Accumbens Shell Region Research Articles

Continuous deep brain stimulation of the nucleus accumbens reduces food intake but does not affect body weight in mice fed a high-fat diet

Obesity is an enormous health problem, and many patients do not respond to any of the available therapies. Deep brain stimulation (DBS) is currently investigated as a potential treatment for morbid obesity. In this study, we tested the hypothesis that high-frequency DBS targeting the nucleus accumbens (NAc) shell region reduces food intake and weight gain in mice fed a high-fat diet. We implanted male C57BL/6J mice with bilateral electrodes and a head-mounted microstimulator enabling continuous stimulation for up to 5 weeks. In successfully operated animals (n = 9 per group, high-frequency vs. sham stimulation), we investigated immediate and long-term stimulation effects on metabolic and behavioral phenotypes. Here we show that stimulation acutely induced a transient reduction in energy expenditure and locomotor activity but did not significantly affect spontaneous food intake, social interaction, anxiety or exploratory behaviors. In contrast, continuous stimulation over 5 weeks led to a decrease in food intake and thigmotaxis (the tendency to stay near walls in an open lit arena). However, chronic stimulation did not substantially change weight gain in mice fed a high-fat diet. Our results do not support the use of continuous high-frequency NAc shell DBS as a treatment for obesity. However, DBS can alter obesity-related parameters with differing short and long-term effects. Therefore, future research should employ time and context-sensitive experimental designs to assess the potential of DBS for clinical translation in this area.

IPAC integrates rewarding and environmental memory during the acquisition of morphine CPP.

The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain unclear. Here, we showed that the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) integrated rewarding and environmental memory information by two different receiving projections from ventral tegmental area (VTA) and nucleus accumbens shell region (NAcSh) to mediate the acquisition of morphine conditioned place preference (CPP). A projection from the VTA GABAergic neurons (VTAGABA) to the IPAC lateral region GABAergic neurons (IPACLGABA) mediated the effect of morphine rewarding, whereas the pathway from NAcSh dopamine receptor 1-expressing neurons (NAcShD1) to the IPAC medial region GABAergic neurons (IPACMGABA) was involved in the acquisition of environmental memory. These findings demonstrated that the distinct IPAC circuits VTAGABA→IPACLGABA and NAcShD1R→IPACMGABA were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.

Cross-tolerance between nitric oxide synthase inhibition and atypical antipsychotics modify nicotinamide-adenine-dinucleotide phosphate-diaphorase activity in mouse lateral striatum.

Previous research indicates that the subchronic administration of NG-nitro-L-arginine (L-NOARG) produces tolerance to haloperidol-induced catalepsy in Swiss mice. The present study aimed to further investigate whether intermittent subchronic systemic administration of L-NOARG induces tolerance to the cataleptic effects of haloperidol as well as olanzapine or clozapine (Clz) in C57Bl mice after subchronic administration for 5 consecutive days. Striatal FosB protein expression was measured in an attempt to gain further insights into striatal mechanisms in antipsychotic-induced extrapyramidal symptoms side effects. An nicotinamide-adenine-dinucleotide phosphate-diaphorase histochemical reaction was also used to investigate whether tolerance could induce changes in the number of nitric oxide synthase-active neurons. Subchronic administration of all antipsychotics produced catalepsy, but cross-tolerance was observed only between L-NOARG (15 mg/kg, intraperitoneally) and Clz (20 mg/kg, intraperitoneally). This cross-tolerance effect was accompanied by decreased FosB protein expression in the dorsal striatum and the nucleus accumbens shell region, and reduced icotinamide-adenine-dinucleotide phosphate-diaphorase activity in the dorsal and ventral lateral striatum. Overall, these results suggest that interference with the formation of nitric oxide, mainly in the dorsal and ventral lateral-striatal regions, appears to improve the cataleptic effects induced by antipsychotics acting as antagonists of low-affinity dopamine D2 receptor, such as Clz.

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats.

Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that "long thin" but not "mushroom" spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence, suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal and thus the whole addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence.

