Additional evidence for the involvement of the basal ganglia inAdditional evidence for the involvement of the basal ganglia in formalin-induced nociception: the role of the nucleus accumbens.

Identification of the brain areas that contribute to pain is an essential undertaking towards understanding persistent pain. Areas of the basal ganglia have been proposed to play important roles in nociception as previous studies have determined the involvement of the substantia nigra pars compacta and the dorsolateral striatum in pain. The purpose of the present study was therefore to expand upon these findings by determining the involvement of other areas of the basal ganglia such as the nucleus accumbens shell and core in formalin-induced nociception. It was found that injection of a local anaesthetic (bupivacaine) into the nucleus accumbens shell had no effect on formalin-induced nociception. However, injection into the nucleus accumbens core enhanced formalin-induced nociception. These results implicate the nucleus accumbens in the processing of pain and provide additional evidence for the involvement of the basal ganglia and possibly dopamine in pain.

CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.

The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.

The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking

Studies addressing behavioral functions of dopamine (DA) in the nucleus accumbens septi (NAS) are reviewed. A role of NAS DA in reward has long been suggested. However, some investigators have questioned the role of NAS DA in rewarding effects because of its role in aversive contexts. As findings supporting the role of NAS DA in mediating aversively motivated behaviors accumulate, it is necessary to accommodate such data for understanding the role of NAS DA in behavior. The aim of the present paper is to provide a unifying interpretation that can account for the functions of NAS DA in a variety of behavioral contexts: (1) its role in appetitive behavioral arousal, (2) its role as a facilitator as well as an inducer of reward processes, and (3) its presently undefined role in aversive contexts. The present analysis suggests that NAS DA plays an important role in sensorimotor integrations that facilitate flexible approach responses. Flexible approach responses are contrasted with fixed instrumental approach responses (habits), which may involve the nigro-striatal DA system more than the meso-accumbens DA system. Functional properties of NAS DA transmission are considered in two stages: unconditioned behavioral invigoration effects and incentive learning effects. (1) When organisms are presented with salient stimuli (e.g., novel stimuli and incentive stimuli), NAS DA is released and invigorates flexible approach responses (invigoration effects). (2) When proximal exteroceptive receptors are stimulated by unconditioned stimuli, NAS DA is released and enables stimulus representations to acquire incentive properties within specific environmental context. It is important to make a distinction that NAS DA is a critical component for the conditional formation of incentive representations but not the retrieval of incentive stimuli or behavioral expressions based on over-learned incentive responses (i.e., habits). Nor is NAS DA essential for the cognitive perception of environmental stimuli. Therefore, even without normal NAS DA transmission, the habit response system still allows animals to perform instrumental responses given that the tasks take place in fixed environment. Such a role of NAS DA as an incentive-property constructor is not limited to appetitive contexts but also aversive contexts. This dual action of NAS DA in invigoration and incentive learning may explain the rewarding effects of NAS DA as well as other effects of NAS DA in a variety of contexts including avoidance and unconditioned/conditioned increases in open-field locomotor activity. Particularly, the present hypothesis offers the following interpretation for the finding that both conditioned and unconditioned aversive stimuli stimulate DA release in the NAS: NAS DA invigorates approach responses toward 'safety'. Moreover, NAS DA modulates incentive properties of the environment so that organisms emit approach responses toward 'safety' (i.e., avoidance responses) when animals later encounter similar environmental contexts. There may be no obligatory relationship between NAS DA release and positive subjective effects, even though these systems probably interact with other brain systems which can mediate such effects. The present conceptual framework may be valuable in understanding the dynamic interplay of NAS DA neurochemistry and behavior, both normal and pathophysiological.

Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.

Abnormalities of the ionotropic glutamate receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid [AMPA], and kainate) have been reported in the brain in schizophrenia, although in complex, region-specific patterns. While limbic cortex and medial temporal lobe structures have been most often studied in psychiatric illnesses, glutamate receptors are expressed in other brain regions associated with limbic circuitry, especially the striatum. In this study, we have determined striatal ionotropic glutamate receptor expression in brains from persons with schizophrenia, bipolar disorder, major depression, and a comparison group, using samples from the Stanley Foundation Neuropathology Consortium. We have determined the expression of these receptors at multiple levels of gene expression by using both in situ hybridization and receptor autoradiography. The expression of nearly all of these molecules was not different in these psychiatric conditions. The only significant changes noted were NR2D and gluR1 transcripts, and [(3)H]AMPA binding. This is the first comprehensive study of striatal ionotropic glutamate receptor expression in schizophrenia and affective disorders, and suggests that there are minimal changes in these receptors in this region of the brain in these illnesses.

mpulsive choice induced in rats by lesions of the nucleus accumbens core Impulsive choice is exemplified by choosing a small or poor reward that is available immediately, in preference to a larger but delayed reward. Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, but its neuroanatomical basis is unclear. Here, we show that selective lesions of the nucleus accumbens core induce persistent impulsive choice in rats. In contrast, damage to two of its afferents, the anterior cingulate cortex and medial prefrontal cortex, had no effect on this capacity. Thus, dysfunction of the nucleus accumbens core may be a key element in the neuropathology of impulsivity.

Long-term lithium administration abolishes the resistance to stress in rats sensitized to morphine.

Morphine sensitized rats appear protected from the sequelae of an unavoidable stress: when exposed to stress (after a 7-day morphine wash-out) and then tested for escape, they perform like naive animals. This protection appears similar to that induced by chronic imipramine treatment, as it is antagonized by the inhibition of D(1)-dopamine receptors before exposure to unavoidable stress. Repeated unavoidable stress induces in rats a condition characterized by hyporeactivity to noxious stimuli and reverted by long-term antidepressant treatments, and this state is regarded as an experimental model of depression. The resistance to stress in morphine sensitized rats could be considered as the behavioral counterpart of the sensitivity to stress in control rats, i.e. as a model of mania. The aim of the present study was to validate such a putative model by studying whether the resistance to stress induced by morphine sensitization would respond to a long-term administration of lithium, the reference antimanic drug. Long-term lithium treatment induces in rats a condition of hyporeactivity to noxious stimuli, accompanied by decreased levels of dopamine in the nucleus accumbens shell. In morphine sensitized rats chronic lithium abolished the resistance to stress, but it did not modify the D(1)-dopamine receptor mediated response to morphine, nor did it modify the levels of extraneuronal dopamine in the nucleus accumbens shell. Thus, lithium treatment abolished the resistance to stress in morphine sensitized rats, conferring predictive validity to the paradigm. Moreover, it did so through a mechanism which appeared to be independent of D(1)-dopamine receptor activity.

Carbamazepine suppresses methamphetamine-induced Fos expression in a regionally specific manner in the rat brain. Possible neural substrates responsible for antimanic effects of mood stabilizers

Carbamazepine (CBZ) has been widely used for treatment of manic states. Because amphetamine produces effects in humans similar to those of idiopathic mania, acute methamphetamine administration could serve as a model of this condition. To elucidate the neurobiological substrates responsible for the antimanic effects of carbamazepine, this study investigated the effects of chronic carbamazepine administration on regional Fos protein expression induced by a single dose of methamphetamine (2mg/kg). Chronic treatment with CBZ (0.25% in food for 7 days, followed by 0.5% for 7 days; final mean serum carbamazepine concentration: 4.09 +/- 0.34 microg/ml) significantly attenuated the number of Fos-like immunoreactivity-positive nuclei induced by methamphetamine administration in the core of the nucleus accumbens and the caudate/putamen. The results indicate these brain regions are involved in the antimanic effects of carbamazepine.

The pathomorphology of schizophrenia and mood disorders: similarities and differences.

n this article, post-mortem neurohistological and structural imaging studies of schizophrenia and mood disorders are briefly reviewed. In contrast to the large number of post-mortem studies on schizophrenia published during the last 20 years, very few histological studies of affective disorders are available. After commenting on CT and MRI studies, as well as on neuropathological findings on whole-brain size, cortex, frontal and temporal lobes, limbic system, basal ganglia, thalamus, brain stem, and cortical asymmetry, it is concluded that despite a broad overlap in structural findings in the so-called endogenous psychoses, heteromodal association cortex, limbic system, and structural asymmetry are more affected in schizophrenia, while subtle structural abnormalities in the basal ganglia, especially in the nucleus accumbens and in hypothalamic areas, might play a crucial role in mood disorders.

The effect of lithium on methamphetamine-induced regional Fos protein expression in the rat brain.

Lithium has been used widely for the treatment of manic states. Since amphetamines produce effects in humans similar to the symptoms of idiopathic mania, amphetamine administration to animals has been proposed as a model of this condition. To investigate the neurobiologic substrates of the antimanic effects of chronic lithium administration, we investigated its effects on methamphetamine-induced regional Fos protein expression in the rat brain. Chronic lithium administration (14 days; serum lithium concentration, 0.41+/-0.02 mEq/l) significantly reduced the number of neuronal nuclei showing immunoreactivity induced by methamphetamine (2mg/kg) in the prefrontal cortex, caudate/putamen, nucleus accumbens, and central nucleus of the amygdala. These results indicate the structural basis in CNS which is responsible for the antimanic effect of lithium.

Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a postmortem study.

Volumes of basal ganglia in postmortem brains of 8 patients with mood disorders and 8 control subjects without neuropsychiatric disorder were determined. Morphometry of serial whole-brain sections under the control of postmortem artifacts revealed reduced volumes of the left nucleus accumbens (-32%, P = 0.01), the right and left external pallidum (-20%, P = 0.04), and the right putamen (-15%, P = 0.04) in the patient group compared with the control group. These results suggest that, in particular, the limbic loop of the basal ganglia involving the nucleus accumbens and the pallidum is affected in mood disorders.

Differential effects of chronic imipramine and fluoxetine on basal and amphetamine-induced extracellular dopamine levels in rat nucleus accumbens.

The effect of chronic treatment with the tricyclic antidepressant drug, imipramine (10 mg/kg per day), the selective serotonin (5-HT) reuptake inhibitor, fluoxetine hydrochloride (10 mg/kg per day), and vehicle, in drinking water for 24-28 days followed by 3-5 days withdrawal, on extracellular dopamine levels was studied in rat nucleus accumbens by in vivo microdialysis. Basal extracellular dopamine levels in the nucleus accumbens were increased after chronic imipramine (12.7 +/- 1.5 fmol/20 microl per 30 min, P = 0.019), and moderately decreased after chronic fluoxetine (6.5 +/- 0.6, P = 0.047), as compared to the vehicle controls (9.1 +/- 0.7), determined by one-way analysis of variance (ANOVA). Repeated measure ANOVA indicated that the D-amphetamine sulfate (0.5 mg/kg, s.c.)-induced increase in extracellular dopamine levels in the nucleus accumbens was potentiated after chronic imipramine (P = 0.002), but unchanged after chronic fluoxetine (P = 0.83). The difference in the effect of amphetamine could be influenced by the significant differences in basal levels. However, these results were also confirmed by analysis of the net area under the curve (net-AUC) for a 180-min period (six samples): for chronic imipramine (337 +/- 45 fmol/180 min, P = 0.005) and chronic fluoxetine (249 +/- 38, P = 0.57), as compared to the vehicle controls (178 +/- 29), determined by one-way ANOVA. We suggest that the effect of treatment with these agents on mesolimbic dopamine is unlikely to be involved in their shared antidepressant action, but may be relevant to other aspects of the therapeutic profile of these two drugs, e.g. the switch into mania which is more common after treatment with imipramine than fluoxetine and exacerbation of positive symptoms in patients with schizophrenia or schizoaffective disorder.

The effects of lithium on a potential cycling model of bipolar disorder.

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

Lithium interferes with reserpine-induced dopamine depletion.

Long-term lithium treatment attenuated the hypokinetic effect of reserpine in a patient with tardive dyskinesia. In rats, prophylactic lithium administration inhibits reserpine-induced dopamine depletion in the brain. These data indicate that lithium may limit the therapeutic efficacy of reserpine in tardive dyskinesia.

INTRODUCTION: The nucleus accumbens is considered as the neural interface between motivation and action, playing a key role on feeding, sexual, reward, stress-related, drug self-administration behaviors, etc. DEVELOPMENT: The nucleus accumbens possesses two territories, the core and shell, whose connectivity wiring gives a good picture of its motor and limbic aspects. The shell seems to behave as a 'coincidence detector', which can be activated during behavioral situations of adaptive value, thanks to its connections with prefrontal cortex, amygdala and hippocampus. The activation of the shell leads to the reinforcing of goal-directed motor sequences mediated by the core and prefrontal cortex, areas which are, linked to pyramidal and extrapyramidal motor systems. Dopamine secreted within the nucleus accumbens would acts as a 'neurostabilizer' of such processes. CONCLUSION: The nucleus accumbens is made up of an 'electrophysiological coincidence detector' or shell serially connected to a 'motor sequencer' or core, both supporting the role of the nucleus accumbens as a limbic-motor interface.

Effects of psychological stress on monoamine systems in subregions of the frontal cortex and nucleus accumbens of the rat.

We investigated the effects of two types of psychological stress, novelty stress and psychological stress using the communication box, on dopamine and serotonin systems in subregions of the frontal cortex and nucleus accumbens of rats. Placement of rats into a compartment of the communication box (novelty stress) increased both dopamine and serotonin metabolism in medial precentral, anterior cingulate, and prelimbic subregions of the frontal cortex as evaluated by the levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid for dopamine, and 5-hydroxyindoleacetic acid for serotonin. In contrast, novelty stress had no effect on these monoamine systems in infralimbic and sulcal subregions of the frontal cortex. In the nucleus accumbens, novelty stress increased both dopamine and serotonin metabolism in the shell, but decreased dopamine metabolism in the core. On the other hand, psychological stress using the communication box augmented dopamine metabolism in the anterior cingulate and prelimbic subregions. This stress, however, failed to affect the dopamine system in the medial precentral, infralimbic and sulcal subregions. In the nucleus accumbens, the stress selectively decreased dopamine metabolism in the shell but showed no effect in the core. The serotonin system showed little change due to the stress. These results demonstrate that psychological stress causes distinct changes in both the dopamine and serotonin systems in the frontal cortex and the nucleus accumbens. These changes vary with the subregions of these areas, suggesting that the region-specific responsiveness to psychological stress reflects the functional differences among these subregions. In addition, our results also suggest that changes in brain monoamine systems induced by psychological stress are quite different from those induced by physical stress.