Dopamine Release In Nucleus Accumbens Research Articles

Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain.

Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.

Behavioral and neurochemical analysis of ongoing bone cancer pain in rats.

Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) μ-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

Circuitry and Molecular Mechanisms Underlying Maladaptive Decision Making Following Chronic Adolescent Alcohol Intake

Alcohol is the most commonly abused substance among adolescents and shows the highest liability of all abused drugs. Using a probability discounting task and fast-scan cyclic voltammetry (FSCV) we previously demonstrated that chronic voluntary consumption of alcohol by adolescent rats results in maladaptive risk-taking behavior and increased phasic dopamine (DA) release within the nucleus accumbens (NAc) during adulthood. In order to investigate the underlying mechanisms, electrical stimulation of discrete neuronal populations in anesthetized rats was used to measure phasic NAc DA release in adulthood following adolescent alcohol intake. Stimulation of the pedunculopontine nucleus (PPT) resulted in enhanced DA release in animals that consumed alcohol during adolescence. Conversely, stimulation of the medial forebrain bundle (MFB) or bed nucleus of the stria terminalis (BNST) resulted in DA release that did not differ between alcohol or control animals, suggesting that increased DA release following adolescent alcohol intake occurs via changes within the VTA in a pathway specific manner. Systemic administration of L-838,417, a GABA(A) receptor α2, 3, and 5 subunit allosteric agonist, normalized the increased PPT-stimulated DA release seen in rats that consumed alcohol during adolescence, suggesting a potential therapeutic target for future studies. Together, these results provide unique insight into the potential circuitry and molecular mechanisms underlying the maladaptive risk-taking behavior seen following adolescent alcohol intake and highlights new potential therapeutic targets.

Glutamatergic transmission is involved in the long lasting sexual inhibition of sexually exhausted male rats

Copulation to satiation induces a series of enduring physiological changes in male rats, with the appearance of a long lasting sexual inhibitory period as the most conspicuous, that are suggestive of the occurrence of neuroplastic changes. Copulation is a natural reward activating the mesocorticolimbic circuit and inducing nucleus accumbens dopamine release. The repeated activation of this system by drug rewards induces neuroplastic changes involving both dopamine and glutamate transmission. We hypothesized that repeated activation of the mesocorticolimbic circuit during copulation to satiation might also activate these neurotransmitter systems. The objective of the present work was to establish the possible participation of glutamate transmission in sexual satiety. To this aim we tested if the systemic injection of specific glutamate receptor antagonists of the NMDA, AMPA and mGluR5 receptor subtypes would reverse the sexual inhibitory state characteristic of sexually satiated rats. Results showed that systemic administration of low doses of the three glutamate receptor antagonists reversed sexual exhaustion evidencing a role for glutamate in the maintenance of the sexual inhibition that follows copulation to satiation, with the participation of NMDA, AMPA and mGluR5 receptors. These glutamate receptor subtypes have been associated to the neuroplastic changes resulting from repeated activation of the mesocorticolimbic circuit by drug rewards, a phenomenon that might also result from its activation by continued copulation.

Adaptation and Dysadaptation of Abuse-Independent Physiological Responses to Amphetamine

Although amphetamine (AMPH) is an addictive drug of abuse which exhibits toxicity to dopaminergic neurons in long-term abusers, AMPH shows some abuse-independent effects. AMPH increases dopamine (DA) release from striatum by enhancing cytosolic DA ＂via＂ the redistribution of neurotransmitters from synaptic vesicles to neuronal cytoplasm and the reverse transport of DA from cytoplasm to synapse ＂via＂ the dopamine transporter (DAT). AMPH competitively binds DAT by facilitating the exchange of cytosolic DA, and inhibits the monoamine oxidase to decreasing the metabolism of postsynaptic DA. AMPH locally applied in ventral tegmental area (VTA) enhances DA release in nucleus accumbens and medial prefrontal cortex by activating noradrenergic neurotransmission in VTA. DA levels in striatum can be enhanced by estradiol ＂via＂ an increase of DAT expression following the administration of AMPH. In male rat tests, AMPH inhibits the basal and human chorionic gonadotropin (hCG)-stimulated secretion of testosterone by increasing cyclic AMP production and decreasing the activities of calcium channel and steroidogenic enzymes. AMPH also inhibits gastric emptying and intestinal transit ＂via＂ a mechanism associated with the hypersecretion of endogenous cholecystokinin (CCK). The offspring of pregnant rats administrated with AMPH shows ventricular hypertrophy, systolic dysfunction, and apoptosis in cardiac muscles. The above findings indicate that AMPH demonstrates multiple effects on cardiac, endocrine and gastrointestinal systems. Both adaptation and dysadaptation of abuse-independent physiological responses to AMPH are highly suggested.

Varenicline enhances dopamine release facilitation more than nicotine after long-term nicotine treatment and withdrawal.

An important factor contributing to the high relapse rates among smokers is nicotine withdrawal symptoms. Multiple studies suggest that decreased dopamine release in nucleus accumbens plays a key role in withdrawal. However, recent reports showed that long-term nicotine exposure itself also decreases accumbal dopamine release, suggesting that additional mechanisms are involved in withdrawal. Here, we used real-time cyclic voltammetry in brain slices containing the nucleus accumbens to further elucidate the changes in dopamine release linked to nicotine withdrawal. Rats received vehicle or nicotine via the drinking water for 2–3 months. Studies assessing the expression of somatic signs in vehicle-treated, nicotine-treated, and 24-h nicotine withdrawn rats showed that nicotine withdrawal led to a significant increase in somatic signs. Subsequent voltammetry studies showed that long-term nicotine decreased single-pulse-stimulated dopamine release via an interaction at α6β2* receptors. Nicotine withdrawal led to a partial recovery in α6β2* receptor-mediated release. In addition, long-term nicotine treatment alone increased dopamine release paired-pulse ratios and this was partially reversed with nicotine removal. We then evaluated the effect of bath-applied nicotine and varenicline on dopamine release. Nicotine and varenicline both decreased single-pulse-stimulated release in vehicle-treated, nicotine-treated, and nicotine withdrawn rats. However, bath-applied varenicline increased paired-pulse ratios to a greater extent than nicotine during long-term nicotine treatment and after its withdrawal. Altogether these data suggest that nicotine withdrawal is associated with a partial restoration of dopamine release measures to control levels and that varenicline's differential modulation of dopamine release may contribute to its mechanism of action.

κ-opioid receptor as a key mediator in the regulation of appetitive 50-kHz ultrasonic vocalizations.

Acute administration of high doses of morphine reduced 50-kHz ultrasonic vocalizations (USVs). Although morphine meets the classical criteria for inducing 50-kHz USVs (it causes place preference and induces dopamine release in nucleus accumbens), it also inhibits appetitive vocalizations. The aims of this study were to (i) study the pharmacological impact of κ-opioid (KOR) and μ-opioid receptor (MOR) ligands on the emission of 50-kHz USVs triggered by social interaction after long-term isolation and (ii) analyze the concentrations of the main neurotransmitters in reward-related structures (ventral tegmental area (VTA), nucleus accumbens (NAcc), and medial prefrontal cortex (mPFC)). In an attempt to define the effects of opioid-receptor activation on the reward system, we used a social interaction test (after 21days isolation). HPLC analysis was used to determine the monoamine and amino acid concentrations in reward-related structures. U-50488 (10.0mg/kg), morphine (5.0 and 1.0mg/kg), and naltrexone (5.0mg/kg) decreased, and nor-BNI (10.0mg/kg) increased 50-kHz USVs. Acute pretreatment with nor-BNI or naltrexone reduced the 50-kHz suppression induced via morphine. The biochemical data showed several variations between groups regarding dopamine concentrations, serotonin, and their metabolites; these data may suggest that the levels of emitted ultrasound in the 50-kHz band are inversely proportional to the 5-hydroxyindoleacetic acid (5-HIAA)/3-methoxytyramine (3-MT) ratio in the VTA. These results indicate an important role for KOR in the regulation of 50-kHz USV emissions and suggest that KOR activation may be a key mediator in the regulation of reward responses. Changes in the balance between serotonin and dopamine concentrations in the VTA may be a key predictor for 50-kHz USV emission.

Mesolimbic Dopamine Dynamically Tracks, and Is Causally Linked to, Discrete Aspects of Value-Based Decision Making

BackgroundTo make appropriate choices, organisms must weigh the costs and benefits of potential valuable outcomes, a process known to involve the nucleus accumbens (NAc) and its dopaminergic input. However, it is currently unknown if dopamine dynamically tracks alterations in expected reward value online as behavioral preferences change and if so, if it is causally linked to specific components of value such as reward magnitude and/or delay to reinforcement. MethodsElectrochemical methods were used to measure subsecond NAc dopamine release during a delay discounting task where magnitude was fixed but delay varied across blocks (n = 7 rats). Next, to assess whether this dopamine signaling was causally related to specific components of choice behavior, we employed selective optogenetic stimulation of dopamine terminals in the NAc using a modified delay discounting task in which both delay and magnitude varied independently (n = 23 rats). ResultsCues predictive of available choices evoked dopamine release that scaled with the rat’s preferred choices and dynamically shifted as delay to reinforcement for the large reward increased. In the second experiment, dopamine signaling was causally related to features of decision making, as optogenetically enhanced dopamine release within the NAc during predictive cue presentation was sufficient to alter subsequent value-related choices. Importantly, this dopamine-mediated shift in choice was limited to delay-based, but not magnitude-based, decisions. ConclusionsThese findings indicate that NAc dopamine dynamically tracks delay discounting and establishes a causal role for this signaling in a subset of value-based associative strategies.

A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.

Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibers of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibers have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release innucleus accumbens. Activation also reinforces instrumental behavior and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR—one of the most sensitive reward sites in the brain—to VTA dopaminergic neurons.

Pick your poison: not all opioids are created equal in the eyes of dopamine (commentary on Vander Weele et al.).

In the current issue, Vander Weele et al. (2014) provide a previously unseen characterization of opioid-induced potentiation of dopamine release in the nucleus accumbens (NAc), an effect shared by all commonly abused drugs and thought to critically contribute to drug reinforcement. This work is extremely timely as prescription opioid abuse and addiction are currently at epidemic levels. Indeed, the rise in prescription opioid abuse may be driven by an elevated prevalence of more addictive opioids. The most common opioid analgesic has traditionally been morphine, a naturally occurring alkaloid from the opium poppy plant. However, newer synthetic opioids, such as oxycodone, are gaining popularity despite (or perhaps because of) their reportedly greater abuse potential. The work by Vander Weele et al. (2014) suggests that the greater abuse potential of oxycodone may arise from its increased ability to produce changes in NAc dopamine release. Fast-scan cyclic voltammetry was used to measure real-time dopamine fluctuations in the NAc of behaving rats. These measures add opioids to the growing list of abused drugs (including ethanol, nicotine, cocaine and cannabinoids) that elicit rapid surges in NAc dopamine concentrations. Because these dopamine ‘transients’ are causally linked to reward seeking, the ability of abused drugs to give rise to these signals is an important mechanism supporting drug reinforcement. Interestingly, Vander Weele et al. (2014) found that morphine exhibits a surprisingly brief effect on dopamine transients, augmenting these signals for <1 min. In stark contrast, oxycodone elicited a stable and significant increase in the frequency of transients for the entire 15 min recording period. Additionally, state-of-the-art microdialysis simultaneously sampled the extracellular levels of 15 different neurotransmitters at 60 s intervals. These elegant measures corroborated the fast-scan cyclic voltammetry dopamine recordings and also showed that morphine, but not oxycodone, elevated extracellular GABA levels in the NAc. If this increase in GABA acts to inhibit terminal dopamine release, it could explain morphine's weak effects on dopamine transmission. The source of this GABA signal, however, remains to be identified. Moreover, this increase in GABA is paradoxical, as it has been theorized that morphine exerts its dopamine-releasing effects through μ-opioid receptor-mediated disinhibition of dopamine neurons. Based on reported differences in the abuse potential of oxycodone and morphine, and their distinct effects on dopamine release, the current findings suggest that monitoring a drug's ability to pharmacologically elicit dopamine transients could serve as an objective assay for rational drug policy, as we have postulated for cannabinoids. Alternatively, the observed differences between morphine and oxycodone may have simply arisen from their different pharmacokinetic actions. Indeed, although both drugs were administered at the same dose, oxycodone can reach brain concentrations six times that of morphine. Nonetheless, the authors state that both drugs evoked a similar maximal increase in extracellular dopamine and inhibited movement for a similar duration. Clearly, future work will need to employ more rigorous behavioral assays (such as drug self-administration) to determine whether the differential effects of morphine and oxycodone on the dynamics of dopamine release cause their different reinforcing properties.

Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers.

Although striatal dopamine (DA) is important in alcohol abuse, the nature of DA release during actual alcohol drinking is unclear, since drinking includes self-administration of both conditioned flavor stimuli (CS) of the alcoholic beverage and subsequent intoxication, the unconditioned stimulus (US). Here, we used a novel self-administration analog to distinguish nucleus accumbens (NAcc) DA responses specific to the CS and US. Right-handed male heavy drinkers (n = 26) received three positron emission tomography (PET) scans with the D2/D3 radioligand [(11)C]raclopride (RAC) and performed a pseudo self-administration task that separately administered a flavor CS of either a habitually consumed beer or the appetitive control Gatorade®, concomitant with the US of ethanol intoxication (0.06g/dL intravenous (IV) administration) or IV saline. Scan conditions were Gatorade flavor + saline (Gat&Sal), Gatorade flavor + ethanol (Gat&Eth), and beer flavor + ethanol (Beer&Eth). Ethanol (US) reduced RAC binding (inferring DA release) in the left (L) NAcc [Gat&Sal > Gat&Eth]. Beer flavor (CS) increased DA in the right (R) NAcc [Gat&Eth > Beer&Eth]. The combination of beer flavor and ethanol (CS + US), [Gat&Sal > Beer&Eth], induced DA release in bilateral NAcc. Self-reported intoxication during scanning correlated with L NAcc DA release. Relative to saline, infusion of ethanol increased alcoholic drink wanting. Our findings suggest lateralized DA function in the NAcc, with L NAcc DA release most reflecting intoxication, R NAcc DA release most reflecting the flavor CS, and the conjoint CS + US producing a bilateral NAcc response.

Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: A potential biomarker of efficacy

Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms.

Dopamine release in nucleus accumbens during rewarded task switching measured by [11C]raclopride

Reward and motivation have positive influences on cognitive-control processes in numerous settings. Models of reward implicate corticostriatal loops and the dopamine (DA) system, with special emphasis on D2 receptors in nucleus accumbens (NAcc). In this study, 11 right-handed males (35–40 years) were scanned with positron emission tomography (PET) in a single [11C]raclopride dynamic scan during rewarded and non-rewarded task switching. Rewarded task switching (relative to baseline task switching) decreased [11C]raclopride binding in NAcc. Decreasing NAcc [11C]raclopride binding was strongly associated with task reaction time measures that reflect individual differences in effort and control strategies. Voxelwise analyses additionally revealed reward-related DA release in anterodorsal caudate, a region previously associated with task-switching. These PET findings provide evidence for striatal DA release during motivated cognitive control, and further suggest that NAcc DA release predicts the task reaction time benefits of reward incentives.

Capturing the aversive state of cephalic pain preclinically

Preclinical evaluation of headache by behavioral assessment of reward from pain relief. Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed. Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc α-flupenthixol, a dopaminergic antagonist. Intravenous α-calcitonin gene-related peptide (αCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury. Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies.

Getting Good or Getting Well?

Getting Good or Getting Well?

The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

BackgroundRepeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear.MethodsWe used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo.ResultsThe present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge.ConclusionsOur results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

Long-Term Nicotine Exposure Depresses Dopamine Release in Nonhuman Primate Nucleus Accumbens

Tobacco use is a leading cause of preventable deaths worldwide. However, current smoking cessation therapies have very limited long-term success rates. Considerable research effort is therefore focused on identification of central nervous system changes with nicotine exposure because this may lead to more successful treatment options. Although recent work suggests that α6β2* nicotinic acetylcholine receptors (nAChRs) play a dominant role in dopaminergic function in rodent nucleus accumbens, the effects of long-term nicotine exposure remain to be determined. Here, we used cyclic voltammetry to investigate α6β2* nAChR-mediated release with long-term nicotine treatment in nonhuman primate nucleus accumbens shell. Control studies showed that nAChR-mediated dopamine release occurs predominantly through the α6β2* receptor subtype. Unexpectedly, there was a complete loss of α6β2* nAChR-mediated activity after several months of nicotine treatment. This decline in function was observed with both single- and multiple-pulse-stimulated dopamine release. Paired-pulse studies showed that the facilitation of dopamine release with multiple pulsing observed in controls in the presence of nAChR antagonist was lost with long-term nicotine treatment. Nicotine-evoked [(3)H]dopamine release from nucleus accumbens synaptosomes was similar in nicotine- and vehicle-treated monkeys, indicating that long-term nicotine administration does not directly modify α6β2* nAChR-mediated dopamine release. Dopamine uptake rates, as well as dopamine transporter and α6β2* nAChRs levels, were also not changed with nicotine administration. These data indicate that nicotine exposure, as occurs with smoking, has major effects on cellular mechanisms linked to α6β2* nAChR-mediated dopamine release and that this receptor subtype may represent a novel therapeutic target for smoking cessation.

Tactile skin stimulation increases dopamine release in the nucleus accumbens in rats

We investigated the effect of mild (non-noxious) tactile stimulation (stroking) of skin on dopamine (DA) release in the nucleus accumbens (NAc) of rats. A coaxial microdialysis probe was stereotaxically implanted in the NAc and perfused with modified Ringer's solution. Dialysate output from consecutive 5-min periods was injected into a high-performance liquid chromatograph and DA was measured using an electrochemical detector. Bilateral tactile stimulation of the back for 5 min significantly increased DA release in conscious and anesthetized animals. Increased DA release was observed by stimulation of the contralateral, but not ipsilateral, back. DA secretion was also increased with stimulation of the forelimb, hindlimb, and abdomen. These effects were abolished after lesioning the ventral tegmental area (VTA). In contrast, noxious stimulation (pinching) of these areas had no effect on DA secretion. In conclusion, innocuous mechanical stimulation of the skin increases DA release in the contralateral NAc via the VTA.

Novel δ1-receptor agonist KNT-127 increases the release of dopamine and l-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex

The effects of systemic δ1-agonist on neurotransmission remains obscure, since no selective δ1-agonist exists that can penetrate the blood–brain barrier. Recently, we succeeded in synthesizing a putative δ1-receptor agonist, KNT-127, which has been demonstrated the effectiveness of systemic administration against anxiety and depressive-like behavior. To clarify the functional selectivity of KNT-127 and neurotransmission regulating system of δ1-receptor, the present study investigated the interaction between KNT-127 and δ-receptor antagonists on the release of dopamine, l-glutamate and GABA in nucleus accumbens (NAc), striatum and median pre-frontal cortex (mPFC) using multi-probe microdialysis. Intraperitoneal administration of KNT-127 increased the release of dopamine and l-glutamate in three regions, but decreased and increased GABA releases in respective NAc and mPFC without affecting that in striatum. The effects of KNT-127 in the three regions were abrogated by δ1-antagonist but not by δ2-antagonist. MK801 inhibited KNT-127-induced dopamine release in striatum and NAc, but enhanced that in mPFC, inhibited KNT-127-induced mPFC GABA release without affecting KNT-127-induced GABA reduction in NAc. Muscimol enhanced KNT-127-induced dopamine release in mPFC. Sulpiride inhibited KNT-127-induced reduction of GABA release in NAc. The results indicated that KNT-127 is a selective δ1-agonist, and suggested that δ1-receptor directly activates the release of dopamine and l-glutamate in the striatum, NAc and mPFC, but not that of GABA in the three regions. δ1-receptor indirectly inhibited GABA release in NAc via activated dopaminergic transmission, while δ1-receptor indirectly enhanced GABA release in mPFC via activated glutamatergic transmission.

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

Nicotine addiction and alcohol use disorders are very widespread and often occur together. Currently, there is no single drug approved for the simultaneous treatment of both conditions. Although these conditions share common genetic factors, the molecular mechanisms underlying their comorbidity are unknown. We have previously shown that mice lacking protein kinase C epsilon (PKCε) show decreased ethanol self-administration and reward as well as increased aversion to ethanol. Here we find that Prkce(-/-) mice self-administer less nicotine and show decreased conditioned place preference for nicotine compared with wild-type mice. In Prkce(-/-) mice, these behaviors are associated with reduced levels of α(6) and β(3) nicotinic receptor subunit mRNA in the ventral midbrain and striatum as well as a functional deficit in cholinergic modulation of dopamine release in nucleus accumbens. Our results indicate that PKCε regulates reward signaling through α(6)-containing nicotinic receptors and suggest that PKCε could be a target for the treatment of comorbid nicotine and alcohol addictions.