Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cage

Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 microg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage.     

Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens

Repeated cocaine administration to rats outside their home cage induces behavioral sensitization that is strongly modulated by the drug administration environment. We hypothesized that stimuli in the drug administration environment activate specific sets of striatal neurons, called neuronal ensembles, for further cocaine-enhanced activation, and that repeated activation of these neuronal ensembles underlies context-specific sensitization. In the present study, we repeatedly administered cocaine or saline to rats on alternate days in two distinct environments outside the home cage, one paired with cocaine and the other with saline. On test day, cocaine challenge injections in the cocaine-paired environment produced strongly enhanced levels of locomotor activity, while cocaine challenge injections in the saline-paired environment did not. The corresponding record of past neuronal activation in nucleus accumbens and caudate-putamen during repeated drug administration was assessed using FosB immunohistochemistry, while acute neuronal activation on test day was assessed using c-fos in situ hybridization. Although only 2% of striatal neurons were FosB labeled, 87% of these FosB-labeled neurons were co-labeled with c-fos when cocaine was injected in the cocaine-paired environment. The degree of co-labeling was significantly less following cocaine or saline challenge injections in the saline-paired environment. Furthermore, the total number of c-fos -labeled neurons was greater with either cocaine or saline challenge injections in the cocaine-paired environment than in the saline-paired environment. These findings demonstrate that the drug administration environment partly determines which striatal neuronal ensembles are activated, and to what extent, following context-specific sensitization to cocaine.     

Blockade of neurotensin receptors during amphetamine discontinuation indicates individual variability

Psychostimulant-induced locomotor sensitization has been related to changes within the mesolimbic dopamine system and has been suggested to be useful to study mechanisms underlying drug craving. Neurotensin is a neuropeptide co-localized with dopamine in the mesolimbic system. The response to novelty has been suggested to be a predictor of enhanced vulnerability to behavioral sensitization. The effects of repeated treatment with the neurotensin antagonist SR48692 after amphetamine discontinuation were investigated in mice previously classified as high responders (HRs) or low responders (LRs) to novelty. Mice were repeatedly treated with 2.0mg/kg amphetamine, every other day for 11 days. During the first 7 days after amphetamine discontinuation, the animals received a daily injection of saline or 0.3mg/kg SR48692. On the eighth day after amphetamine discontinuation all subjects received a 2.0mg/kg amphetamine challenge injection. Then, mice were tested for an open field behavior and after 90min, were sacrificed for Fos expression quantification in the nucleus accumbens. Both HRs and LRs expressed amphetamine-induced sensitized locomotor activation and increased expression of Fos protein. Treatment with SR48692 prevented behavioral sensitization and Fos protein expression enhancement in LRs but not in HRs mice. These data suggest that neurotensin plays a role in individual variability to amphetamine-induced sensitization.     

Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.     

Increased locomotor response to amphetamine induced by the repeated administration of the selective kappa-opioid receptor agonist U-69593

Acute administration of kappa opioid receptor (KOR) agonists decreases both dopamine (DA) extracellular levels in the nucleus accumbens (NAc) and locomotor activity. Opposing to its acute effects, recent studies show that chronic administration of KOR agonists potentiates both stimulated DA release and induced locomotor activity. Since KOR agonists have been considered as potential treatment for stimulant dependence, the effects of their repeated administration on psychostimulant actions are of major concern. The present study was undertaken to investigate the in vivo effect of repeated administration of the KOR agonist U-69593 on DA extracellular levels in the NAc and on the locomotor activity challenged with amphetamine. Rats were injected once daily with the selective KOR agonist U-69593 or vehicle for four consecutive days. One-day after the last U-69593 injection, microdialysis studies assessing extracellular DA levels in the NAc and locomotor activity challenged with amphetamine were conducted. Microdialysis studies revealed that preexposure to U-69593 had no effect on basal DA levels but significantly augmented amphetamine-induced DA extracellular levels. Accordingly, amphetamine-induced locomotor activity was also significantly potentiated in U-69593 preexposed rats. These results suggest that long-term effect of KOR activation results in facilitation of amphetamine-induced DA extracellular levels in the NAc accompanied by sensitization of amphetamine-induced increase in locomotor activity.     

Amphetamine and haloperidol modulate preprotachykinin A mRNA expression in rat nucleus accumbens and caudate-putamen.

