-Keuls post hoc test]. Conclusions: The results suggest (1) that EtOH drinking experience induces neuroadaptations that increase DA release in the NAc, and (2) that additional elevation in synaptic levels of DA in the NAc does not influence the maintenance of ongoing alcohol drinking under scheduled access conditions in alcohol-preferring animals.

γ-Aminobutyric acid mimetic drugs differentially inhibit the dopaminergic response to cocaine

Dopaminergic activity in the mesocorticolimbic system is associated with reinforcing properties of psychostimulant drugs. We previously demonstrated that increased γ-aminobutyric acid (GABA)-ergic activity produced by γ-vinyl GABA [ d, l-4-amino-hex-5-enoic acid (Vigabatrin®)], an irreversible inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well as behaviors associated with these biochemical changes. In the present study, using in vivo microdialysis techniques, we compared three different strategies to increase GABAergic activity in order to modulate cocaine-induced increase in extracellular dopamine. Our data demonstrate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GABA uptake inhibitor, dose and time dependently diminished increases in extracellular dopamine following acute cocaine challenge. Furthermore, we demonstrated that cyclized analogue of vigabatrin, a competitive reversible GABA-transaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversible inhibition of GABA transaminase, inhibition of GABA uptake represent another potentially effective, indirect strategy for the treatment of cocaine abuse.

Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate.

We have previously shown that during the acute response to amphetamine, a stimulant that released dopamine, behavioral sensitivity to the drug undergoes dynamic changes, as evident in the altered behavioral profile expressed to the subsequent administration of a low dose of the drug. The present studies were designed to determine if these dynamic changes in sensitivity occur with amphetamine-like stimulants that act primarily by blocking dopamine uptake. Groups of animals were primed with 40 mg/kg cocaine or 30 mg/kg methylphenidate, then during the acute response, a low, locomotor-stimulant dose of amphetamine (1.5 mg/kg) was administered to probe for changes in sensitivity. Conversely, to determine whether the manifestation of the increased responsivity is idiosyncratic to amphetamine, animals were also primed with amphetamine (4 mg/kg), then probed with low doses of cocaine (10 and 20 mg/kg) or methylphenidate (10 mg/kg). Parallel microdialysis studies were performed to assess the caudate-put-amen and nucleus accumbens extracellular dopamine responses. Priming with the uptake blockers each resulted in a stereotypy response to the subsequent low-dose amphetamine probe. Likewise, after priming with amphetamine, the uptake blockers each induced a pronounced stereotypy response. In each case, these changes in behavioral responsivity were expressed in the absence of corresponding changes in the probe-induced regional dopamine responses. Dynamic changes in behavioral sensitivity during the response to acute stimulant administration are a characteristic common to both dopamine releasers and uptake blockers. These rapid changes in sensitivity may contribute to the behaviors associated with binge patterns of drug abuse.

Gamma-vinyl γ-aminobutyric acid attenuates the synergistic elevations of nucleus accumbens dopamine produced by a cocaine/heroin (speedball) challenge

In the present study, we examined the effect of an acute administration of the selective suicide inhibitor of γ-aminobutyric acid (GABA)-transaminase, gamma-vinyl GABA on increases in nucleus accumbens dopamine produced by a cocaine/heroin challenge in freely moving animals. Cocaine (20 mg/kg, i.p.) produced an elevation in extracellular nucleus accumbens dopamine of approximately 380% above baseline, while heroin produced only a moderate increase of 70%. Coadministration of these two drugs, however, produced a synergistic elevation in nucleus accumbens dopamine of 1000%. This response was reduced by 50% in animals pretreated with gamma-vinyl GABA (300 mg/kg, i.p.) 2.5 h prior to challenge. This same dose of gamma-vinyl GABA inhibited cocaine-induced increases in nucleus accumbens dopamine by 25% and completely abolished heroin-induced increase. These findings indicate that gamma-vinyl GABA can interfere with the synergistic effects produced by the combination of an indirect dopamine releaser (heroin) and a dopamine reuptake blocker (cocaine).

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D 1 and D 2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D 1 and D 2 dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D 1 and D 2 dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (`priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D 1 and D 2 receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D 1/D 2 agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D 1 and D 2 dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.

A pharmacologic strategy for the treatment of nicotine addiction.

Like many psychostimulant drugs, nicotine elevates extracellular and synaptic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevation has been linked to its reinforcing properties. Dopaminergic transmission within the NAc is modulated by gamma-aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl-GABA (GVG, Vigabatrin) for inhibiting nicotine's biochemical effects on NAc DA as well as its effects on behaviors associated with these biochemical changes. Given 2.5 hours prior to nicotine, GVG (75 mg/kg) had no effect on nicotine-induced increases in extracellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine-induced increases by approximately 50% while at 100 or 150 mg/kg, GVG completely abolished nicotine-induced increases in both naive and chronically nicotine-treated animals. When given 12 or 24 hours prior to nicotine administration at a dose of 100 mg/kg, GVG-induced inhibition was diminished or abolished, respectively. In addition, at a dose of 18.75 mg/kg GVG abolished the expression of nicotine-induced conditioned place preference (CPP) while a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and 11C-raclopride in primates, GVG (100 mg/kg) abolished nicotine-induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional distribution. Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA-transaminase for the treatment of drug addiction.

