Facilitation Of Dopamine Release Research Articles

PLCγ1 in dopamine neurons critically regulates striatal dopamine release via VMAT2 and synapsin III

Dopamine neurons are essential for voluntary movement, reward learning, and motivation, and their dysfunction is closely linked to various psychological and neurodegenerative diseases. Hence, understanding the detailed signaling mechanisms that functionally modulate dopamine neurons is crucial for the development of better therapeutic strategies against dopamine-related disorders. Phospholipase Cγ1 (PLCγ1) is a key enzyme in intracellular signaling that regulates diverse neuronal functions in the brain. It was proposed that PLCγ1 is implicated in the development of dopaminergic neurons, while the physiological function of PLCγ1 remains to be determined. In this study, we investigated the physiological role of PLCγ1, one of the key effector enzymes in intracellular signaling, in regulating dopaminergic function in vivo. We found that cell type-specific deletion of PLCγ1 does not adversely affect the development and cellular morphology of midbrain dopamine neurons but does facilitate dopamine release from dopaminergic axon terminals in the striatum. The enhancement of dopamine release was accompanied by increased colocalization of vesicular monoamine transporter 2 (VMAT2) at dopaminergic axon terminals. Notably, dopamine neuron-specific knockout of PLCγ1 also led to heightened expression and colocalization of synapsin III, which controls the trafficking of synaptic vesicles. Furthermore, the knockdown of VMAT2 and synapsin III in dopamine neurons resulted in a significant attenuation of dopamine release, while this attenuation was less severe in PLCγ1 cKO mice. Our findings suggest that PLCγ1 in dopamine neurons could critically modulate dopamine release at axon terminals by directly or indirectly interacting with synaptic machinery, including VMAT2 and synapsin III.

Sex steroid hormone levels associated with dopamine D2/3 receptor availability in people who smoke cigarettes.

Sex differences exist in tobacco smoking. Women have greater difficulty quitting smoking than men. Tobacco smoking is driven by the reinforcing effects of nicotine, the primary addictive component in cigarettes. Nicotine binds to nicotinic acetylcholine receptors, facilitating dopamine release in striatal and cortical brain regions. Dysregulated dopamine D2/3 receptor signaling in the dorsolateral prefrontal cortex (dlPFC) is associated with cognitive deficits such as impairments in attention, learning, and inhibitory control that impede quit attempts. Sex steroid hormones, such as estradiol and progesterone, influence drug-taking behaviors, through dopaminergic actions, suggesting that their influence may explain sex differences in tobacco smoking. The goal of this study was to relate dlPFC dopamine metrics to sex steroid hormone levels in people who smoke and healthy controls. Twenty-four (12 women) people who smoke cigarettes and 25 sex- and age-matched controls participated in two same-day [11C]FLB457 positron emission tomography scans, one before and one after amphetamine administration. D2R availability (BPND) at baseline and after amphetamine administration was calculated. On the same day, plasma samples were collected for the analysis of sex steroid hormone levels: estradiol, progesterone, and free testosterone. Women who smoke had trending lower levels of estradiol than their sex-matched counterparts. Men who smoke had higher levels of estradiol and trending higher levels of free testosterone than their sex-matched counterparts. Among women only, lower estradiol levels were significantly associated with lower pre-amphetamine dlPFC BPND. This study demonstrated that lower estradiol levels are associated with lower dlPFC D2R availability in women which may underlie difficulty resisting smoking.

Cholinergic and dopaminergic-mediated motivated behavior in healthy states and in substance use and mood disorders.

Acetylcholine is an important neuromodulator of the mesolimbic dopamine (DA) system, which itself is a mediator of motivated behavior. Motivated behavior can be described by two primary components, termed directional and activational motivation, both of which can be examined and dissociated using effort-choice tasks. The directional component refers to motivated behavior directed towards reinforcing stimuli and away from aversive stimuli. Behaviors characterized by increased vigor, persistence, and work output are considered to reflect activational components of motivation. Disruption of DA signaling has been shown to decrease activational components of motivation, while leaving directional features intact. Facilitation of DA release promotes the activational aspects of motivated behavior. In this review, we discuss cholinergic and DA regulation of motivated behaviors. We place emphasis on effort-choice processes and the ability of effort-choice tasks to examine and dissociate changes of motivated behavior in the context of substance use and mood disorders. Furthermore, we consider how altered cholinergic transmission impacts motivated behavior across disease states, and the possible role of cholinergic dysregulation in the etiology of these illnesses. Finally, we suggest that treatments targeting cholinergic activity may be useful in ameliorating motivational disruptions associated with substance use and comorbid substance use and mood disorders.