In situ hybridization was used to measure the effect of repeated amphetamine (1.5 mg/kg) and haloperidol (0.5 mg/kg) treatment for 7 days on the expression of preprotachykinin A (PPT-A) mRNA in rat nucleus accumbens (Acb) and caudate-putamen (CPu). Amphetamine elevated the level of PPT-A mRNA in Acb, but not in CPu. Haloperidol decreased the levels in Acb shell and CPu, but not in Acb core. Haloperidol injected together with amphetamine, prevented the amphetamine-induced increase in PPT-A mRNA expression in both Acb core and shell.     

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.     

Association of the mesencephalic locomotor region with locomotor activity induced by injections of amphetamine into the nucleus accumbens

Injections of amphetamine into the nucleus accumbens increased locomotor activity of rats. Subsequent injections of procaine into the midbrain, in the region of the pedunculopontine nucleus, significantly reduced the amphetamine-induced locomotor activity. Control experiments showed that procaine injections into the contralateral pedunculopontine nucleus had little or no effect, as well as ipsilateral injections dorsal and ventral to the pedunculopontine nucleus. These findings suggest that release of dopamine from amphetamine injections into the accumbens gives rise to ipsilateral descending influences on the region of the pedunculopontine nucleus, a major component of the mesencephalic locomotor region. Descending influences from the nucleus accumbens to mesencephalic locomotor region may serve as a link for limbic-motor integration in behavioral response initiation.     

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.     

Effect of Pertussis Toxin Injected Into the Ventral Tegmental Area on Amphetamine-Induced c-Fos in the Nucleus Accumbens

Amphetamine produces an enhanced locomotor stimulatory response in animals injected with pertussis toxin into the ventral tegmental area. This response is dependent on the activation of D₁ receptors in the nucleus accumbens. The immediate early gene, c-Fos, has been used as a cellular marker for increases in dopamine neurotransmission in the nucleus accumbens. The purpose of the present study was to determine whether the administration of pertussis toxin into the ventral tegmental area results in an increased ability of amphetamine to induce c-Fos-positive immunoreactivity in the nucleus accumbens. Amphetamine (1 mg/kg and 2 mg/kg IP) produced a greater number of c-Fos-positive cells in the nucleus accumbens of pertussis toxin-treated animals as compared to vehicle-treated controls. However, the increase in Fos immunoreactivity at the higher amphetamine dose was not associated with a corresponding increase in locomotor activity. These data suggest that amphetamine produces an enhanced increase in dopamine neurotransmission in the nucleus accumbens of pertussis toxin-treated animals, resulting in an increased induction of c-Fos or Fos-related antigens.     

Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology

Behavioral sensitization to the locomotor activating effects of amphetamine refers to the progressive, long lasting increase in locomotor activity that occurs with repeated injections. This phenomenon is thought to result from neuroadaptations occurring in the projection fields of mesocorticolimbic dopaminergic neurons. In the present study, we investigated the effects of amphetamine sensitization on Fos immunoreactivity (Fos-IR) in subterritories of the nucleus accumbens (core and shell) and medial prefrontal cortex (mPFC; dorsal and ventral) using stereology. Rats received five daily injections of amphetamine (1.5 mg/kg, i.p.) or saline. Behavioral sensitization was measured 48 h following the last injection, in response to a challenge injection of 1.5 mg/kg amphetamine. Sensitized rats showed a greater enhancement of locomotor activity upon drug challenge compared with their saline counterparts. Densities of Fos-positive nuclei were enhanced more in the dorsal than the ventral mPFC subterritory, whereas in the nucleus accumbens, densities of Fos-positive nuclei were increased more in the core than the shell of amphetamine-sensitized rats compared to controls. These results represent, to our knowledge, the first published report using stereological methods to quantify Fos-IR in the brain and suggest functional specialization of cortical and limbic regions in the expression of behavioral sensitization to amphetamine.     