The effect of repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in freely moving rats

Evidence exists that modulation of neuronal activity in nucleus accumbens shell region may re-establish normal function in various neuropsychiatric conditions such as drug-withdrawal, obsessive–compulsive disorder, depression and chronic pain. Here, we study the effects of acute repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in awake and freely moving rats using in vivo microdialysis. To scale the biochemical results to the induced electric field in the rat brain, we obtained a realistic simulation of the stimulation scenario using a finite element model. Applying 20 Hz repetitive transcranial magnetic stimulation in 6 trains of 50 stimuli with 280 μs pulse width at a magnetic field strength of 130% of the individual motor threshold, dopamine as well as serotonin outflow in the nucleus accumbens shell significantly increased compared to sham stimulation. Since the electric field decays rapidly with depth in the rat brain, we can conclude that the modulation in neurotransmitter outflow from the nucleus accumbens shell is presumably a remote effect of cortical stimulation.

Descending projections from the nucleus accumbens shell suppress activity of taste-responsive neurons in the hamster parabrachial nuclei

The parabrachial nuclei (PbN), the second central relay for the gustatory pathway, transfers taste information to various forebrain gustatory nuclei and to the gustatory cortex. The nucleus accumbens is one of the critical neural substrates of the reward system, and the nucleus accumbens shell region (NAcSh) is associated with feeding behavior. Taste-evoked neuronal responses of PbN neurons are modulated by descending projections from the gustatory nuclei in the forebrain. In the present study, we investigated whether taste-responsive neurons in the PbN project to the NAcSh and whether pontine gustatory neurons are subject to modulatory influence from the NAcSh in urethane-anesthetized hamsters. Extracellular single-unit activity was recorded in the PbN, and taste responses were confirmed by the delivery of 32 mM sucrose, NaCl, quinine hydrochloride, and 3.2 mM citric acid to the anterior tongue. The NAcSh was then stimulated (0.5 ms, ≤100 μA) bilaterally using concentric bipolar stimulating electrodes. A total of 98 taste neurons were recorded from the PbN. Eighteen neurons were antidromically invaded from the NAcSh, mostly the ipsilateral NAcSh (n = 16). Stimulation of the ipsilateral and contralateral NAcSh suppressed the neuronal activity of 88 and 55 neurons, respectively; 52 cells were affected bilaterally. In a subset of pontine neurons tested, electrical stimulation of the NAcSh during taste stimulation also suppressed taste-evoked neuronal firing. These results demonstrated that taste-responsive neurons in the PbN not only project to the NAcSh but also are under substantial descending inhibitory influence from the bilateral NAcSh.

Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation

The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ∼175–350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ∼135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0–3mg/kg) alone did not affect monoamine release, it dose-dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine.

Dietary conditions and highly palatable food access alter rat cannabinoid receptor expression and binding density

Endogenous cannabinoid signaling, mediated predominately by CB1 receptor activation, is involved in food intake control and body weight regulation. Despite advances in determining the role of the CB1 receptor in obesity, its involvement in the driven nature of eating pathologies has received little attention. The present study examined CB1 receptor alterations as a consequence of dietary-induced binge eating in female Sprague Dawley rats. Four control groups were used to control for calorie restriction and highly palatable food variables characterizing this behavioral model. All groups were kept on their respective feeding schedules for 6-weeks and were given a uniform 33% calorie restriction (~22h food deprivation) prior to sacrifice. Our findings indicate that regional CB1 mRNA and density were influenced by dietary conditions, but were not specific to the dietary-induced binge eating paradigm used. An increase of approximately 50% (compared with naive controls) in CB1 receptor mRNA levels in the nucleus of the solitary tract as measured by in situ hybridization was found in animals receiving continuous access to a highly palatable food (i.e., vegetable shortening with 10% sucrose). This group also had a significant increase in body weight and adiposity. An approximate 20% reduction in CB1 mRNA was observed in the cingulate cortex (areas 1 and 2) in animals exposed to an intermittent schedule of feeding, compared with groups that had ad libitum feeding schedules (i.e., continuous access and naive controls). Receptor density as measured by [3H]CP55,940 autoradiography, was reduced by approximately 30% in the nucleus accumbens shell region in groups receiving repeated access to the highly palatable food. Taken together, these findings indicate that dietary conditions can differentially influence CB1 receptors in forebrain and hindbrain regions.

μ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice.

Acute challenges with psychostimulants such as amphetamine affect impulsive behavior in both animals and humans. With regard to amphetamine, it is important to unravel how this drug affects impulsivity since it is not only a widely abused recreational drug but also regularly prescribed to ameliorate maladaptive impulsivity. Therefore, we studied the effects of amphetamine in two rat models of impulsivity, the five-choice serial reaction time task and the delayed-reward task, providing measures of inhibitory control and impulsive choice, respectively. We focused on the role of opioid receptor activation in amphetamine-induced impulsivity as there is ample evidence indicating an important role for endogenous opioids in several behavioral and neurochemical effects of amphetamine. Results showed that amphetamine-induced inhibitory control deficits were dose-dependently attenuated by the preferential μ-opioid receptor antagonist naloxone, but not by the selective δ-opioid receptor antagonist naltrindole or κ-opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). In contrast, naloxone did not affect amphetamine-induced improvements in impulsive decision making. Naloxone also completely prevented inhibitory control deficits induced by GBR 12909 [1-(2-[bis(4-fluorophenyl)methoxy] ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a selective dopamine transporter inhibitor. Intracranial infusions of naloxone, the selective μ-opioid receptor antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)), morphine, and the selective μ-opioid receptor agonist DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin acetate salt) revealed that μ-opioid receptor activation in the shell rather than the core subregion of the nucleus accumbens (NAc) modulates inhibitory control and subserves the effect of amphetamine thereon. Together, these results indicate an important role for NAc shell μ-opioid receptors in the regulation of inhibitory control, probably via an interaction between these receptors and the mesolimbic dopamine system.

Regional specificity in dopamine signaling during reward‐related learning (Commentary on Aragona et al.)

Dopamine transmission is known to play a critical role in associative learning about environmental stimuli linked to natural or drug rewards. Much of our understanding of how the dopamine system contributes to learning comes from studies analyzing changes in midbrain dopamine neuron activity occurring while animals learn to associate predictive cues with food rewards. Dopamine neurons initially respond with brief phasic bursts of activity in response to primary rewards, but over training, control of this phasic activity transfers to conditioned stimuli that are predictive of these rewards (Schultz, 1998, 2007). These bursts of activity in dopamine neurons are thought to represent a fundamental form of communication in this system (Floresco, 2007; Grace et al., 2007). Despite these findings, it remains as of yet unclear how these patterns of midbrain dopamine neural activity translate into transmitter release in forebrain terminal regions. Do phasic dopamine bursts, triggered by reward-related stimuli, result in corresponding increases in dopamine release? Are these changes uniform across different terminal regions? Moreover, do changes in dopamine signaling that occur during learning natural rewards, such as food, also occur during learning about drug rewards (e.g. cocaine), which cause unconditioned increases in dopamine release? In this issue of EJN, Aragona et al. (2009) investigated these questions by employing fast-scan cyclic voltametry to monitor real-time (sub-second) changes in dopamine release in two adjacent regions of the ventral striatum, the nucleus accumbens core and shell. Each of these regions receives dense dopaminergic innervation from midbrain dopamine neurons, and can be distinguished based on efferent and afferent connectivity and their functional contributions to reward-related behaviors (Zahm & Brog, 1992; Brog et al., 1993; Corbit et al., 2001; Ito et al., 2004). In this study, rats were subjected to a Pavlovian conditioning procedure, whereby over one session, they learned to associate the presentation of a discrete light and tone stimulus with intravenous delivery of cocaine. During the early phases of learning (i.e. the first few conditioning trials), presentation of the cue did not induce any reliable change in dopamine release. However, after about ten trials, the dopamine signal in the accumbens core appeared to ‘learn’ the predictive nature of the conditioned stimulus. Presentation of the drug-associated cue yielded a rapid and robust increase in dopamine release, in a manner similar to that displayed by the activity of midbrain dopamine neurons during similar learning about food rewards. What is particularly striking about these data is the fact that this effect was not observed in the adjacent nucleus accumbens shell region. Instead, repeated presentation of the cocaine-associated stimulus eventually resulted in cue-induced decreases in dopamine efflux, followed by an increase in release that corresponded to the pharmacological time course of cocaine effects. Similar phasic decreases in dopamine release were also observed in a separate experiment, where subjects were trained to associate a cue with a sucrose reward, suggesting that these effects could not be attributed to conditioned aversive properties of the cocaine infusions. These findings highlight the complexity of the dopamine system with respect to how rapid fluctuations in release contribute to associative learning about natural and drug rewards. Instead of showing similar changes in activity across terminal regions, dopamine signaling actually shows distinct regional specificity in terms of how it responds to reward-related stimuli. Phasic dopamine transmission within the accumbens core may serve as an incentive signal during early acquisition and subsequent maintenance of learned association with both food and drug rewards. Conversely, dynamic changes in dopamine signaling in the shell may be related to unconditioned rewarding properties of drugs of abuse. Perhaps the greatest impact of this study is that it suggests that a ‘grand unified theory’ of dopamine function may not be the most appropriate manner in which to view this neurotransmitter. Instead, dopamine transmission in different brain regions may require different theories to best explain its function.

Fluoxetine inhibits corticotropin-releasing factor (CRF)-induced behavioural responses in rats

Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 μg, intracerebroventricular (i.c.v.)) or vehicle was infused in the presence or absence of the selective serotonin re-uptake inhibitor fluoxetine (0, 0.1, 1 or 10 mg/kg, intravenous (i.v.)). Fluoxetine was used at these doses because it is known to decrease serotonin cell firing rates while increasing extracellular serotonin concentrations in select forebrain regions. We then measured behavioural, neurochemical and endocrine responses. CRF increased locomotion and spontaneous non-ambulatory motor activity (SNAMA) in the home cages. Fluoxetine decreased tissue 5-hydroxyindoleacetic acid concentrations, a measure of serotonin metabolism, in specific limbic brain regions of CRF-treated rats (nucleus accumbens shell region, entorhinal cortex, central nucleus of the amygdala). Furthermore, fluoxetine inhibited CRF-induced SNAMA. CRF and fluoxetine independently increased plasma corticosterone concentrations, but the responses had distinct temporal profiles. Overall, these data are consistent with the hypothesis that CRF-induced facilitation of behavioural activity is dependent on brainstem serotonergic systems. Therefore, fluoxetine may attenuate or alleviate some behavioural responses to stress by interfering with CRF-induced responses.

Roles of hippocampal NMDA receptors and nucleus accumbens D1 receptors in the amphetamine-produced conditioned place preference in rats

There are glutamatergic projections from the hippocampus to the nucleus accumbens (NAc), which regulate DA transmission in this structure. To be precise, the ventral hippocampal (VH) glutamatergic neurons project to the nucleus accumbens shell region (NAcSh), whereas the dorsal hippocampus (DH) sends glutamatergic projections to the nucleus accumbens core region (NAcC). This study investigates the roles of hippocampal N-methyl- d-aspartate (NMDA) glutamate receptors and NAc type 1 dopamine receptor (D1) in amphetamine-produced conditioned place preference (AMPH-CPP) in rats. Our earlier reports showed that AMPH-CPP results in the enhancement of hippocampal CaMKII activity and it can be impaired by NMDA antagonist (AP5). In this study AMPH-CPP did not alter the NAc CaMKII activity, although AMPH-CPP was impaired by a blockade of D1 receptors (SCH23390) during conditioning. Moreover, inactivation of hippocampal area (dorsal hippocampus or ventral hippocampus) impaired AMPH-CPP, but its effect was diminished by the activation of D1 receptors in accumbal region (NAc core or NAc shell). By inactivating both DH and NAc core resulted in the disruption of rat’s CPP expression. However, the impaired CPP expression was recovered during the next testing session, suggesting the disruption of CPP expression was a short term effect. Moreover, the disruption of CPP expression was not exhibited if NAc core was not inactivated. Interestingly, the rats that received activation in VH but an inactivation in NAc shell before testing show impaired CPP expression compared to those received inactivation in both VH and NAc shell. DH activation plus an inactivation in NAc core before testing show a significantly higher rate of the weakening of AMPH-CPP expression. Similarly, an activation of VH plus an inactivation of NAc shell before testing also show a statistically significant lower CPP score on tests 3 and 4. These results, taken together, indicate that NMDA receptor activation in DH and VH have different enhancing effects on the AMPH-CPP as their innervations onto the different NAc regions are essential for AMPH-CPP establishment. If the deterioration of AMPH-CPP expression (or extinction process) resembles the formation of new learning, then this active process might have been facilitated by the hippocampal NMDA receptor activations during testing.

Dopamine D2-Like Receptor in the Nucleus Accumbens Is Involved in the Antinociceptive Effect of Nitrous Oxide

The mechanism of the antinociceptive effects of nitrous oxide (N(2)O) has not been completely elucidated. On the other hand, numerous studies have indicated that mesolimbic dopaminergic neurons, which are thought to be involved in rewarding and reinforcement processes, play important roles in the supraspinal pain-suppression system. We hypothesized that the mesolimbic dopaminergic system is involved in the antinociceptive effect of N(2)O. Adult male Fischer rats were used in this study. To examine whether the dopaminergic system is activated by N(2)O, frozen sections of the ventral tegmental area of rats exposed to 75% N(2)O were double-stained for c-Fos and tyrosine hydroxylase. To clarify whether the dopaminergic system is involved in the antinociceptive action of N(2)O, saline or raclopride, a dopamine D(2)-like receptor antagonist, was injected into the nucleus accumbens (NAc) shell region. After exposure to 25% oxygen-75% nitrogen or 25% oxygen-75% N(2)O for 30 min, rats were subjected to formalin test, and the spinal cord was examined immunohistochemically. Exposure to 75% N(2)O increased c-Fos expression in tyrosine hydroxylase-positive cells in the ventral tegmental area. Raclopride, injected into the NAc shell region, attenuated the antinociceptive effect of N(2)O in the formalin test, and blocked the suppressive effect of N(2)O on the formalin-induced c-Fos expression in the dorsal horn of the spinal cord by N(2)O. It is possible that inhalation of N(2)O activates mesolimbic dopaminergic neurons, and that the antinociceptive effect of N(2)O is at least partially mediated by dopamine D(2)-like receptors in the NAc shell region.

Acute ethanol induces Fos in GABAergic and non-GABAergic forebrain neurons: A double-labeling study in the medial prefrontal cortex and extended amygdala

The purpose of this study was to further address the hypothesis that ethanol activates GABAergic neurons in specific brain neurocircuits that mediate motivated behavior and control of action, such as the central extended amygdala and medial prefrontal cortex. Male Sprague–Dawley rats received habituation to 7 days of daily intragastric administration of water (5 ml/kg) followed by a single acute intragastric dose of ethanol (2.5 g/kg) or water then, 2 h later, by paraformaldehyde perfusion. Rats left undisturbed in the animal room throughout the experiment were also perfused (naive group). Brain sections were processed for single Fos immunohistochemistry or dual Fos immunohistochemistry/glutamic acid decarboxylase (GAD) mRNA in situ hybridization. Intragastric water administration increased the number of Fos-immunoreactive cells in the infralimbic cortex and lateral part of the central nucleus of the amygdala compared with the naive group. Ethanol administration increased the number of Fos-immunoreactive cells in the infralimbic (+57.5%) and prelimbic (+105.3%) cortices, nucleus accumbens shell region (+88.2%), medial part of the central nucleus of the amygdala (+160%), and lateral part of the bed nucleus of the stria terminalis (+198.8%) compared with the water-treated group. In the nucleus accumbens shell region, central nucleus of the amygdala, and bed nucleus of the stria terminalis, more than 80% of Fos-immunoreactive neurons were GABAergic after ethanol administration. In contrast, in the prelimbic cortex, 75% of Fos-immunoreactive neurons were not GABAergic. These results constitute new evidence for region-specific functional interactions between ethanol and GABAergic neurons.

Amphetamine-induced 50 kHz calls from rat nucleus accumbens: A quantitative mapping study and acoustic analysis

Emission of 50 kHz ultrasonic calls in rats is known to be associated with appetitive behavioural situations and positive social interactions. The purpose of the study was to pharmacologically characterize amphetamine-induced 50 kHz calls and to perform quantitative mapping of this response in the nucleus accumbens. Injections of amphetamine into the nucleus accumbens induced species-typical 50 kHz calls in adult rats. The acoustic parameters of the calls were not affected by different amphetamine doses or combination of agents. The increase in the number of calls occurred predominantly from the accumbens shell and to a lesser degree from the core region. This effect was dose-dependent within the range of 1–20 μg of amphetamine and was reversed by pretreatment with D 1 or D 2 dopamine antagonists (SKF-83566 or raclopride) administered to the same brain site. However, another D 2 dopamine receptor antagonist, haloperidol, which is known to increase the accumbens dopamine level, was ineffective in reversing the increase in call number at the dose studied. On the contrary, intraacumbens haloperidol, when injected alone, caused an increase in 50 kHz calls. It is concluded that the release of dopamine, predominantly in the accumbens shell region, is responsible for production of 50 kHz calls and the calls may indicate an appetitive state compatible with anticipation of reward and positive affect. Both D 1 and D 2 subtypes of dopamine receptors may be necessary to induce 50 kHz calls and signal the appetitive state.

Alterations in food intake by opioid and dopamine signaling pathways between the ventral tegmental area and the shell of the nucleus accumbens

Reward is an important factor motivating food intake in satiated animals. Two sites involved in the reward response are the ventral tegmental area (VTA) and the nucleus accumbens shell region (sNAcc), between which communication is partially regulated by opioids and dopamine (DA). Previous studies have shown that the μ-opioid agonist Tyr- d-Ala-Gly-MePhe-Gly(ol)-enkephalin (DAMGO) dose-dependently enhances food intake in satiated animals when injected into either the VTA or the sNAcc. The enhanced intake elicited by DAMGO injected into the sNAcc was dose-dependently blocked by injection of naltrexone (NTX) bilaterally into the VTA, indicating an opioid-dependent signaling pathway from the sNAcc to the VTA in mediation of food intake. In the present study, we cannulated animals bilaterally in both the VTA and the sNAcc to further study the nature of opioid- and DA-dependent communication between the sites. Food intake elicited by DAMGO (2 or 5 nmol) injected unilaterally into the VTA was dose-dependently diminished by bilateral injection of NTX (2.5, 5, and 25 g/side) or the D1 antagonist SCH 23390 (3, 1, 0.3, 0.15, 0.05, and 0.015 nmol/side) into the sNAcc. When DAMGO (5 nmol) was injected into the sNAcc, the resulting food intake was decreased by doses of SCH 23390 ranging from 0.05 to 100 nmol/side injected bilaterally into the VTA, but not by equimolar doses of Raclopride, a D2 antagonist. These results, combined with previous findings, suggest a signaling pathway between the VTA and the sNAcc in which opioids and DA facilitate feeding in an interdependent manner.

Amygdala Regulation of Nucleus Accumbens Dopamine Output is Governed by the Prefrontal Cortex

A dynamic interaction between the prefrontal cortex (PFC), amygdala, and nucleus accumbens (NAc) may be fundamental to regulation of goal-directed behavior by affective and cognitive processes. This study demonstrates that a mechanism for this triadic relationship is an inhibitory control by prefrontal cortex on accumbal dopamine release during amygdala activation. In freely moving rats, microstimulation of basolateral amygdala at intensities that produced mild behavioral activation produced an expected rapid increase in glutamate efflux in the prefrontal cortex and the nucleus accumbens shell region of the ventral striatum. However, during the stimulation, dopamine release increased only in the prefrontal cortex, not in the nucleus accumbens. An increase in accumbal dopamine release was observed during the stimulation if glutamate activation in the prefrontal cortex was inhibited at either presynaptic or postsynaptic levels. Some behaviors expressed during the stimulation were intensified in animals in which prefrontal cortex glutamate activation was blocked. In addition, these animals continued to express stimulus-induced behaviors after the termination of stimulation, whereas normal poststimulus behaviors such as ambulation and grooming were not displayed as frequently. Considering that dopamine neurotransmission in the nucleus accumbens is thought to play an integral role in goal-directed motor behavior, these findings suggest that the prefrontal cortex influences the behavioral impact of amygdala activation via a concomitant active suppression of accumbal dopamine release. Absence of this cortical influence appears to result in an aberrant pattern of behavioral expression in response to amygdala activation, including behavioral perseveration after stimulus termination.

Neonatal phencyclidine treatment selectively attenuates mesolimbic dopamine function in adult rats as revealed by methamphetamine-induced behavior and c-fos mRNA expression in the brain.

One of the major hypotheses regarding the pathogenesis of schizophrenia is the implication of neurodevelopmental abnormality. However, the mechanism of delayed onset of schizophrenic symptoms, in which increased dopaminergic activity in mesolimbic or mesocortical dopamine systems plays a pathological role, is not known. In this study, we investigated whether the chronic blockade of N-methyl-D-aspartate (NMDA) receptor by phencyclidine (PCP), an NMDA channel blocker, during development could disrupt the dopamine system during later life. Neonatal rats were injected with PCP subcutaneously daily from postnatal day (PD) 1 to PD 14 and their dopaminergic function was evaluated on PD 42 by rating the methamphetamine (MAP)-induced behavior. To illustrate the activated brain regions, the expression of c-fos mRNA in response to a MAP challenge was also studied utilizing in situ hybridization. Chronic neonatal PCP treatment attenuated MAP-induced oral stereotypy (licking and gnawing) and reduced MAP-induced expression of c-fos mRNA in the N. accumbens shell region and VTA but not in the N. accumbens core region, medial striatum, or substantia nigra. These results suggest that neonatal blockade of NMDA receptor, which induces a number of effects in the developing nervous system, may cause long-lasting functional changes of the mesolimbic dopamine system.

RGβ1: A Psychostimulant-Regulated Gene Essential for Establishing Cocaine Sensitization

Repeated doses of cocaine or amphetamine lead to long-lasting behavioral manifestations that include enhanced responses termed sensitization. Although biochemical mechanisms that underlie these manifestations currently remain largely unknown, new protein synthesis has been implicated in several of these neuroadaptive processes. To seek candidate biochemical mechanisms for these drug-induced neuroplastic behavioral responses, we have used an approach termed subtracted differential display (SDD) to identify genes whose expression is regulated by these psychostimulants. rGbeta1 is one of the SDD products that encodes a rat G-protein beta subunit. rGbeta1 expression is upregulated by cocaine or amphetamine treatments in neurons of the nucleus accumbens shell region, a major center for psychostimulant effects in locomotor control and behavioral reward. Antisense oligonucleotide treatments that attenuate rGbeta1 expression in regions including the nucleus accumbens abolish the development of behavioral sensitization when they are administrated during the repeated cocaine exposures that establish sensitization. These treatments fail to alter acute behavioral responses to cocaine, and they do not block the expression of cocaine sensitization when it is established before oligonucleotide administrations. Full, regulated rGbeta1 expression is a biochemical component essential to the establishment of a key consequence of repeated cocaine administrations, sensitization.

Excitatory Amino Acid Receptors in the Ventral Tegmental Area Regulate Dopamine Release in the Ventral Striatum

The role of excitatory amino acid (EAA) receptors located in the ventral tegmental area (VTA) in tonic and phasic regulation of dopamine release in the ventral striatum was investigated. Microdialysis in conscious rats was used to assess dopamine release primarily from the nucleus accumbens shell region of the ventral striatum while applying EAA antagonists or agonists to the VTA. Infusion of the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (25 and 100 microM) into the VTA did not affect dopamine release in the ventral striatum. In contrast, intra-VTA infusion of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (100 and 500 microM) dose-dependently decreased the striatal release of dopamine. Intra-VTA application of the ionotropic EAA receptor agonists NMDA and AMPA dose-dependently (10 and 100 microM) increased dopamine efflux in the ventral striatum. However, infusion of 50 or 500 microM trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), a metabotropic EAA receptor agonist, did not significantly affect these levels. These data suggest that NMDA receptors in the VTA exert a tonic excitatory influence on dopamine release in the ventral striatum. Furthermore, dopamine neurotransmission in this region may be enhanced by activation of NMDA and AMPA receptors, but not ACPD-sensitive metabotropic receptors, located in the VTA. These data further suggest that EAA regulation of dopamine release primarily occurs in the VTA as opposed to presynaptically at the terminal level.