The residence of synaptically released dopamine on D2 autoreceptors.

SUMMARYNeuromodulation mediated by synaptically released endogenous transmitters acting in G-protein-coupled receptors (GPCRs) is slow primarily because of multistep downstream signaling. What is less well understood is the spatial and temporal kinetics of transmitter and receptor interaction. The present work uses the combination of the dopamine sensor, dLight, to detect the spatial release and diffusion of dopamine and a caged form of a D2-dopamine receptor antagonist, CyHQ-sulpiride, to rapidly block the D2 autoreceptors. Photoactivation of the CyHQ-sulpiride blocks receptors in milliseconds such that the time course of dopamine/receptor interaction is mapped onto the downstream signaling. The results show that highly localized release, but not dopamine diffusion, defines the time course of the functional interaction between dopamine and D2 autoreceptors, which determines downstream inhibition.

Modulation of striatal dopamine release by nicotinic receptors in adolescent and adult rats

Adolescence is a developmental period characterized by increased vulnerability to substance use and dependence. However, mechanisms mediating this vulnerability are not well understood. Previous work has shown that locomotor responses in a novel environment predict acquisition of nicotine and cocaine self‐administration in adult rats, with high‐responders (HR) acquiring faster and at lower doses than low‐responders (LR). Additionally, adult rats with higher vulnerability have more sensitive nicotine acetylcholine receptor (nAChR) modulation of striatal dopamine release to phasic firing‐like stimulation, which is known to be important in acquisition of self‐administration. Here we examined how antagonism of nAChRs altered dopamine release in the nucleus accumbens core in adolescent and adult rats using fast scan cyclic voltammetry. We found that non‐selective antagonism of nAChRs, by mecamylamine (2 uM) or a desensitizing dose of nicotine (500 nM), increased dopamine release in HRs to stimulation that models phasic dopamine release, but suppressed dopamine release in LR rats. Further, we report a‐conotoxin PIA (100 nM), an a6‐selective antagonist, produced similar effects as the non‐selective antagonists, indicating that facilitation of dopamine in the HR rats is mediated by a6‐containing nAChR. When dopamine release in adolescent rats was tested under the same parameters, nAChR modulation of dopamine release was similar to HR adult rats, with non‐selective and a6‐selective antagonists facilitating dopamine release following phasic firing‐like stimulation. This suggests a role for a6‐containing nAChR modulation of striatal dopamine release in mediating vulnerability to drug abuse.Support or Funding InformationThis work is supported by NIDA grant R00 DA031791 awarded to MJFThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dopamine-sensitive signaling mediators modulate psychostimulant-induced ultrasonic vocalization behavior in rats

The mesolimbic dopamine system plays a major role in psychostimulant-induced ultrasonic vocalization (USV) behavior in rodents. Within this system, psychostimulants elevate synaptic concentrations of dopamine thereby leading to exaggerated activation of postsynaptic dopamine receptors within the D1-like and D2-like subfamilies. Dopamine receptor stimulation activate several transmembrane signaling systems and cognate intracellular mediators; downstream activation of transcription factors then conveys the information from receptor activation to appropriate modulation of cellular and physiologic functions. We previously showed that cocaine-induced USV behavior was associated with enhanced expression of the neurotrophin BDNF. Like cocaine, amphetamine also increases synaptic dopamine levels, albeit primarily through facilitating dopamine release. Therefore, in the present study we investigated whether amphetamine and cocaine similarly activate dopamine-linked signaling cascades to regulate intracellular mediators leading to induction of USV behavior. The results show that amphetamine increased the emission of 50kHz USVs and this effect was blocked by SCH23390, a D1 receptor antagonist. Similar to cocaine, amphetamine increased BDNF protein expression in discrete brain regions, while pretreatment with K252a, a trkB neurotrophin receptor inhibitor, significantly reduced amphetamine-induced USV behavior. Inhibition of cyclic-AMP/PKA signaling with H89 or inhibition of PLC signaling with U73122 significantly blocked both the acute and subchronic amphetamine-induced USV behavior. In contrast, pharmacologic inhibition of either pathway enhanced cocaine-induced USV behavior. Although cocaine and amphetamine similarly modulate neurotrophin expression and USV, the molecular mechanisms by which these psychostimulants differentially activate dopamine receptor subtypes or other monoaminergic systems may be responsible for the distinct aspects of behavioral responses.