Amphetamine administration does not alter protein levels of the GLT-1 and EAAC1 glutamate transporter subtypes in rat midbrain, nucleus accumbens, striatum, or prefrontal cortex

Our laboratory and others have previously shown that glutamate transmission is required for chronic amphetamine-induced neuroadaptations, and that glutamate transmission itself is altered by chronic amphetamine administration. For example, N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunit expression are altered in a region- and withdrawal-specific manner. The goal of this study was to determine whether repeated amphetamine administration influences the expression of two glutamate transporter subtypes, GLT-1 and EAAC1. Rats were treated with saline or 5 mg/kg amphetamine for 5 days (chronic saline and amphetamine groups, respectively), or saline for 4 days and 5 mg/kg amphetamine on day 5 (acute amphetamine group), and decapitated 24 h after the last injection. Tissue was dissected from brain regions involved in the psychomotor effects of amphetamine (nucleus accumbens, striatum, prefrontal cortex, ventral tegmental area, and substantia nigra). Levels of GLT-1 and EAAC1 were quantified by Western blotting and normalized to actin levels. We found no significant change in levels of GLT-1 or EAAC1 in response to either acute or chronic amphetamine treatment. These findings suggest that the transporter component of the glutamate system might not play a significant role in the alterations in glutamate transmission observed following repeated amphetamine administration.     

Differential effect of amphetamine on c-fos expression in female aromatase knockout (ArKO) mice compared to wildtype controls

Estrogen may be involved in psychosis by an interaction with central dopaminergic activity. Aromatase knockout mice are unable to produce estrogen and have been shown to display altered behavioural responses and effects of the dopamine releaser, amphetamine. This study investigates the effect of gonadal status on amphetamine-induced c-fos expression in the brains of female aromatase knockout and wildtype mice. Six groups of mice were treated intraperitoneally with saline or 5mg/kg amphetamine. Fos immunoreactivity was assessed in the cingulate cortex, caudate putamen and nucleus accumbens. Aromatase knockout mice showed markedly reduced amphetamine-induced Fos immunoreactivity compared to wildtype mice. However, the amphetamine response was restored in aromatase-knockout mice after ovariectomy, which reduced this effect in wildtype controls. Estrogen supplementation reversed the effect of ovariectomy in wildtype mice but had no additional significant effect in aromatase-knockout mice. These results indicate that mechanisms involved in amphetamine-induced c-fos expression are altered in aromatase knockout mice and that the primary hormone involved in this effect is not estrogen, but may be another factor released from the ovaries, such as an androgen. These results provide new insight into the effect of gonadal hormones on amphetamine induced c-fos expression in this mouse model of estrogen deficiency. These results could be important for our understanding of the role of sex steroid hormones in psychosis.     

The ability of amphetamine to evoke arc (Arg 3.1) mRNA expression in the caudate, nucleus accumbens and neocortex is modulated by environmental context

The ability of amphetamine or cocaine to induce the expression of c-fos mRNA in a number of brain regions is greatly enhanced when these drugs are administered in a distinct and relatively novel environment, relative to when they are given in the home cage. The purpose of this study was to determine if environmental context has a similar effect on the ability of amphetamine to induce the expression of arc (also known as Arg 3.1), an ‘effector’ immediate early gene (IEG) thought to play a direct role in cellular plasticity. Rats were administered either saline or amphetamine (0.5 mg/kg, i.v.), in their home cage or in a distinct test environment. Fifty minutes later, they were decapitated and their brains processed for in situ hybridization histochemistry. In the prefrontal cortex, caudate-putamen and core of the nucleus accumbens, amphetamine significantly increased arc mRNA expression under both conditions, but the level of expression was significantly enhanced when amphetamine was given in a distinct environment. In the shell of the nucleus accumbens amphetamine significantly increased the expression of arc mRNA only when it was administered in the distinct environment. Thus, the ability of amphetamine to induce the expression of arc varies as a function of the environmental context in which it is administered. This could contribute to the ability of environmental context to modulate forms of drug experience-dependent neuroplasticity, including behavioral sensitization.     

Compartment-specific changes in striatal neuronal activity during expression of amphetamine sensitization are the result of drug hypersensitivity

Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a persistent hypersensitivity to the psychomotor stimulant effects of these drugs. This may be the result of increased responsiveness, to drugs, of mesostriatal dopamine systems and their projections, but it has also been suggested that acute and sensitized behavioural responses to psychostimulant drugs involve activation of distinct neuronal circuits. In order to distinguish between these possibilities, we studied amphetamine-induced c-fos immunoreactivity in subregions of rat striatum (patch and matrix compartments of caudate-putamen and nucleus accumbens core and shell) in drug-naive rats, as well as during long-term expression of amphetamine sensitization. We found that, in sensitized animals, amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive cells in striatal patch and matrix compartments, suggesting a preferential involvement of striatal patches in the sensitized response to amphetamine. In drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos expression in all striatal subregions. Remarkably, the highest dose of amphetamine also evoked an increase in patch : matrix ratio of c-fos immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline-pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos expression. These data indicate that distinct striatal compartments display a differential sensitivity to amphetamine in both drug-naive and amphetamine-sensitized animals. In addition, they suggest that the shift in amphetamine-induced c-fos expression from striatal matrix to patches in sensitized animals is the consequence of a change in the sensitivity to amphetamine, rather than a long-term circuitry reorganization that is exclusive to the sensitized state.     

