Psychostimulant sensitization: differential changes in accumbal shell and core dopamine

The nucleus accumbens has been subdivided into a shell and a core compartment on the basis of histochemical and connectional differences. Recently, we reported that behavioral sensitization to morphine is associated with an increased dopamine transmission in the caudate-putamen and in the nucleus accumbens core as well as a decreased response in the nucleus accumbens shell following acute morphine challenge. We have now performed a similar study in rats sensitized to amphetamine and to cocaine. Behavioral sensitization was induced by daily administration of a single dose of 1 mg/kg s.c. of amphetamine for 10 days or of 10 mg/kg i.p. of cocaine twice a day for 14 days. Microdialysis was performed 10-14 days after the last injection of amphetamine and 7-10 days after the last injection of cocaine. Both schedules resulted in robust behavioral sensitization in response to challenge with 0.25 and 0.5 mg/kg of amphetamine and to 5 and 10 mg/kg of cocaine, respectively. Subjects pre-exposed to amphetamine showed a sensitization of dopamine transmission in the nucleus accumbens core but not in the nucleus accumbens shell. Subjects pre-exposed to cocaine showed sensitization of dopamine transmission in the core only to the lower dose of cocaine. In the shell no change was observed after the lower dose of cocaine while a significant reduction of the dopamine response was observed after the higher dose. These results suggest that behavioral sensitization might result from reciprocal changes in the response of nucleus accumbens dopamine in the shell and in the core to drug challenge.     

Effects of repeated cocaine treatment on striatal dopamine release in alcohol-preferring AA and alcohol-avoiding ANA rats

Modulation of striatal dopamine (DA) release by acute or repeated cocaine treatment was studied in the nucleus accumbens and caudate-putamen of alcohol-preferring (AA, Alko Alcohol) and alcohol-avoiding (ANA, Alko Non-Alcohol) rats. Cocaine (5-10 mg/kg i.p.) was administered daily for 4 days and the concentrations of extracellular DA measured by in vivo microdialysis on days 1 and 4 in the freely moving rats. The first administration of cocaine increased DA concentration similarly in rats of both lines in both the nucleus accumbens and caudate-putamen. On the 4th day, the effect of cocaine was significantly larger in the nucleus accumbens of AA than in that of ANA rats, whereas no such enhanced effect of cocaine was found in the caudate-putamen of either line. The results suggest that mesolimbic DA release in response to cocaine is sensitized more readily in AA than in ANA rats, which would not only render the former more susceptible to alcohol, but to other drugs of abuse, and might explain our previous findings that AA rats are more susceptible to psychomotor sensitization than ANA rats.     

Differential neurochemical and behavioral adaptation to cocaine after response contingent and noncontingent exposure in the rat

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.     

Subregion-specific down-regulation of 5-HT3 immunoreactivity in the nucleus accumbens shell during the induction of cocaine sensitization

Repeated exposure to psychostimulants such as cocaine and amphetamine can result in behavioral sensitization, which is believed to model the onset of drug addiction, as well as neural adaptations that occur after repeated drug abuse that lead to addictive behaviors. Dopamine (DA) in the nucleus accumbens (NAc) has been shown to play an integral role in this phenomenon. However, cocaine also acts on the serotonin (5-HT) system, which has been shown to modulate psychostimulant-induced increases in motor behavior and DA release in the NAc. Recently, it has been demonstrated that the shell portion of the NAc can no longer be considered a homogeneous structure and can be subdivided into at least five separate regions. The present study examines 5-HT(3) receptors in the subdivisions of the NAc in cocaine-sensitized rats. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg ip for five consecutive days). Two or 14 days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg ip) and sacrificed 2 h later. Sections of the NAc were processed for 5-HT(3) immunoreactivity (5-HT(3)-IR), and the number of puncta was quantified in each of the subregions of the shell, as well as the core of the accumbens. Repeated cocaine administration resulted in robust sensitization that correlated with a transient decrease in the density of 5-HT(3) immunoreactive puncta in the intermediate zone of the accumbens shell. After a 2-week withdrawal period, sensitized animals no longer showed any differences in any of the areas examined. These data suggest a possible role for 5-HT(3) receptors in the intermediate zone during the induction of cocaine sensitization.     

