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The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A 2A adenosine receptors (A 2A R), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A 1 R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A 2A R antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A 2A R antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder., (© 2024. The Author(s).)

Background: Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)-related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD-1 mice., Methods: Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol-induced (1.5 to 3.5 g/kg) changes in open-field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor-dependent phosphorylation markers were assessed: extracellular signal-regulated kinase (pERK), and dopamine-and cAMP-regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP-32-Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol-sensitized (1.5 g/kg) mice., Results: Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol -induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol-induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol-sensitized mice in an ethanol-free state resulted in blunted stimulant effects compared with those seen in ethanol-naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP-32(Thr75) immunoreactivity., Conclusions: The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol-sensitized animals., (© 2021 by the Research Society on Alcoholism.)

Rationale: Extracellular signal-regulated kinase (ERK 1/2 ) phosphorylation is critical for neuronal and behavioural functions; in particular, phosphorylated ERK 1/2 (pERK 1/2 ) expression in the nucleus accumbens (Acb) of the rat is stimulated by addictive drugs with the exception of morphine, which decreases accumbal ERK 1/2 phosphorylation in the Sprague-Dawley and Wistar rats. The psychogenetically selected Roman low- (RLA) and high-avoidance (RHA) rats differ behaviourally and neurochemically in many responses to addictive drugs. In particular, morphine elicits a greater increment in locomotor activity and in dopamine transmission in the Acb of RHA vs RLA rats. However, the effects of morphine on place conditioning (conditioned place preference (CPP)) and ERK 1/2 phosphorylation in the Roman lines remain unknown., Objectives and Methods: To characterize in the Roman lines the reinforcing properties of morphine (i.e. morphine-elicited CPP acquisition) and the relationship between these properties and its effects on ERK 1/2 phosphorylation in the Acb, the behavioural effects of morphine were evaluated in a place-conditioning apparatus and ERK 1/2 phosphorylation was assessed by immunohistochemistry in the shell and core subregions of the Acb of rats both acutely administered with morphine or undergoing conditioning., Results: Morphine elicited CPP in both Roman lines and decreased pERK 1/2 expression in the Acb of RLA but not RHA rats. Such decrease was prevented by conditioning., Conclusions: These findings indicate that the selective breeding of the Roman lines has generated a divergence, in terms of morphine-elicited pERK 1/2 expression but not of morphine-elicited CPP, between RLA and RHA rats and sustain the observation that changes in pERK 1/2 expression in the Acb are not a requisite for the reinforcing effects of morphine.

Rationale: Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial., Objectives: In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and μ-opioid receptors in Sprague-Dawley rats and CD-1 mice., Methods: The pERK1/2 expression was assessed by immunohistochemistry., Results: In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice., Conclusions: These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine's ability to decrease pERK1/2 expression is mediated by Acb μ-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb.

Background: Alcoholism is a neuroadaptive disorder, and the understanding of the mechanisms of the high rates of relapse, which characterize it, represents one of the most demanding challenges in alcoholism and addiction research. The extracellular signal-regulated kinase (ERK) is an intracellular kinase, critical for neuroplasticity in the adult brain that is suggested to play a fundamental role in the molecular mechanisms underlying drug addiction and relapse. We previously observed that a nonessential amino acid, L-cysteine, significantly decreases oral ethanol (EtOH) self-administration, reinstatement of EtOH-drinking behavior, and EtOH self-administration break point., Methods: Here, we tested whether L-cysteine can affect the ability of EtOH priming to induce reinstatement of EtOH-seeking behavior. In addition, we determined the ability of EtOH priming to induce ERK phosphorylation as well as the ability of L-cysteine to affect reinstatement-elicited ERK activation. To these purposes, Wistar rats were trained to nose-poke for a 10% v/v EtOH solution. After stable drug-taking behavior was obtained, nose-poking for EtOH was extinguished, and reinstatement of drug seeking, as well as reinstatement-elicited pERK, was determined after an oral, noncontingent, priming of EtOH (0.08 g/kg). Rats were pretreated with either saline or L-cysteine (80 to 120 mg/kg) 30 minutes before testing for reinstatement., Results: The findings of this study confirm that the noncontingent delivery of a nonpharmacologically active dose of EtOH to rats, whose previous self-administration behavior had been extinguished, results in significant reinstatement into EtOH-seeking behavior. In addition, the results indicate that reinstatement selectively activates ERK phosphorylation in the shell of the nucleus accumbens (Acb) and that pretreatment with L-cysteine reduces either reinstatement of EtOH seeking and reinstatement-elicited pERK in the AcbSh., Conclusions: Altogether, these results indicate that L-cysteine could be an effective pharmacological agent for the prevention of behavioral and molecular correlates of EtOH-primed reinstatement of EtOH seeking and that the shell of the Acb represents a critical neural substrate for priming-elicited reinstatement mechanisms involving ERK phosphorylation., (Copyright © 2012 by the Research Society on Alcoholism.)

We have previously shown that acetaldehyde (ACD), the first metabolite of ethanol, regulates its motivational properties and possesses reinforcing effects by itself. A large and still growing body of evidence indicates that the endogenous opioidergic system plays a critical role in the motivational effects of ethanol and suggests a role for extracellular signal-regulated kinase (ERK) in these effects of both ethanol and ACD. The present study was undertaken to examine if opioid-mediated mechanisms are involved in the reinforcing properties of ACD and in ACD-elicited ERK activation. To this end, Wistar rats were trained to orally self-administer ACD (0.2%) by nose poking. Responses on active nose poke caused delivery of ACD solution, whereas responses on inactive nose poke had no consequences. The effect of pretreatment with a nonselective opioid receptor antagonist, naltrexone (NTX), was evaluated during (1) maintenance of ACD self-administration, (2) deprivation effect after ACD extinction, and (3) ACD self-administration under a progressive-ratio schedule of reinforcement. Additionally, we tested the effect of NTX on saccharin (0.05%) reinforcement, as assessed by oral self-administration, and on ACD-elicited ERK phosphorylation in the nucleus accumbens (Acb), as assessed by immunohistochemistry. Finally, we examined the effect of a μ(1)-selective opioid receptor antagonist, naloxonazine (NLZ), on the maintenance phase of ACD and saccharin self-administration. The results indicate that NTX (0.4-0.8mg/kg) reduced the maintenance, the deprivation effect, and the break points of ACD self-administration without suppressing saccharin self-administration. Moreover, NTX decreased ACD-elicited ERK activation in the Acb shell and core. NLZ (10-15mg/kg) reduced the maintenance phase of ACD self-administration without interfering with saccharin self-administration, whereas both NTX and NLZ failed to modify responses on inactive nose poke indicating the lack of a nonspecific behavioral activation. Overall, these results indicate that the opioid system is implicated in the reinforcing properties of ACD and suggest an involvement of ERK. The finding that NTX and NLZ reduce ACD but not saccharin self-administration indicates that these effects are specific to ACD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Recent advances suggest that acetaldehyde mediates some of the neurobiological properties of ethanol. In a recent study, we have shown that ethanol elicits the phosphorylation of extracellular signal-regulated kinase (pERK) in the nucleus accumbens and extended amygdala, via a dopamine D(1) receptor-mediated mechanism. The aim of this study was to determine whether acetaldehyde and ethanol-derived acetaldehyde elicit the activation of ERK in the nucleus accumbens and extended amygdala. The effects of acetaldehyde (10 and 20 mg/kg) and ethanol (1 g/kg), administered to rats intragastrically, were assessed by pERK peroxidase immunohistochemistry. To establish the role of ethanol-derived acetaldehyde, the alcohol dehydrogenase inhibitor, 4-methylpyrazole (90 mg/kg), and the acetaldehyde-sequestering agent, D-penicillamine (50 mg/kg), were administered before ethanol. Acetaldehyde increased pERK immunoreactivity in the nucleus accumbens and extended amygdala. Inhibition of ethanol metabolism and sequestration of newly synthesized acetaldehyde completely prevented ERK activation by ethanol. In addition, to establish the role of D(1) receptors stimulation in acetaldehyde-elicited ERK phosphorylation, we studied the effect of the D(1) receptor antagonist, SCH 39166. Pretreatment with the D(1) receptor antagonist (50 μg/kg) fully prevented acetaldehyde-elicited ERK activation. Overall, these results indicate that ethanol activates ERK by means of its metabolic conversion into acetaldehyde and strengthen the view that acetaldehyde is a centrally acting compound with a pharmacological profile similar to ethanol., (© 2010 Wiley-Liss, Inc.)

