The release of exosomes in the medial prefrontal cortex and nucleus accumbens brain regions of chronic constriction injury (CCI) model mice could elevate the pain sensation.

BACKGROUND: Brain function relies on the capacity of neurons to locally modulate each other at the level of synapses. Therefore, the exosomal pathway may constitute a well-designed mechanism for local and systemic interneuronal transfer of information within functional brain networks. Exosomes bind to and are endocytosed by neurons of different brain regions to play a definite role. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) brain regions are known to involve in pain modulation. Our study observes the roles of exosomal activity in these two dominant regions of the pain-related pathway, and there influence on the analgesic effects in CCI mice. METHODS: We induced pain exosomes in the mPFC and NAc in the mice of chronic constriction injury of the sciatic nerve model to produce neuropathic pain, and assessed changes that might affect analgesic behaviors. These changes were measured through a combination of behavioral, surgical, and other cellular testings. RESULTS: Our study found that pain expression was elevated in mice given exogenous exosomes isolated from CCI mice, especially at the 2 h and 4 h time interval, in mice given exosomes at the mPFC and NAc, respectively. We also found that inhibiting formation of pain exosomes through GW4869 within the mPFC and NAc can elevate the pain threshold. CONCLUSION: Results from our study supported the idea that the release of mPFC and NAc exosomes of CCI model has elevated the pain sensations in the subjected mice. This study will further help in designing new clinical trials, and will revolutionize the drug-induced anesthetic responses.

Repeated exposure to methiopropamine increases dendritic spine density in the rat nucleus accumbens core.

Repeated exposure to classical psychomotor stimulants, like amphetamine (AMPH), produces locomotor sensitization and accompanied structural plasticity of dendritic spines in the nucleus accumbens (NAcc). Following our previous report that repeated administration of methiopropamine (MPA), a structural analog to meth-AMPH, produces locomotor sensitization, it was examined in the present study whether this behavioral change also accompanies with structural plasticity in the NAcc in a similar way to AMPH. A week after adeno-associated viral vectors containing enhanced green fluorescent protein (eGFP) were microinjected into the NAcc core, rats were repeatedly injected with saline, AMPH (1 mg/kg, IP), or MPA (5 mg/kg, IP) once every 2-3 days for a total of 4 times. Two weeks after last injection, all rats were perfused and their brains were processed for immunohistochemical staining. The image stacks for dendrite segments of medium spiny neuronal cells in the NAcc core were obtained and dendritic spines were quantitatively analyzed. Interestingly, it was found that the number of total spine density, with thin spine as a major contributor, was significantly increased in MPA compared to saline pre-exposed group, in a similar way to AMPH. These results indicate that MPA, a novel psychoactive substance, has similar characteristics with AMPH in that they both produce structural as well as behavioral changes, further supporting MPA's dependence and abuse potential.

Simultaneous wireless and high-resolution detection of nucleus accumbens shell ethanol concentrations and free motion of rats upon voluntary ethanol intake.

Highly sensitive detection of ethanol concentrations in discrete brain regions of rats voluntarily accessing ethanol, with high temporal resolution, would represent a source of greatly desirable data in studies devoted to understanding the kinetics of the neurobiological basis of ethanol's ability to impact behavior. In the present study, we present a series of experiments aiming to validate and apply an original high-tech implantable device, consisting of the coupling, for the first time, of an amperometric biosensor for brain ethanol detection, with a sensor for detecting the microvibrations of the animal. This device allows the real-time comparison between the ethanol intake, its cerebral concentrations, and their effect on the motion when the animal is in the condition of voluntary drinking. To this end, we assessed in vitro the efficiency of three different biosensor designs loading diverse alcohol oxidase enzymes (AOx) obtained from three different AOx-donor strains: Hansenula polymorpha, Candida boidinii, and Pichia pastoris. In vitro data disclosed that the devices loading H. polymorpha and C. boidinii were similarly efficient (respectively, linear region slope [LRS]: 1.98 ± 0.07 and 1.38 ± 0.04 nA/mM) but significantly less than the P. pastoris-loaded one (LRS: 7.57 ± 0.12 nA/mM). The in vivo results indicate that this last biosensor design detected the rise of ethanol in the nucleus accumbens shell (AcbSh) after 15 minutes of voluntary 10% ethanol solution intake. At the same time, the microvibration sensor detected a significant increase in the rat's motion signal. Notably, both the biosensor and microvibration sensor described similar and parallel time-dependent U-shaped curves, thus providing a highly sensitive and time-locked high-resolution detection of the neurochemical and behavioral kinetics upon voluntary ethanol intake. The results overall indicate that such a dual telemetry unit represents a powerful device which, implanted in different brain areas, may boost further investigations on the neurobiological mechanisms that underlie ethanol-induced motor activity and reward.

Expression and localization of CB1R, NAPE-PLD, and FAAH in the vervet monkey nucleus accumbens.

Extensive rodent literature suggests that the endocannabinoid (eCB) system present in the nucleus accumbens (NAc) modulates dopamine (DA) release in this area. However, expression patterns of the cannabinoid receptor type 1 (CB1R), the synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), and the degradation enzyme fatty acid amide hydrolase (FAAH) in the NAc have not yet been described in non-human primates. The goal of this study is therefore to characterize the expression and localization of the eCB system within the NAc of vervet monkeys (Chlorocebus sabaeus) using Western blots and immunohistochemistry. Results show that CB1R, NAPE-PLD, and FAAH are expressed across the NAc rostrocaudal axis, both in the core and shell. CB1R, NAPE-PLD, and FAAH are localized in medium spiny neurons (MSNs) and fast-spiking GABAergic interneurons (FSIs). Dopaminergic projections and astrocytes did not express CB1R, NAPE-PLD, or FAAH. These data show that the eCB system is present in the vervet monkey NAc and supports its role in the primate brain reward circuit.

Adolescent isolation rearing produces a prepulse inhibition deficit correlated with expression of the NMDA GluN1 subunit in the nucleus accumbens.

Adolescence is a transition period during which social interaction is necessary for normal brain and behavior development. Severely abnormal social interactions during adolescence can increase the incidence of lifelong psychiatric disease. Decreased prepulse inhibition (PPI) is a quantifiable hallmark of some psychiatric illnesses in humans and can be elicited in rodents by isolation rearing throughout the adolescent transition period. PPI is a measure of sensorimotor gating in which the nucleus accumbens (Acb) is crucially involved. The Acb is comprised of core and shell subregions, which receive convergent dopaminergic and glutamatergic inputs. To gain insight into the neurobiological correlates of adolescent adversity, we conducted electron microscopic immunolabeling of dopamine D1 receptors (D1Rs) and the GluN1 subunit of glutamate NMDA receptors in the Acb of isolation-reared (IR) adult male rats. In all animals, GluN1 was primarily located in dendritic profiles, many of which also contained D1Rs. GluN1 was also observed in perisynaptic glia and axon terminals. In IR rats compared with group-reared controls, GluN1 density was selectively decreased in D1R-containing dendrites of the Acb core. Across all animals, dendritic GluN1 density correlated with average percent PPI, implicating endogenous expression of NMDA receptors of the Acb as a possible substrate of the PPI response. These results suggest that adolescent isolation dampens NMDA-mediated excitation in direct (D1R-containing) output neurons of the Acb, and that these changes influence the operational measure of PPI.

Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking.

Dysfunction of N-methyl-d-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng-/- mice). We used adeno-associated virus (AAV)-mediated Ng expression and pharmacological manipulation to validate behavioral responses in Ng-/- mice. The results from our multidisciplinary approaches demonstrated that deficit of Ng increases tolerance to NMDAR inhibition and elicit faster cue reactivity during PIT without changes in ethanol reward. Operant conditioning results demonstrated that Ng-/- mice self-administered significantly more ethanol and displayed reduced sensitivity to aversive motivation. We identified that ethanol exposure decreases mGluR5 (metabotropic glutamate receptor 5) expression in the NAc of Ng-/- mice and pharmacological inhibition of mGluR5 reverses NMDAR desensitization in Ng-/- mice. Together these findings specifically suggest that accumbal Ng plays an essential role in the counterbalance between NMDAR and mGluR5 signaling; which alters NMDAR resistance, and thereby altering aversive motivation for ethanol and may ultimately contribute to susceptibility for alcohol addiction.

α1b-Adrenergic Receptor Localization and Relationship to the D1-Dopamine Receptor in the Rat Nucleus Accumbens.

The α1-adrenergic receptors (α1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the α1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the α1b-adrenergic receptor (α1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, α1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the α1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co-expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the α1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously.

Dopaminergic responses in the core part of the nucleus accumbens to subcutaneous MK801 administration are increased following postnatal transient blockade of the prefrontal cortex.

Schizophrenia is a complex and devastating neuropsychiatric disease thought to result from impaired connectivity between several integrative regions, stemming from developmental failures. In particular, the left prefrontal cortex of schizophrenia patients seems to be targeted by such early developmental disturbances. Data obtained over the last three decades support the hypothesis of a dopaminergic dysfunction in schizophrenia. Striatal dopaminergic dysregulation in schizophrenia may result from a dysconnection between the prefrontal cortex and the striatum (dorsal and ventral) involving glutamatergic N-methyl-d-aspartate (NMDA) receptors. In the context of animal modeling of the pathophysiology of schizophrenia, the present study was designed to investigate the effects of MK 801 (dizocilpine) on locomotor activity and dopaminergic responses in the left core part of the nucleus accumbens (ventral striatum) in adult rats following neonatal tetrodotoxin inactivation of the left prefrontal cortex (infralimbic/prelimbic region) at postnatal day 8. Dopaminergic variations were recorded in the nucleus accumbens by means of in vivo voltammetry in freely moving adult animals. Following MK 801 administration, and in comparison to control (PBS) animals, animals microinjected with tetrodotoxin display locomotor hyperactivity and increased extracellular dopamine levels in the core part of the nucleus accumbens. These findings suggest neonatal functional inactivation of the prefrontal cortex may lead to a dysregulation of dopamine release in the core part of the nucleus accumbens involving NMDA receptors. The results obtained may provide new insight into the involvement of NMDA receptors in the pathophysiology of schizophrenia and suggest that future studies should look carefully at the core of the nucleus accumbens.

Axonal Type III Nrg1 Controls Glutamate Synapse Formation and GluA2 Trafficking in Hippocampal-Accumbens Connections.

Altered neuregulin 1 (Nrg1)/ErbB signaling and glutamatergic hypofunction have been implicated in the pathophysiology of schizophrenia. Here, we employed gene chimeric ventral hippocampus (vHipp)-nucleus accumbens (nAcc) coculture from mouse, electrophysiology, immunocytochemistry, FM1-43 vesicle fusion, and electron microscopy techniques to examine the pre- and postsynaptic mechanisms of genetic deficits in Nrg1/ErbB signaling-induced glutamatergic dysfunctions. Reduced presynaptic type III Nrg1 expression along vHipp axons decreases the number of glutamate synapses and impairs GluA2 trafficking in the postsynaptic nAcc neurons, resulting in decreased frequency and amplitude of miniature EPSCs (mEPSCs). Reduced expression of axonal type III Nrg1 along vHipp projections also decreases functional synaptic vesicle (SV) clustering and vesicular trafficking to presynaptic vHipp axonal terminals. These findings suggest that Nrg1/ErbB signaling modulate glutamatergic transmission via both pre- and postsynaptic mechanisms.

Loss of estrogen-related receptor alpha disrupts ventral-striatal synaptic function in female mice.

Eating disorders (EDs), including anorexia nervosa, bulimia nervosa and binge-ED, are mental illnesses characterized by high morbidity and mortality. While several studies have identified neural deficits in patients with EDs, the cellular and molecular basis of the underlying dysfunction has remained poorly understood. We previously identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA) associated with development of EDs. Because ventral-striatal signaling is related to the reward and motivation circuitry thought to underlie EDs, we performed functional and structural analysis of ventral-striatal synapses in Esrra-null mice. Esrra-null female, but not male, mice exhibit altered miniature excitatory postsynaptic currents on medium spiny neurons (MSNs) in the ventral striatum, including increased frequency, increased amplitude, and decreased paired pulse ratio. These electrophysiological measures are associated with structural and molecular changes in synapses of MSNs in the ventral striatum, including fewer pre-synaptic glutamatergic vesicles and enhanced GluR1 function. Neuronal Esrra is thus required for maintaining normal synaptic function in the ventral striatum, which may offer mechanistic insights into the behavioral deficits observed in Esrra-null mice.

VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons.

The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens glutamatergic pathway remains unknown. Here we report that nAcc photoactivation of mesoaccumbens glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens glutamatergic fibers lack GABA, the aversion evoked by their photoactivation depended on glutamate- and GABA-receptor signaling, and not on dopamine-receptor signaling. We found that mesoaccumbens glutamatergic fibers established multiple asymmetric synapses on single parvalbumin GABAergic interneurons and that nAcc photoactivation of these fibers drove AMPA-mediated cellular firing of parvalbumin GABAergic interneurons. These parvalbumin GABAergic interneurons in turn inhibited nAcc medium spiny output neurons, thereby controlling inhibitory neurotransmission in nAcc. To our knowledge, the mesoaccumbens glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin GABAergic interneurons.

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study.

The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.

Effects of ethanol exposure and withdrawal on dendritic morphology and spine density in the nucleus accumbens core and shell.

Exposure to drugs of abuse can result in profound structural modifications on neurons in circuits involved in addiction that may contribute to drug dependence, withdrawal and related processes. Structural alterations on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) have been observed following exposure to and withdrawal from a variety of drugs; however, relatively little is known about the effects of alcohol exposure and withdrawal on structural alterations of NAc MSNs. In the present study male rats were chronically exposed to vaporized ethanol for 10 days and underwent 1 or 7 days of withdrawal after which the brains were processed for Golgi-Cox staining and analysis of dendritic length, branching and spine density. MSNs of the NAc shell and core underwent different patterns of changes following ethanol exposure and withdrawal. At 1 day of withdrawal there were modest reductions in the dendritic length and branching of MSNs in both the core and the shell compared to control animals exposed only to air. At 7 days of withdrawal the length and branching of shell MSNs was reduced, whereas the length and branching of core MSNs were increased relative to the shell. The density of mature spines was increased in the core at 1 day of withdrawal, whereas the density of less mature spines was increased in both regions at 7 days of withdrawal. Collectively, these observations indicate that MSNs of the NAc core and shell undergo distinct patterns of structural modifications following ethanol exposure and withdrawal suggesting that modifications in dendritic structure in these regions may contribute differentially to ethanol withdrawal.

Effects of thienorphine on synaptic structure and synaptophysin expression in the rat nucleus accumbens.

The partial opioid agonist thienorphine is currently in Phase II clinical trials in China as a candidate drug for the treatment of opioid dependence. However, its effect on synaptic plasticity in the NAc (nucleus accumbens) remains unclear. In the present study, we measured structural parameters of the synaptic interface to investigate the effect of thienorphine, morphine or a combination of both on synaptic morphology in the NAc of rats. Expression of synaptophysin was also examined. Ultrastructural observation showed that synaptic alterations were less pronounced after chronic thienorphine administration than after chronic morphine administration. Animals that received thienorphine had thinner postsynaptic densities and shorter active zones in the NAc compared with those in the saline group, but the active zone was larger, and the cleft narrower, than those in the morphine group. Furthermore, synaptophysin expression in the NAc was significantly greater after chronic administration of thienorphine, morphine, or both, than after saline. These results identified interesting differences between thienorphine and morphine in their effects on synaptic structure and synaptophysin expression in the rat NAc. Further study is deserved to investigate thienorphine as a new treatment for opioid dependence.

Ultrastructural localization of tyrosine hydroxylase in tree shrew nucleus accumbens core and shell.

Many behavioral, physiological, and anatomical studies utilize animal models to investigate human striatal pathologies. Although commonly used, rodent striatum may not present the optimal animal model for certain studies due to a lesser morphological complexity than that of non-human primates, which are increasingly restricted in research. As an alternative, the tree shrew could provide a beneficial animal model for studies of the striatum. The gross morphology of the tree shrew striatum resembles that of primates, with separation of the caudate and putamen by the internal capsule. The neurochemical anatomy of the ventral striatum, specifically the nucleus accumbens, has never been examined. This major region of the limbic system plays a role in normal physiological functioning and is also an area of interest for human striatal disorders. The current study uses immunohistochemistry of calbindin and tyrosine hydroxylase (TH) to determine the ultrastructural organization of the nucleus accumbens core and shell of the tree shrew (Tupaia glis belangeri). Stereology was used to quantify the ultrastructural localization of TH, which displays weaker immunoreactivity in the core and denser immunoreactivity in the shell. In both regions, synapses with TH-immunoreactive axon terminals were primarily symmetric and showed no preference for targeting dendrites versus dendritic spines. The results were compared to previous ultrastructural studies of TH and dopamine in rat and monkey nucleus accumbens. Tree shrews and monkeys show no preference for the postsynaptic target in the shell, in contrast to rats which show a preference for synapsing with dendrites. Tree shrews have a ratio of asymmetric to symmetric synapses formed by TH-immunoreactive terminals that is intermediate between rats and monkeys. The findings from this study support the tree shrew as an alternative model for studies of human striatal pathologies.

A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem.

Cholinergic transmission in the striatal complex is critical for the modulation of the activity of local microcircuits and dopamine release. Release of acetylcholine has been considered to originate exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre(+) transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.

Microstructural changes of the nucleus accumbens due to increase of estradiol level during menstrual cycle contribute to recurrent manic episodes--a single case study.

We examined a rapid-cycling bipolar disorder patient who demonstrated manic episode regularly at around day 7 of the menstrual cycle. We hypothesize that gonadal hormones may induce a state-dependent change in cerebral microstructure and function. Following this hypothesis, the serum levels of estradiol and progesterone were analyzed and diffusion tensor imaging data were examined between the manic and euthymic states of the patient. Estradiol levels increased in the late follicular phase at manic state when compared to the luteal or early follicular phase at euthymic state. DTI results showed that the patient had increased fractional anisotropy values at manic state in the bilateral nucleus accumbens (NAc) and its connected areas, which is a major projection field of the mesolimbic dopamine (DA) system, perhaps reflecting microstructural changes due to neuronal activation related to manic episodes. According to these results, we consider that the mesolimbic DA system of this patient has hypersensitivity to estradiol, and elevation of the estradiol level increases the activity of the dopaminergic system, which in turn may contribute to recurrent manic episodes. Our findings provide a clue for understanding how fluctuations in gonadal hormone may amplify or ameliorate the symptomatology of psychiatric disorders related to the menstrual cycle.

Reduced D-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity.

Cocaine seeking behaviour and relapse have been linked to impaired potentiation and depression at excitatory synapses in the nucleus accumbens, but the mechanism underlying this process is poorly understood. We show that, in the rat nucleus accumbens core, D-serine is the endogenous coagonist of N-methyl-D-aspartate receptors, and its presence is essential for N-methyl-D-aspartate receptor-dependent potentiation and depression of synaptic transmission. Nucleus accumbens core slices obtained from cocaine-treated rats after 1 day of abstinence presented significantly reduced D-serine concentrations, increased expression of the D-serine degrading enzyme, D-amino acid oxidase, and downregulated expression of serine racemase, the enzyme responsible for D-serine synthesis. The D-serine deficit was associated with impairment of potentiation and depression of glutamatergic synaptic transmission, which was restored by slice perfusion with exogenous D-serine. Furthermore, in vivo administration of D-serine directly into the nucleus accumbens core blocked behavioural sensitization to cocaine. These results provide evidence for a critical role of D-serine signalling in synaptic plasticity relevant to cocaine addiction.

The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens.

Benztropine (BZT) analogs, a family of agents with high affinity for the dopamine transporter have been postulated as potential treatments in stimulant abuse due to their ability to attenuate a wide range of effects evoked by psychomotor stimulants such as cocaine and amphetamine (AMPH). Repeating administration of drugs, including stimulants, can result in behavioral sensitization, a progressive increase in their psychomotor activating effects. We examined in mice the sensitizing effects and the neuroplasticity changes elicited by chronic AMPH exposure, and the modulation of these effects by the BZT derivative and atypical dopamine uptake inhibitor, JHW007, a candidate medication for stimulant abuse. The results indicated that JHW007 did not produce sensitized locomotor activity when given alone but prevented the sensitized motor behavior induced by chronic AMPH administration. Morphological analysis of medium spiny neurons of the nucleus accumbens revealed that JHW 007 prevented the neuroadaptations induced by chronic AMPH exposure, including increments in dendritic arborization, lengthening of dendritic processes and increases in spine density. Furthermore, data revealed that AMPH produced an increase in the density of asymmetric, possibly glutamatergic synapses in the nucleus accumbens, an effect that was also blocked by JHW007 pretreatment. The present observations demonstrate that JHW007 is able to prevent not only AMPH-induced behavioral sensitization but also the long-term structural changes induced by chronic AMPH in the nucleus accumbens. Such findings support the development and evaluation of BZT derivatives as possible leads for treatment in stimulant addiction.

Direct and indirect interactions of the dopamine D3 receptor with glutamate pathways: implications for the treatment of schizophrenia.

This article, based on original data as well as on previously reported preclinical and clinical data that are reviewed, describes direct and indirect interactions of the D(3) receptor with N-methyl-D-aspartate receptor (NMDA) signaling and their functional consequences and therapeutic implications for schizophrenia. D(3) receptor immunoreactivity at ultrastructural level with electron microscopy was identified at presumably glutamatergic, asymmetric synapses of the medium-sized spiny neurons of the nucleus accumbens. This finding supports the existence of a direct interaction of the D(3) receptor with glutamate, in line with previously described interactions with NMDA signaling involving Ca(2+)/calmodulin-dependent protein kinase II at post-synaptic densities (Liu et al. 2009). Indirect interactions of the D(3) receptor with glutamate could involve a negative control exerted by the D(3) receptor on mesocortical dopamine neurons and the complex regulation of the glutamatergic pyramidal cells by dopamine in the prefrontal cortex. This could be exemplified here by the regulation of pyramidal cell activity in conditions of chronic NMDA receptor blockade with dizocilpine (MK-801). BP897, a D(3) receptor-selective partial agonist, reversed the dysregulation of cortical c-fos mRNA expression and pyramidal cell hyperexcitability, as measured by paired-pulse electrophysiology. At the behavioral level, blockade of the D(3) receptor, by known D(3) receptor antagonists or the novel D(3) receptor-selective antagonist F17141, produces antipsychotic-like effects in reversing hyperactivity and social interaction deficits induced by NMDA receptor blockade by MK-801 in mice. The glutamate-D(3) receptor interactions described here offer a conceptual framework for developing new D(3) receptor-selective drugs, which may appear as an original, efficacious, and safe way to potentially indirectly target glutamate in schizophrenia.