Effects of 5-HT(1B) receptor ligands microinjected into the accumbal shell or core on the sensitization to cocaine in rats.

The present study was designed to find out whether 5-HT(1B) receptors located in subareas of the nucleus accumbens played a role in cocaine sensitization in rats, and whether pharmacological activation of these receptors could modify this drug effect. Male Wistar rats implanted bilaterally with cannulae into the accumbens shell or core were microinjected with GR 55562 (an antagonist of 5-HT(1B) receptors) or CP 93129 (an agonist of 5-HT(1B) receptors). The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. GR 55562 (0.1-10 microg/side), administered for 5 days into the accumbens shell, but not into the core, prior to cocaine dose-dependently attenuated cocaine sensitization. When injected for 5 days into either the accumbens shell or core before cocaine, CP 93129 (0.1-10 microg/side) had no effect on the development of cocaine sensitization. To examine the effects of GR 55562 and CP 93129 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. No change in cocaine sensitization was observed after injection of GR 55562 (0.1-10 microg/side) to the either accumbens subregion or after injection of CP 93129 (0.1-10 microg/side) into the core. However, an intra-accumbens shell injection of CP 93129 (10-30 microg/side) increased sensitization to cocaine, and this enhancement was attenuated after local injection of GR 55562 (1 microg/side). Our findings indicate that behavioral sensitization to cocaine may be modulated by 5-HT(1B) receptor ligands in the accumbens shell, but not into the core. They suggest that the inhibition of 5-HT(1B) receptors in the accumbens shell attenuates the development, whereas their pharmacological activation enhances the expression of cocaine sensitization.     

Implication of the nucleus accumbens shell, but not core, in the acute and sensitizing effects of cocaine in rats

Expression of cocaine-evoked motor behaviors appears to be dependent on dopamine neurotransmission particularly in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc). To test potential anatomical component of the locomotor effects of cocaine and expression of its behavioral sensitization, male Wistar rats were implanted with bilateral cannulae aimed at the two subregions of the NAc (the shell or the core) and then intracranially injected with cocaine (locomotor activity) or injected with cocaine given either systemically or intracranially following the repeated (5 days) systemic drug administration (sensitization). Sensitization was measured at early (5-day) and late (21-day) withdrawal periods. Acute administration of intra-NAc shell cocaine (6.73-50 microg/side) in a dose-dependent manner increased locomotor activity in rats; significant hyperactivation was observed after 25 and 50 microg/side of cocaine. Intra-NAc core injection of cocaine (12.5-50 microg/side) did not change rats' locomotor activity. After 5- or 21-day withdrawal, behavioral sensitization (ca. 2 times higher locomotor activity than that after acute drug administration) was observed when cocaine was injected either systemically (10 mg/kg) or intra-NAc shell (12.5-25 microg/side) in animals repeatedly treated with cocaine (10 mg/kg). No difference was observed in the response to the challenge with intra-NAc core cocaine (12.5-25 micorg/side) in rats treated repeatedly with cocaine at either withdrawal period. The above findings show the differential regulation of motor responses to cocaine within the subregions of the NAc. They also indicate a preferential effect for the NAc shell in expression of the acute and sensitizing effects of cocaine in rats.     

Chronic cocaine treatment impairs the regulation of synaptosomal 3H-DA release by D2 autoreceptors

The effect of repeated administration of cocaine on presynaptic D2 autoreceptor sensitivity in synaptosomes was studied. In rats treated chronically with saline, the dopamine D2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) caused a significant inhibition of the Ca2(+)-evoked 3H-DA release from synaptosomes prepared from the nucleus accumbens and from the striatum; this effect was blocked by the D2 antagonist sulpiride. However, chronic cocaine pretreatment abolished the effect of N-0437 in both areas, suggesting a subsensitivity of release-modulating terminal DA autoreceptors. Subsensitive DA autoreceptors would enhance stimulated DA release from mesolimbic and nigrostriatal terminals and may play a role in the behavioral sensitization observed in this paradigm.     

Decreased accumbens dopamine release after cocaine challenge in behaviorally sensitized female rats

The effects of the competitive NMDA receptor antagonist CPP on the initiation of behavioral sensitization to acute cocaine and basal and acute cocaine-induced dopamine (DA) release in the nucleus accumbens (NAC) were assessed in female Sprague-Dawley rats. Cocaine pretreated rats (30 mg/kg IP, once daily for 7 days) challenged with cocaine (10 mg/kg) on day 8 displayed increased motor activity relative to controls challenged with cocaine on day 8. This effect was blocked in rats receiving CPP (2 mg/kg) 15 min prior to all cocaine pretreatments. Basal DA levels in the NAC of both cocaine-pretreated and CPP plus cocaine-pretreated rats were higher on day 8 compared to controls. Acute cocaine challenge on day 8 resulted in increased extracellular DA concentrations in the NAC in control rats, no increase in rats pretreated with CPP plus cocaine, and a decrease in rats pretreated with cocaine only. These data demonstrate that development of behavioral sensitization to cocaine in female Sprague-Dawley rats can be completely blocked by a peripherally administered competitive NMDA receptor antagonist and that an increase in DA release in the NAC after a cocaine challenge is not an absolute requirement for expression of motor sensitization to cocaine in female rats.     

Inhibitory effects of ginseng total saponins on behavioral sensitization and dopamine release induced by cocaine

Many studies have suggested that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. It has been shown that repeated injections of cocaine produce an increase in locomotor activity, the expression of the immediate-early gene, c-fos, and the release of dopamine (DA) in the nucleus accumbens (NAc), which is one of the main dopaminergic terminal areas. Several studies have shown that behavioral activation and changes in extracellular dopamine levels in the central nervous system induced by psychomotor stimulants are prevented by ginseng total saponins (GTS). In order to investigate the effects of GTS on the repeated cocaine-induced behavioral and neurochemical alterations, we examined the influence of GTS on the cocaine-induced behavioral sensitization and on c-Fos expression in the brain using immunohistochemistry in rats repeatedly treated with cocaine. We also examined the effect of GTS on cocaine-induced dopamine release in the NAc of freely moving rats repeatedly treated with cocaine using an in vivo microdialysis technique. Pretreatment with GTS (100, 200, 400 mg/kg, i.p.) 30 min before the daily injections of cocaine (15 mg/kg, i.p.) significantly inhibited the repeated cocaine-induced increase in locomotor activity as well as the c-Fos expression in the core and shell in a dose-dependent manner. Also, pretreatment with GTS significantly decreased the repeated cocaine-induced increase in dopamine release in the NAc. Our data demonstrate that the inhibitory effects of GTS on the repeated cocaine-induced behavioral sensitization were closely associated with the reduction of dopamine release and the postsynaptic neuronal activity. The results of the present study suggest that GTS may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. These results also suggest that GTS may prove to be a useful therapeutic agent for cocaine addiction.     

Ethanol, like psychostimulants and morphine, causes long-lasting hyperreactivity of dopamine and acetylcholine neurons of rat nucleus accumbens: possible role in behavioural sensitization

Repeated treatment of rats with ethanol (1 g/kg, once daily for 15 days) enhanced the locomotor effect of morphine, 3 weeks post-treatment. This ethanol-induced long-term behavioural sensitization to morphine was associated with an increase in the electrically evoked release of [³H]dopamine (DA) and [¹⁴C]acetylcholine (ACh) from nucleus accumbens slices. A similar enhanced responsiveness of accumbal dopaminergic and cholinergic neurons to depolarization was apparent 3 weeks after repeated morphine, amphetamine or cocaine administration. Prior ethanol exposure also caused a long-term enhancement of electrically evoked release of [³H]DA and [¹⁴C]ACh from slices of the caudate-putamen. Unlike the locomotor effect of morphine, that of amphetamine was not enhanced in ethanol-pretreated rats. These data indicate that ethanol administration may cause long-term behavioural sensitization associated with adaptive changes in dopaminergic and cholinergic neurons of rat nucleus accumbens and caudate-putamen. Furthermore, an enhanced reactivity of nucleus accumbens dopaminergic nerve terminals and dopamine-sensitive cholinergic neurons appears to be a common long-term neuroadaptive effect of distinct types of addictive drugs. However, since repeated ethanol exposure did not cause a long-term increase in the locomotor effect of amphetamine, these neuroadaptations may not always be sufficient to cause long-lasting behavioural (cross-)sensitization. Received: 15 January 1997 / Final version: 25 March 1997     

The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats

Rationale Recent studies have implicated an important role for the dorsal striatum during craving for cocaine and in cocaine-seeking after abstinence in rats. Objectives We compared the effects of pharmacological inactivation of mesencephalic dopamine (DA) cell body regions and dorsal vs ventral striatal terminal fields in an animal model of relapse after chronic cocaine self-administration. Materials and methods Rats self-administered cocaine for 2 h/day for ten sessions, followed by 2 weeks of abstinence (i.e., no extinction training). Immediately before being returned to the self-administration chamber, we assessed the effects of gamma-aminobutyric acid agonist inhibition of midbrain DA regions (substantia nigra [SN] and ventral tegmental area [VTA]) and striatum (dorsolateral caudate–putamen, nucleus accumbens core, and nucleus accumbens shell) on relapse to cocaine-seeking in the absence of reinforcement. Further testing examined daily extinction responding subsequent to the initial relapse test. Results Inactivation of the dorsal caudate–putamen and midbrain regions attenuated cocaine seeking, while inactivation of the ventral striatum had no such effects. However, subsequent sessions under extinction conditions revealed a rebound in cocaine seeking in animals that had undergone inactivation in all regions except the dorsolateral caudate–putamen. Conclusions The dorsal but not ventral striatum plays a critical role in cocaine seeking immediately after abstinence. These data support the theory that chronic cocaine may shift activity from the ventral to dorsal striatum during drug seeking under certain conditions. While not necessary at the time of relapse, the ventral striatum appears to be involved in processing critical information of the relapse event. An erratum to this article can be found at     

Neonatal fibroblast growth factor treatment enhances cocaine sensitization

Growth factors are critical in neurodevelopment and neuroplasticity, and recent studies point to their involvement in addiction. We previously reported increased levels of basic fibroblast growth factor (FGF2) in high novelty/drug-seeking rats (bred high responders, bHR) compared to low novelty/drug-seeking rats (bred low responders, bLRs). The present study asked whether an early life manipulation of the FGF system (a single FGF2 injection on postnatal day 2) can impact cocaine sensitization and associated neurobiological markers in adult bHR/bLR animals. Neonatal FGF2- and vehicle-treated bHR/bLR rats were sensitized to cocaine (7 daily injections, 15 mg/kg/day, i.p.) in adulthood. Neonatal FGF2 markedly increased bLRs' typically low psychomotor sensitization to cocaine (day 7 locomotor response to cocaine), but had little effect on bHRs' cocaine sensitization. Gene expression studies examined dopaminergic molecules as well as FGF2 and the FGFR1 receptor in cocaine naïve animals, to investigate possible neurobiological alterations induced by neonatal FGF2 exposure that may influence behavioral response to cocaine. bLRs showed decreased tyrosine hydroxylase in the ventral tegmental area (VTA), decreased D1 and increased D2 receptor expression in the nucleus accumbens core, as well as decreased FGF2 in the VTA, substantia nigra, accumbens core, and caudate putamen compared to bHRs. Neonatal FGF2 selectively increased D1 receptor and FGF2 mRNA in the accumbens core of bLRs, which may contribute to their heightened cocaine sensitization. Our results suggest increased FGF2 in the mesodopaminergic circuit (as in baseline bHRs and neonatal FGF2-exposed bLRs vs. baseline bLRs) enhances an individual's susceptibility to cocaine sensitization and may increase vulnerability to drug seeking and addiction.     

Cocaine increases 5-HT1B mRNA in rat nucleus accumbens shell neurons

Serotonin 5-HT(1B) receptors modulate behavioral responses to cocaine, but the effects of cocaine on endogenous 5-HT(1B) receptor expression are not known. Therefore, we examined the effect of binge cocaine administration on 5-HT1B mRNA expression in rat brain. We found that chronic, but not acute, binge cocaine exposure increased 5-HT(1B) mRNA by approximately 80% in nucleus accumbens shell and dorsal striatum. Surprisingly, 5-HT(1B) mRNA was increased in nucleus accumbens shell after chronic vehicle treatment as well, but this effect was driven by animals that were housed with cocaine-treated animals. Thus, 5-HT(1B) mRNA is upregulated by repeated exposure to cocaine and perhaps by social stress as well; both of these factors are relevant to the risk for relapse in cocaine addiction.     

Behavioral sensitization to MK-801 (dizocilpine): neurochemical and electrophysiological correlates in the mesoaccumbens dopamine system

MK-801, a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) subtype of central glutamate receptor, stimulates locomotor activity in rats. Administration of MK-801 (0.25mg/kg, i.p.) on four consecutive days results in progressive sensitization of its locomotor stimulatory effects. Because of the importance of dopamine (DA) systems in locomotor sensitization to other stimulants (e.g. amphetamine and cocaine), we examined the possible role of DA transmission in MK-801 sensitization. The D1 antagonist SCH 23390 was used for these experiments because of the well-established ability of D1 antagonists to block both D1- and D2-mediated unconditioned behaviors. Acute behavioral effects of MK-801 were reduced by SCH 23390 only at doses that decreased basal activity, while the expression of MK-801 sensitization was attenuated by SCH 23390 in some experiments but never completely prevented. Co-administration of SCH 23390 with MK-801 on pretreatment days did not prevent the development of sensitization. In vivo microdialysis experiments compared the effect of MK-801 on extracellular DA levels in the nucleus accumbens (NAc) on Days 1 and 4 of repeated administration. On Day 1, MK-801 produced a modest elevation of DA levels. On Day 4, only 6/17 rats in microdialysis experiments expressed sensitization; these rats, however, exhibited a more rapid rise in DA levels than Day 1 rats or non-sensitized Day 4 rats. Electrophysiological studies revealed that repeated MK-801 administration resulted in supersensitivity of D1 receptors on NAc neurons. Thus, behavioral studies support the importance of non-dopaminergic mechanisms in MK-801 sensitization, while neurochemical and electrophysiological studies suggest that MK-801 sensitization is accompanied by changes in DA transmission in the NAc similar to those observed in amphetamine- or cocaine-sensitized rats.     

Behavioral sensitization and extracellular dopamine responses to amphetamine after various treatments

The repeated administration of amphetamine (AMPH) results in a pattern of behavioral changes which includes an augmentation of some behaviors, generally referred to as behavioral sensitization. Some investigators have suggested that an increased dopamine (DA) response to AMPH challenge may underlie behavioral sensitization, while others have reported behavioral sensitization in the absence of an enhanced DA response. Because temporal and dosage parameters of the AMPH pretreatment regimen have been suggested to play a role in the appearance of an enhanced DA response, we utilized a variety of AMPH pretreatment regimens to assess the relationship between pretreatment dose of AMPH, duration of withdrawal and the DA response in caudate-putamen and nucleus accumbens to a subsequent AMPH challenge. Under our experimental conditions, behavioral sensitization was observed after each of these treatments in the absence of an enhanced DA response in either brain region. Received: 9 October 1996 /Final version: 15 May 1997     

Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats

Rationale

It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.