Implication of the GABA(B) receptor in gamma vinyl-GABA's inhibition of cocaine-induced increases in nucleus accumbens dopamine.

Previously, we demonstrated that gamma vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-induced increases in dopamine (DA) concentrations in both the rodent and primate brain. Furthermore, it abolishes cocaine self-administration and conditioned place preference, while having no effect on locomotor activity or drug delivery to the brain. In an effort to better understand the mechanisms underlying this inhibition, we examined the effect of the selective GABA(B) receptor antagonist SCH 50911 on the GVG-induced decrease in cocaine's elevation of extracellular DA concentrations in the nucleus accumbens (NACC). Cocaine administration alone (20 mg/kg i.p.) produced a 480% increase in extracellular NACC DA levels. GVG (300 mg/kg i.p.) significantly reduced this increase by 25% (P<0.01). In sharp contrast, extracellular DA levels increased to 550% after the sequential administration of SCH 50911 (3 mg/kg i.p.), GVG, and cocaine. This increase is significantly different than GVG and cocaine (P<0.05) but similar to cocaine alone. These results demonstrate that the GABA(B) antagonist SCH 50911 was able to completely abolish GVG's inhibition of cocaine-induced increases in DA in the NACC and implicates the GABA(B) receptor in the mechanism underlying this inhibition.

A microdialysis study of nucleus accumbens core and shell dopamine during operant responding in the rat

This investigation examined dopamine release and metabolism in nucleus accumbens core and shell during three operant tasks in the rat. Rats were trained to lever press on a fixed-ratio 5, variable-interval 30 s, or a tandem variable interval 30/fixed-ratio 5 schedules; these three schedules were chosen because they generate a wide range of response and reinforcement rates. After several weeks of training, dialysis probes were implanted into nucleus accumbens core or shell subregions. A single 30 min behavioural session was conducted during the dialysis test session. Rats lever pressing on each of the three operant schedules showed a significant increase in extracellular dopamine relative to the food-deprived control group during the behavioural session. In addition, increases in dopamine in nucleus accumbens shell were found to be significantly greater than in the core during the lever pressing period. Across all three schedules, extracellular dopamine in the nucleus accumbens was significantly correlated with the number of lever presses performed, but was not correlated with the number of food pellets delivered. Analysis of covariance, which used amount of food consumed as the covariate, showed an overall group difference, indicating that dopamine levels increased in lever pressing animals even if one corrected for the amount of food consumed. These results indicate that dopamine release was more responsive in the nucleus accumbens shell than in the core during operant responding, and that increases in extracellular dopamine in nucleus accumbens are related to response rate rather than reinforcement magnitude.

Eating-induced dopamine release from mesolimbic neurons is mediated by NMDA receptors in the ventral tegmental area: a dual-probe microdialysis study.

This study was aimed at identifying the neuronal pathways that mediate the eating-induced increase in the release of dopamine in the nucleus accumbens of the rat brain. For that purpose, a microdialysis probe was implanted in the ventral tegmental area and a second probe was placed in the ipsilateral nucleus accumbens. Receptor-specific compounds acting on GABA(A) (40 microM muscimol; 50 microM bicuculline), GABA(B) (50 microM baclofen), acetylcholine (50 microM carbachol), NMDA [30 microM (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP)], and non-NMDA [300 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] receptors were infused into the ventral tegmental area by retrograde dialysis, whereas extracellular dopamine was recorded in the ipsilateral nucleus accumbens. Intrategmental infusion of muscimol or baclofen decreased extracellular dopamine in the ipsilateral nucleus accumbens; CPP and CNQX were without effect, and bicuculline and carbachol increased dopamine release. During infusion of the various compounds, food-deprived rats were allowed to eat for 10 min. The infusions of muscimol, bicuculline, baclofen, carbachol, and CNQX did not prevent the eating-induced increase in extracellular dopamine in the nucleus accumbens. However, during intrategmental infusion of CPP, the eating-induced increase in extracellular dopamine in the nucleus accumbens was suppressed. These results indicate that a glutamatergic projection to the ventral tegmental area mediates, via an NMDA receptor, the eating-induced increase in dopamine release from mesolimbic dopamine neurons.

Repeated administration of 3,4-methylenedioxymethamphetamine augments cocaine's action on dopamine in the nucleus accumbens:: A microdialysis study

In this study, we examined the ability of a single injection of cocaine (20 mg/kg, i.p.) to augment extracellular dopamine levels in the nucleus accumbens two weeks after pretreating rats with either saline (1 ml/kg, i.p.) or the serotonin neurotoxin 3,4-methylenedioxymethamphetamine (20 mg/kg, s.c., twice daily for 4 days). The level of dopamine in the nucleus accumbens was measured using in vivo microdialysis. Cocaine produced a 400% increase in extracellular nucleus accumbens dopamine levels in control rats, whereas in 3,4-methylenedioxymethamphetamine treated rats the increase produced by cocaine was 800%, which was significantly different from controls. This suggests that 3,4-methylenedioxymethamphetamine, a relatively common drug of abuse, may alter subsequent vulnerability to cocaine dependence and abuse.