The effect of 'binge' cocaine administration on the expression of cyclin-dependent kinase 5 and its activator p35 in various regions of rat brain

The present study was aimed at determining whether the administration of cocaine in 'binge' pattern regimen that evoked tolerance to the locomotor stimulant effects of cocaine also influenced the expression of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in the amygdala, medial prefrontal cortex, nucleus accumbens septi and caudate-putamen. Western blot techniques revealed that acute and repeated 'binge' cocaine decreased expression of the Cdk5 protein in the amygdala. In the medial prefrontal cortex, only exposure to repeated 'binge' cocaine decreased the content of the Cdk5 protein. 'Binge' cocaine administration also altered the expression of Cdk5 activator p35 protein. In the amygdala, only repeated 'binge' cocaine decreased the expression of p35, while in the medial prefrontal cortex, a decrease was observed after acute and repeated 'binge' cocaine exposure. In neither the nucleus accumbens septi nor the caudate-putamen acute or repeated 'binge' cocaine modified the expression of Cdk5 and p35. The above data indicate that in contrast to sensitizing doses of cocaine, a single and repeated binge of cocaine, which evoked tolerance to its locomotor stimulant effects, decreases expression of Cdk5 and p35 and possibly decreases the efficacy of neurotransmission or induces brain plastic changes regulated by Cdk5 and its activator p35.     

Pairing mild stress with increased serotonin-1B receptor expression in the nucleus accumbens increases susceptibility to amphetamine

Both serotonin-1B (5-HT_1B) receptors and stress modulate the behavioral and neurobiological effects of psychostimulant drugs. In order to examine how these factors interact to influence the development of behaviors associated with addiction, we used viral-mediated gene transfer to transiently increase expression of 5-HT_1B receptors in the nucleus accumbens (NAc) shell along with exposure to repeated mild stress (novelty + saline injection) in rats. Once the viral-mediated increases in gene expression had dissipated, the resulting effects of this 5-HT_1B/stress pairing on the acute locomotor response to amphetamine and on the development of psychomotor sensitization were examined. We report that the increasing expression of 5-HT_1B receptors on the terminals of NAc shell neurons that project to the ventral tegmental area and repeatedly exposing rats to mild stress subsequently enhance the acute locomotor-activating effects of amphetamine. In addition, the development of psychomotor sensitization (both locomotor activity and stereotypy components) is facilitated. These results suggest that serotonin signaling through NAc 5-HT_1B heteroreceptors can interact with stress to increase susceptibility to the enduring forms of drug-induced plasticity that are associated with addiction.     

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.     

NMDA receptor blockade attenuates the haloperidol induction of Fos protein in the dorsal but not the ventral striatum.

Neuroleptic blockade of dopamine receptors is known to produce an increase in the expression of Fos. This increase may be related to elevations in glutamate transmission which in turn activates N-methyl-D-aspartate (NMDA) receptors. In the present study, we examine the role of these receptors in the haloperidol-induced augmentation of Fos in the caudate-putamen and nucleus accumbens of Wistar rats. Animals were divided into four groups for each experiment and each was injected either with saline; a noncompetitive NMDA antagonist, dizocilpine maleate (MK801, 5 mg/kg); haloperidol (0.5 mg/kg); or MK801 followed by an injection of haloperidol. Fos-immunoreactive cells appear in large numbers in all parts of the striatum 3 h after the administration of haloperidol. Pretreatment with MK801 attenuates the haloperidol-induced increase in Fos in the caudate-putamen. However, antagonism of the NMDA receptor does not significantly reduce the density of Fos-immunoreactive cells in any territory of nucleus accumbens, i.e., shell, core, or rostral pole. These data suggest that haloperidol acts in an NMDA-dependent manner in the caudate-putamen, but independently in parts of nucleus accumbens traditionally considered to be targets of antipsychotic drugs.     

Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies

The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity.