Dopamine Release In Accumbens Research Articles

Diazepam Concurrently Increases the Frequency and Decreases the Amplitude of Transient Dopamine Release Events in the Nucleus Accumbens.

Benzodiazepines are commonly prescribed anxiolytics that pose abuse liability in susceptible individuals. Although it is well established that all drugs of abuse increase brain dopamine levels, and benzodiazepines are allosteric modulators of the GABAA receptor, it remains unclear how they alter dopamine release. Using in vivo fast-scan cyclic voltammetry, we measured diazepam-induced changes in the frequency and amplitude of transient dopamine release events. We found that diazepam concurrently increases the frequency and decreases the amplitude of transient dopamine release events in the awake and freely moving rat. The time course during which diazepam altered the frequency and amplitude of dopamine release events diverged, with the decreased amplitude effect being shorter lived than the increase in frequency, but both showing similar rates of onset. We conclude that diazepam increases the frequency of accumbal dopamine release events by disinhibiting dopamine neurons, but also decreases their amplitude. We speculate that the modest abuse liability of benzodiazepines is due to their ability to decrease the amplitude of dopamine release events in addition to increasing their frequency.

VTA mTOR Signaling Regulates Dopamine Dynamics, Cocaine-Induced Synaptic Alterations, and Reward.

Mechanistic target of rapamycin (mTOR) regulates long-term synaptic plasticity, learning, and memory by controlling dendritic protein synthesis. The mTOR inhibitor rapamycin has been shown to attenuate the behavioral effects of drugs of abuse, including cocaine. Using viral vectors to selectively delete mTOR in the ventral tegmental area (VTA) in adult male mTORloxP/loxP mice, we investigated the role of mTOR in regulating neuronal morphology, basal synaptic transmission, dopamine dynamics, and cocaine-induced synaptic plasticity and rewarding effects. We find that targeted deletion of mTOR in the VTA had no significant effects on soma size and dendritic morphology of VTA neurons but significantly decreased dopamine release and reuptake in the nucleus accumbens (NAc) shell, a major target region. Western blot analysis revealed that mTOR deletion led to decreases in phosphorylated tyrosine hydroxylase (pTH-Ser40) levels in the VTA and dopamine transporter expression in the NAc. mTOR deletion had no significant effects on basal excitatory transmission in VTA dopamine neurons but caused an increase in GABAergic inhibition because of an increase in VTA GABAergic neuron firing. Furthermore, mTOR deletion attenuated conditioned place preference to cocaine and cocaine-induced potentiation of excitation and reduction of GABAergic inhibition in VTA dopamine neurons. Taken together, these results suggest that loss of mTOR in the VTA shifts the balance of excitatory and inhibitory synaptic transmission and decreases dopamine release and reuptake in the NAc. In addition, VTA mTOR signaling regulates cocaine-cue associative learning and cocaine-induced synaptic plasticity in VTA dopamine neurons.

Chronic light exposure alters serotonergic and orexinergic systems in the rat brain and reverses maternal separation-induced increase in orexin receptors in the prefrontal cortex.

Maternal separation (MS) is a well-established rodent model of depression. Chronic constant light (CCL) treatment during adolescence has been shown to reverse the depression-like behaviour induced by MS. We aimed to further delineate the antidepressant effect of light by investigating the involvement of the dopaminergic, serotonergic and orexinergic systems. MS was used to induce changes in adult male Sprague-Dawley rats, some of whom were also treated with CCL for 3weeks during adolescence. At P80, rats were decapitated and brain tissue collected for analysis of glutamate- and potassium-stimulated dopamine release in the nucleus accumbens (NAc) using an in vitro superfusion technique. Enzyme-linked immunosorbent assays were employed to measure 5-hydroxytryptamine (5-HT) levels in the hypothalamus and prefrontal cortex (PFC). Western blotting was used to measure orexin receptor 1 (OXR-1) and 2 (OXR-2) in the PFC. MS did not affect 5-HT levels in these rats. However, CCL increased hypothalamic 5-HT and reduced 5-HT levels in the PFC. CCL had opposite effects on OXR levels in the PFC of maternally separated and non-separated rats. MS increased OXR-1 and OXR-2 levels in the PFC, an effect that was normalized by CCL treatment. MS reduced glutamate-stimulated dopamine release in the NAc, an effect that was not reversed by CCL. The present results suggest that CCL treatment affects 5-HT and orexinergic systems in the MS model while not affecting the MS-induced decrease in dopamine release in the NAc. The reversal of changes in the orexinergic system may be of particular relevance to the antidepressant effect of CCL in depression.

Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats

The nucleus accumbens contains delta-opioid receptors that may reduce inhibitory neurotransmission. Reduction in GABAA receptor-mediated inhibition of accumbal dopamine release due to delta-opioid receptor activation should be suppressed by stimulating accumbal GABAA receptors. As delta-opioid receptors are divided into delta2- and delta1-opioid receptors, we analysed the effects of the GABAA receptor agonist muscimol on delta2- and delta1-opioid receptor-mediated accumbal dopamine efflux in freely moving rats using in vivo microdialysis. Drugs were administered intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 25–50min infusions. The delta2-opioid receptor agonist deltorphin II (25.0nmol)- and delta1-opioid receptor agonist DPDPE (5.0nmol)-induced increases in dopamine efflux were inhibited by the delta2-opioid receptor antagonist naltriben (1.5nmol) and the delta1-opioid receptor antagonist BNTX (150.0pmol), respectively. Muscimol (250.0pmol) inhibited deltorphin II (25.0nmol)-induced dopamine efflux. The GABAA receptor antagonist bicuculline (50.0pmol), which failed to affect deltorphin II (25.0nmol)-induced dopamine efflux, counteracted the inhibitory effect of muscimol on deltorphin II-induced dopamine efflux. Neither muscimol (250.0pmol) nor bicuculline (50.0 and 500.0pmol) altered DPDPE (5.0nmol)-induced dopamine efflux. The present results show that reduction in accumbal GABAA receptor-mediated inhibition of dopaminergic activity is necessary to produce delta2-opioid receptor-induced increase in accumbal dopamine efflux. This study indicates that activation of delta2- but not delta1-opioid receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABAA receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal dopamine efflux.

Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2–0.8mg/kg), cotinine (0.5–5.0mg/kg), anatabine (0.5–5.0mg/kg), and myosmine (5.0–20.0mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated.

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain.

Gabapentin (GBP) is a first-line therapy for neuropathic pain, but its mechanisms and sites of action remain uncertain. We investigated GBP-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal GBP reversed evoked mechanical hypersensitivity and produced conditioned place preference (CPP) and dopamine (DA) release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal GBP also significantly inhibited dorsal horn wide-dynamic-range neuronal responses to a range of evoked stimuli in SNL rats. By contrast, GBP microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP, and elicited NAc DA release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on wide-dynamic-range neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous GBP-induced CPP and NAc DA release but failed to block its inhibition of tactile allodynia. Gabapentin, therefore, can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity, and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from nonopioid analgesics, GBP requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain-motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of GBP's analgesic effects in patients.

Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens.

CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine-induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [3H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1μM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal levels of DOPET. At the same concentration, 0.1μM, CART (55-102) peptide did not have any effect on the release of noradrenaline. In the presence of CART (55-102) peptide, 0.1μM, the effect of cocaine, 30μM, on the basal dopamine release was inhibited and the effect on the basal DOPAC release substantially increased. To our knowledge, our findings are the first to show direct neurochemical evidence that CART (55-102) peptide plays a neuromodulatory role on the dopaminergic reward system by decreasing dopamine in the mouse nucleus accumbens and by attenuating cocaine-induced effects on dopamine release.

Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens.

Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non-cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p<0.001) and resulted in a strong post-nicotine elevation in DA levels (p<0.01). However, there were no differences between the genotypes at higher doses. Furthermore, FAAH KO mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p<0.05), with no differences between the genotypes at higher doses. Compared with vehicle-pretreated mice, mice pretreated with PF-3845 displayed an enhancement of the effect of low-dose nicotine on NAc DA release (p<0.001), which resulted in a sustained increase in DA levels (p<0.05). Similar to FAAH KO mice, PF-3845-pretreated mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p<0.01). These observations in mice suggest that enhanced nicotine-induced NAc DA release might contribute to increased sensitivity to the conditioned rewarding effects of low-dose nicotine following FAAH inhibition, which has been previously reported. Future studies combining behavioral and neurochemical approaches are needed to elucidate the precise mechanism of these effects.

Blast–related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release

Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the “signature injury” of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast-induced mTBI. However, the underlying mechanisms are not well understood. Here we used a battlefield-relevant mouse model of blast-induced mTBI and in vivo fast-scan cyclic voltammetry (FSCV) to investigate whether the mesolimbic dopamine system contributes to the mechanisms underlying blast-induced behavioral dysfunction. In mice, blast exposure increased novelty seeking, a behavior closely associated with disinhibition and risk for subsequent maladaptive behaviors. In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans.

Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats.

BackgroundIncreased locomotor activity in response to the same stimulus is an index of behavioral sensitization observed in preclinical models of drug addiction and compulsive behaviors. Repeated administration of quinpirole, a D2/D3 dopamine agonist, induces locomotor sensitization. This effect is potentiated and accelerated by co-administration of U69593, a kappa opioid receptor agonist. The mechanism underlying kappa opioid receptor potentiation of quinpirole-induced locomotor sensitization remains to be elucidated.MethodsImmunofluorescence anatomical studies were undertaken in mice brain slices and rat presynaptic synaptosomes to reveal kappa opioid receptor and D2R pre- and postsynaptic colocalization in the nucleus accumbens. Tonic and phasic dopamine release in the nucleus accumbens of rats repeatedly treated with U69593 and quinpirole was assessed by microdialysis and fast scan cyclic voltammetry.ResultsAnatomical data show that kappa opioid receptor and D2R colocalize postsynaptically in medium spiny neurons of the nucleus accumbens and the highest presynaptic colocalization occurs on the same dopamine terminals. Significantly reduced dopamine levels were observed in quinpirole, and U69593-quinpirole treated rats, explaining sensitization of D2R. Presynaptic inhibition induced by kappa opioid receptor and D2R of electrically evoked dopamine release was faster in U69593-quinpirole compared with quinpirole-repeatedly treated rats.ConclusionsPre- and postsynaptic colocalization of kappa opioid receptor and D2R supports a role for kappa opioid receptor potentiating both the D2R inhibitory autoreceptor function and the inhibitory action of D2R on efferent medium spiny neurons. Kappa opioid receptor co-activation accelerates D2R sensitization by contributing to decrease dopamine release in the nucleus accumbens.

Mechanism for optimization of signal-to-noise ratio of dopamine release based on short-term bidirectional plasticity

Repeated electrical stimulation of dopamine (dopamine) fibers can cause variable effects on further dopamine release; sometimes there are short-term decreases while in other cases short-term increases have been reported. Previous studies have failed to discover what factors determine in which way dopamine neurons will respond to repeated stimulation. The aim of the present study was therefore to investigate what determines the direction and magnitude of this particular form of short-term plasticity. Fixed potential amperometry was used to measure dopamine release in the nucleus accumbens in response to two trains of electrical pulses administered to the ventral tegmental area of anesthetized mice. When the pulse trains were of equal magnitude we found that low magnitude stimulation was associated with short-term suppression and high magnitude stimulation with short-term facilitation of dopamine release. Secondly, we found that the magnitude of the second pulse train was critical for determining the sign of the plasticity (suppression or facilitation), while the magnitude of the first pulse train determined the extent to which the response to the second train was suppressed or facilitated. This form of bidirectional plasticity might provide a mechanism to enhance signal-to-noise ratio of dopamine neurotransmission.

Suppression of reward-induced dopamine release in the nucleus accumbens in animal models of depression: Differential responses to drug treatment

Anhedonia, the loss of interest or pleasure in previously enjoyable activities, is a core symptom of major depressive disorder, suggesting that the brain reward system may be dysfunctional in this condition. Neurochemical changes in the mesolimbic dopamine (DA) system are not fully understood in animal models of depression. We investigated reward (30% sucrose intake)-induced DA release in the nucleus accumbens (NAc) and the effect of chronic treatment with the antidepressant escitalopram (5mg/kg, intraperitoneally twice daily for 3 weeks) in two animal models of depression. Exposure to chronic mild stress (CMS) during adulthood completely suppressed reward-induced intra-NAc DA release; however, this effect was reversed by chronic treatment with escitalopram. Our findings suggest that reward-induced intra-NAc DA release may be an indicator of depression severity and therapeutic efficacy. Exposure to neonatal maternal separation (MS) and CMS in adulthood completely suppressed reward-induced intra-NAc DA release. Chronic treatment with escitalopram did not restore reward-induced DA release in these animals, suggesting that this paradigm may serve as an animal model for treatment-resistant depression. Further study of the mesolimbic dopaminergic system in these animal models of depression may clarify the neural mechanisms underlying depression and treatment resistance.

The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc)

The pancreatic hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic ‘reward’ pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN. To determine whether and how peripheral amylin or sCT affect mesolimbic reward circuitry we utilized fast scan cyclic voltammetry under anesthesia to measure phasic DA release in the NAc evoked by electrical stimulation of the VTA in intact, AP lesioned and bilaterally PBN lesioned rats.Amylin (50μg/kg i.p.) did not change phasic DA responses compared to saline control rats. However, sCT (50μg/kg i.p.) decreased evoked DA release to VTA-stimulation over 1h compared to saline treated control rats. Further investigations determined that AP and bilateral PBN lesions abolished the ability of sCT to suppress evoked phasic DA responses to VTA-stimulation. These findings implicate the AP and the PBN as important sites for peripheral sCT to decrease evoked DA release in the NAc and suggest that these nuclei may influence hedonic and motivational processes to modulate food intake.

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

Drugs of abuse increase the frequency and magnitude of brief (1–3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release – possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.

Acupuncture reduces relapse to cocaine-seeking behavior via activation of GABA neurons in the ventral tegmental area.

There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA.

Dopamine release in the nucleus accumbens is altered following traumatic brain injury

Mild-to-severe traumatic brain injury (TBI) is frequently associated with prolonged dysfunction of reward circuitry, including motivation and salience, which suggests alterations of dopamine (DA) processing within the core and shell of the nucleus accumbens (NAC). Using fast-scan cyclic voltammetry in a rodent model of traumatic brain injury, we found that stimulus-evoked DA release is distinct in the core and shell of the NAC, with the shell being less responsive to tonic stimulation and more sensitive to the number of pulses when phasic stimulation is applied. Exposure to TBI was associated with major changes in both release and reuptake of DA in both the core and shell of NAC, with greater changes seen in the core. These alterations evolved over time, becoming most severe 1–2weeks after injury with subsequent recovery, and the extent and progression of these abnormalities was correlated with severity of injury. Taken together, these data support behavior and anatomical studies suggesting the NAC core and striatum may subserve parallel functions, whereas the shell is distinct. These data offer a unique window on how different neurological systems respond to TBI and may help explain affective and cognitive changes that are seen.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine.

Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.

Biological Mechanisms Whereby Social Exclusion May Contribute to the Etiology of Psychosis: A Narrative Review.

The purpose of this review is to examine whether a contribution of social exclusion to the pathogenesis of psychosis is compatible with the dopamine hypothesis and/or the neurodevelopmental hypothesis. Humans experience social exclusion as defeating. An animal model for defeat is the resident-intruder paradigm. The defeated animal shows evidence of an increased sensitivity to amphetamine, increased dopamine release in the nucleus accumbens and prefrontal cortex, and increased firing of dopaminergic neurons in the ventral tegmental area. As for humans, one study showed that amphetamine-induced striatal dopamine release was significantly greater among nonpsychotic young adults with severe hearing impairment than among normal hearing controls. Two other studies reported an association between childhood trauma and increased dopamine function in striatal subregions. Several studies have suggested that the perigenual anterior cingulate cortex (pgACC) may play a role in the processing of social stress. Importantly, the pgACC regulates the activity of the ventral striatum through bidirectional interconnections. We are not aware of studies in humans that examined whether (proxies for) social exclusion contributes to the structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in volume of the total brain, hippocampus, or medial prefrontal cortex. Other animal studies reported that social defeat can reduce neurogenesis. In conclusion, the answer to the question as to whether there are plausible mechanisms whereby social exclusion can contribute to the pathogenesis of psychosis is cautiously affirmative.

Effects of nucleus accumbens amphetamine administration on performance in a delay discounting task

Chronic administration of cocaine can cause pronounced and enduring cognitive alterations such as increases in impulsive choice. Chronic cocaine can also result in enhanced dopamine (DA) release in the nucleus accumbens (NAc) in response to reward-related cues. It is possible that this enhanced DA release in the NAc is a mechanism by which cocaine increases impulsive choice. To date, however, the specific role of DA in the NAc in impulsive choice is unclear. To begin to address this, rats received acute microinjections of the indirect DA agonist amphetamine directly into the NAc prior to testing in a delay discounting task in which rats chose between a small, immediate and a large, delayed food reward. When delays to the large reward increased within test sessions, amphetamine increased choice of the large reward. When delays decreased within test sessions, however, amphetamine decreased choice of the large reward. These findings suggest that, rather than specifically mediating impulsive choice, DA neurotransmission in the NAc is necessary for flexible adaptation of choice strategies in the presence of shifting reward contingencies. These results further indicate that enhancements in NAc DA release likely do not account for lasting increases in impulsive choice caused by chronic cocaine.