Opiate withdrawal is associated with morphological changes of dopamine neurons in the ventral tegmental area and with reduction of spine density of second-order dendrites of medium size spiny neurons in the nucleus accumbens shell but not core. Withania somnifera has long been used in the Middle East, Africa, and India as a remedy for different conditions and diseases and a growing body of evidence points to its beneficial effects on a number of experimental models of neurological disorders. Recently, many studies focused on the potential neuritic regeneration and synaptic reconstruction properties of its methanolic extract and its constituents (withanolides). This study investigates whether morphine withdrawal-induced spine reduction in the nucleus accumbens is affected by the administration of a Withania somnifera extract. To this end, rats were chronically treated with Withania somnifera extract along with morphine or saline and, upon spontaneous (1 and 3 days) or pharmacologically precipitated withdrawal, their brains were fixed in Golgi-Cox stain for confocal microscopic examination. In a separate group of animals, Withania somnifera extract was administered during three days of spontaneous withdrawal. Withania somnifera extract treatment reduced the severity of the withdrawal syndrome when given during chronic morphine but not during withdrawal. In addition, treatment with Withania somnifera extract during chronic morphine, but not during withdrawal, fully prevented the reduction of spine density in the nucleus accumbens shell in spontaneous and pharmacologically precipitated morphine withdrawal. These results indicate that pretreatment with Withania somnifera extract protects from the structural changes induced by morphine withdrawal potentially providing beneficial effects on the consequences related to this condition.

Rationale: Although passive administration of heroin to drug-naive rats increases extracellular dopamine (DA) in the nucleus accumbens (NAc), its ability to do so also after active drug exposure (self-administration) is debated., Objectives: This study investigated by repeated microdialysis sampling the inter- and intrasession changes in the responsiveness of the NAc shell and core DA and the behavioral effects of active and passive heroin exposure in the intravenous self-administration/yoked paradigm., Materials and Methods: Rats were implanted with jugular catheters and bilateral intracerebral chronic guide cannulae. Nose poking in the active hole by master rats resulted in heroin administration to the same subjects and to their yoked mates. Concentric microdialysis probes were inserted daily in the guide cannulae, and changes in dialysate DA in response to heroin exposure (0.05 mg/kg) were monitored in the same subject for 90 min for 4 weeks. Behavior associated with heroin exposure, distinguished into nonstereotyped and stereotyped, was also recorded., Results: Dialysate DA increased preferentially in the shell of master rats from the first session (+112%) and throughout the 4 weeks of self-administration (+130-140%). In yoked rats, a preferential but lesser increase in DA in the shell was observed only on the first session (+60%), as the DA response in the NAc core increased progressively (+25-118%), so that within a week, the shell/core ratio was reversed, and this pattern was maintained for the following 2 weeks. Yoked rats showed a progressive and larger increase in stereotyped behaviors than master rats., Conclusions: Chronic heroin self-administration increases extracellular DA preferentially in the NAc shell. Response-noncontingent heroin administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.

R,S(+/-)-3,4-methylenedioxymethamphetamine (R,S(+/-)-MDMA, 'Ecstasy') is known to stimulate dopamine (DA) transmission in the nucleus accumbens (NAc). In order to investigate the post-synaptic correlates of pre-synaptic changes in DA transmission and their relationship with MDMA enantiomers, we studied the effects of R,S(+/-)-MDMA, S(+)-MDMA, and R(-)-MDMA on extracellular DA and phosphorylated extracellular signal regulated kinase (pERK) in the NAc shell and core. Male Sprague-Dawley rats, implanted with a catheter in the femoral vein and vertical concentric dialysis probes in the NAc shell and core, were administered i.v. saline, R,S(+/-)-MDMA, S(+)-MDMA, or R(-)-MDMA. Extracellular DA was monitored by in vivo microdialysis with HPLC. Intravenous R,S(+/-)-MDMA (0.64, 1, and 2 mg/kg) increased dialysate DA, preferentially in the shell, in a dose-related manner. S(+)-MDMA exerted similar effects but at lower doses than R,S(+/-)-MDMA, while R(-)-MDMA (1 and 2 mg/kg) failed to affect dialysate DA. R,S(+/-)- and S(+)-MDMA but not R(-)-MDMA increased ERK phosphorylation (expressed as density/neuron and number of pERK-positive neurons/area) in both subdivisions of the NAc. The administration of the D1 receptor antagonist, SCH 39166, prevented the increase in pERK elicited by R,S(+/-)-MDMA and S(+)-MDMA, while the D2/3 receptor antagonist, raclopride, increased pERK in the NAc core per se but failed to affect the R,S(+/-)-MDMA-elicited stimulation of pERK. The present results provide evidence that the DA stimulant effects of racemic MDMA are accounted for by the S(+)-enantiomer and that pERK may represent a post-synaptic correlate of the stimulant effect of R,S(+/-)-MDMA on D1-dependent DA transmission.

Rationale: In naive rats, passive administration of drugs of abuse preferentially increases extracellular dopamine (DA) in the nucleus accumbens (NAc) shell as compared to the core. Repeated exposure to the same drugs results in behavioral and biochemical sensitization characterized by stereotyped activity and reduction of the shell/core DA response ratio., Objectives: The aim of this work is to study the neurochemical and behavioral effects of response-contingent vs response-noncontingent drug administration in rats, who were bilaterally implanted with chronic intracerebral guide cannulae and trained to self-administer cocaine by nose poking in daily 1-h sessions for 3 weeks (5 days/week). Nose poking in the active hole by master rats resulted in intravenous injection of cocaine (0.25 mg/kg) in master rats and in rats yoked to them. Dialysate DA was monitored before, during, and for 30 min after cocaine availability on alternate days by inserting the probe into the NAc shell and core. Stereotyped and non-stereotyped behavior was recorded during the sessions., Results: In master rats, dialysate DA increased preferentially in the NAc shell during cocaine self-administration throughout the 3 weeks of cocaine exposure. In yoked rats, DA increased preferentially in the shell but to a lesser extent than in master rats. With continued exposure to cocaine, the shell/core ratio of DA changes decreased progressively and, on the third week, was reversed so that DA increased more in the core than in the shell. Yoked rats showed a progressive and faster increase in stereotyped behaviors than master rats., Conclusions: Response-noncontingent cocaine administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.

Morphine withdrawal produces a hypofunction of mesencephalic dopamine (DA) neurons which impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment rats were either spontaneously or pharmacologically withdrawn from chronic morphine: under these two distinct conditions we studied the effects of withdrawal on spine density of MSN of the core and shell of the nucleus accumbens (NAcc) at various times (1-3-7-14 days). MSN were stained with the Golgi-Cox procedure and analyzed by a confocal laser-scanning microscope. Our analysis shows that both spontaneous and naloxone-induced withdrawal produces a long-lasting but reversible reduction in spines' density in shell MSN, as compared with core MSN. This effect is selectively localized at the level of second-order dendritic trunks and persists up to 14 days when spine density was found within control (pretreatment) values. By contrast, spine density counts of NAcc MSN from rats chronically treated with morphine, did not reveal any change over time. Collectively, the results of the present article suggest that spontaneous and pharmacologically precipitated withdrawal, but not chronic morphine, persistently but reversibly reduce spines' density under a condition of reduced mesolimbic DA transmission, and the reduction of spines' density in second-order dendritic trunks is selectively segregated in the MSN of the shell of the NAcc. Morphine withdrawal dramatically, lastingly, and reversibly reduces spine density, selectively in second-order dendritic trunks of NAcc shell MSN, thereby further impoverishing the already abated DA transmission. These results may be relevant in the most harmful consequences of drug addiction such as craving and loss of control over intake and are in line with recent views suggesting the hypodopaminergic state as a cardinal feature of drug dependence.

It is known that most of drugs abused by humans preferentially stimulate dopamine transmission in the shell subdivision of the nucleus accumbens as compared to the core. The aim of the present study was to evaluate whether this applies also to intravenous 3,4-methylendioxymethamphetamine (MDMA, "ecstasy") administered at doses that sustain self-administration behavior in rats. The effect of 0.32, 0.64, 1.0, 2.0 and 3.2 mg/kg i.v. of MDMA on dopamine transmission in the nucleus accumbens shell and core was studied in freely moving rats by means of dual probe microdialysis. MDMA dose-dependently stimulated dopamine transmission both in the shell and in the core but the increase in the shell was more pronounced compared to the core at doses of 0.64, 1.0 and 2.0 mg/kg. The increase of dialysate dopamine obtained after 0.32 mg/kg and after 3.2 mg/kg was not significantly different in the shell compared to the core of nucleus accumbens. This study extends to MDMA the property of other drugs of abuse to increase preferentially nucleus accumbens shell dopamine.

Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular dopamine (DA) in the n. accumbens (NAc). Brain imaging studies, while extending these finding to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and 'high' (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistently with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs.

The effects of caffeine on extracellular dopamine and acetylcholine have been studied in freely moving rats implanted with concentric microdialysis probes in the nucleus accumbens shell and core and in the medial prefrontal cortex. Intravenous administration of caffeine (0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg) dose-dependently increased dopamine and acetylcholine dialysate concentrations in the medial prefrontal cortex, while it did not affect dialysate dopamine in the shell and core of the nucleus accumbens. Intraperitoneal administration of caffeine (1.5, 3, 10, 30 mg/kg) also failed to affect DA in the shell and core of the nucleus accumbens. Such effects were duplicated by intravenous administration of DPCPX, a selective antagonist of adenosine A1 receptors, and of SCH 58261, an antagonist of A2a receptors. The effect of caffeine on prefrontal dopamine and acetylcholine transmission was also studied in rats chronically administered with caffeine (25 mg/kg, twice a day for seven days). At the end of this treatment rats became tolerant to the locomotor stimulating effects of a dose of 1 and 2.5 mg/kg i.v. of caffeine; these doses, however, still increased dialysate acetylcholine but did not affect dopamine in the prefrontal cortex. Therefore, in rats made tolerant to the locomotor stimulant effects of caffeine, tolerance developed to the dopamine stimulant but not to the acetylcholine stimulant effect of caffeine in the prefrontal cortex. The lack of acute stimulation of dopamine release in the nucleus accumbens shell by caffeine is relevant to the issue of its addictive properties and of the role of DA in drug- and substance-addiction. On the other hand, the dissociation between tolerance to the locomotor effects of caffeine and stimulation of acetylcholine release in the prefrontal cortex suggests that this effect might be correlated to the arousing effects of caffeine as distinct from its locomotor stimulant properties.

Conventional reinforcers phasically stimulate dopamine transmission in the nucleus accumbens shell. This property undergoes one-trial habituation consistent with a role of nucleus accumbens shell dopamine in associative learning. Experimental studies with place- and taste-conditioning paradigms confirm this role. Addictive drugs share with conventional reinforcers the property of stimulating dopamine transmission in the nucleus accumbens shell. This response, however, undergoes one-trial habituation in the case of conventional reinforcers but not of drugs. Resistance to habituation allows drugs to repetitively activate dopamine transmission in the shell upon repeated self-administration. This process abnormally facilitates associative learning, leading to the attribution of excessive motivational value to discrete stimuli or contexts predictive of drug availability. Addiction is therefore the expression of the excessive control over behavior acquired by drug-related stimuli as a result of abnormal strenghtening of stimulus-drug contingencies by nondecremental drug-induced stimulation of dopamine transmission in the nucleus accumbens shell.

Naltrindole, a specific delta-opioid antagonist, infused by reverse dialysis in the nucleus accumbens of freely moving rats completely prevented the increase in extracellular dopamine concentrations elicited in the nucleus accumbens by ethanol (1.0 g/kg i.p.) as well as by the delta-opioid receptor agonist [D-Ala2]deltorphin II (50 microM), also perfused by reverse dialysis, but not by cocaine (15 mg/kg s.c.). The results provide in vivo evidence for a critical role of delta-opioid receptors in the dopamine-releasing properties of ethanol in vivo.