Objectives

The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.

Materials and methods

Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.

Results

Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.

Conclusion

The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.

     

Behavioral sensitization and long-term neurochemical alterations associated with the fungicide triadimefon

Triadimefon (TDF), a widely used triazole fungicide, blocks reuptake of the neurotransmitter dopamine (DA), similarly to cocaine. Preliminary studies show that intermittent intraperitoneal injections of TDF increase ambulatory and vertical activity across repeated injections [Neurotoxicology (in press)] leading to the hypothesis tested here, that exposure to TDF may influence the development and expression of behavioral sensitization, a model of psychostimulant-induced psychosis. Exposure of adult male C57BL/6 mice to 75 mg/kg i.p. TDF (TDF75) twice a week for 7 weeks increased vertical activity at each injection. Following a 2-week withdrawal period, a TDF challenge to test for expression of behavioral sensitization revealed further increases in vertical activity levels relative to all other conditions. TDF induction/expression of behavioral sensitization was associated with long-term, perhaps permanent modulation of dopaminergic function that included increases in striatal dihydroxyphenylacetic acid (DOPAC) and DA turnover, increases in medial prefrontal cortex (mPFC) dopamine transporter (DAT) binding, as well as decreases in DA D1 and increases in DA D2 and DAT receptor binding that appeared to target the nucleus accumbens shell (NAs) subregion. Thus, TDF exposure may serve as an environmental risk factor for DA system dysfunctions.     

Withdrawal of repeated cocaine decreases autoradiographic [3H]mazindol-labelling of dopamine transporter in rat nucleus accumbens.

The in vitro autoradiographic distribution of desipramine-insensitive specific [3H]mazindol binding sites (labelling the dopamine transporter) was determined in brain sections from rats receiving repeated i.v. infusions of saline or cocaine (1 mg/kg, every 12 min for 2 h/day), for 10 days. Brains were removed either within 15 min of or 10 days after the last treatment. A marked dorsal-to-ventral gradient in [3H]mazindol binding appeared in the striatum with the dorsal caudate putamen showing the greatest binding and the medial shell of the nucleus accumbens the least. Cocaine-associated changes in [3H]mazindol-labelled dopamine uptake sites occurred only in the nucleus accumbens (57 and 66% decrease in the lateral core and medial shell, respectively), of animals 10 days after the last treatment. Down-regulation of the dopamine transporter in the nucleus accumbens by withdrawal of chronic cocaine may be one of the mechanisms involved in cocaine's long-term abstinence effects.     

Repetitive transcranial magnetic stimulation increases the release of dopamine in the nucleus accumbens shell of morphine-sensitized rats during abstinence.

Recent studies in rodents have shown that withdrawal from chronic drug abuse is associated with a significant decrease in dopamine (DA) release in mesolimbic structures, especially in the shell region of the nucleus accumbens. Since the DA system is known to play an important role in reward processes, a withdrawal-associated impairment in mesolimbic DA-mediated transmission could possibly implicate reward deficit and thus enhance vulnerability to drug craving and relapse. We have previously demonstrated that acute repetitive transcranial magnetic stimulation (rTMS) has a modulatory effect on DA release in several areas of the rat brain, including dorsal striatum, hippocampus, and nucleus accumbens shell. In the present study, we investigated the possible use of rTMS as a tool in re-establishing the dysregulated DA secretion observed during withdrawal in morphine-sensitized male Sprague-Dawley rats. Using intracerebral microdialysis, we monitored the effects of acute rTMS (20 Hz) on the intra-accumbal release-patterns of DA in freely moving animals that were subjected to a morphine sensitization scheme for a period of 8 days. We provide first evidence that acute rTMS (20 Hz) is able to increase DA concentration in the shell region of the nucleus accumbens in both control animals and morphine-sensitized rats during abstinence. The DA release in morphine-sensitized rats was significantly higher than in controls. rTMS, therefore, might gain a potential therapeutic role in the treatment of dysphoric and anhedonic states during drug withdrawal in humans.