The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues

Based on a report that sulfanylphthalimides are highly potent monoamine oxidase (MAO) B selective inhibitors, the present study examines the adenosine receptor affinities and MAO-B inhibitory properties of a series of 4- and 5-sulfanylphthalimide analogues. Since adenosine antagonists (A1 and A2A subtypes) and MAO-B inhibitors are considered agents for the therapy of neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, dual-target-directed drugs that antagonize adenosine receptors and inhibit MAO-B may have enhanced therapeutic value. The results document that the sulfanylphthalimide analogues are selective for the adenosine A1 receptor over the A2A receptor subtype, with a number of compounds also possessing MAO-B inhibitory properties. Among the compounds evaluated, 5-[(4-methoxybenzyl)sulfanyl]phthalimide was found to possess the highest binding affinity to adenosine A1 receptors with a Ki value of 0.369μM. This compound is reported to also inhibit MAO-B with an IC50 value of 0.020μM. Such dual-target-directed compounds may act synergistic in the treatment of Parkinson’s disease: antagonism of the A1 receptor may facilitate dopamine release, while MAO-B inhibition may reduce dopamine metabolism. Additionally, dual-target-directed compounds may find therapeutic value in Alzheimer’s disease: antagonism of the A1 receptor may be beneficial in the treatment of cognitive dysfunction, while MAO-B inhibition may exhibit neuroprotective properties. In neurological diseases, such as Parkinson’s disease and Alzheimer’s disease, dual-target-directed drugs are expected to be advantageous over single-target treatments.

Modulation of dopamine release in the striatum by physiologically relevant levels of nicotine.

Striatal dopamine (DA) release can be independently triggered not only by action potentials (APs) in dopaminergic axons but also APs in cholinergic interneurons (ChIs). Nicotine causes addiction by modulating DA release, but with paradoxical findings. Here, we investigate how physiologically relevant levels of nicotine modulate striatal DA release. The optogenetic stimulation of ChIs elicits DA release, which is potently inhibited by nicotine with an IC50 of 28 nM in the dorsal striatum slice. This ChI-driven DA release is predominantly mediated by α6β2* nAChRs. Local electrical stimulus (Estim) activates both dopaminergic axons and ChIs. Nicotine does not affect the AP(DA)-dependent DA release (AP(DA), AP of dopaminergic axon). During burst Estim, nicotine permits the facilitation of DA release by prevention of DA depletion. Our work indicates that cholinergic stimulation-induced DA release is profoundly modulated by physiologically relevant levels of nicotine and resolves the paradoxical observation of nicotine's effects on striatal DA release.

Cortisol administration induces global down-regulation of the brain's reward circuitry.

Research in rodents and humans has shown divergent effects of the glucocorticoids corticosterone and cortisol (CRT) on reward processing. In rodents, administration of CRT increases reward drive by facilitating dopamine release in the ventral striatum. In humans, correspondingly, risky decision-making increases when CRT levels are elevated. Human stress studies contrariwise show that elevated CRT is accompanied by a decrease in reward-related brain activity. There are however no direct insights into how CRT acts on the reward system in the human brain. Accordingly, we used pharmacological functional magnetic resonance imaging (pharmaco-fMRI) to investigate the effects of CRT on the brain's reward system. In a randomized within-subject design we administered a high dose of CRT (40 mg) and placebo to twenty healthy male volunteers on separate days, and used a monetary incentive delay task to assess the effects of the hormone on the striatum and the amygdala in anticipation of potential reward. In contrast to animal studies, we show that this high dose of CRT strongly decreases activity of the striatum in both reward and non-reward conditions. Furthermore, we observed reductions in activity in the basolateral amygdala, a key regulator of the brain's reward system. Crucially, the overall down-regulation of the brain's reward circuit was verified on the subjective level as subjects reported significantly reduced reward preference after CRT. In sum, we provide here direct evidence in humans that CRT acts on brain regions involved in reward-related behavior, that is, the basolateral amygdala and the striatum. Our findings suggest that CRT in the quantity and time course presently used globally down-regulates the reward system, and thereby decreases motivational processing in general.

Computational studies of the role of serotonin in the basal ganglia

It has been well established that serotonin (5-HT) plays an important role in the striatum. For example, during levodopa therapy for Parkinson's disease (PD), the serotonergic projections from the dorsal raphe nucleus (DRN) release dopamine as a false transmitter, and there are strong indications that this pulsatile release is connected to dyskinesias that reduce the effectiveness of the therapy. Here we present hypotheses about the functional role of 5-HT in the normal striatum and present computational studies showing the feasibility of these hypotheses. Dopaminergic projections to the striatum inhibit the medium spiny neurons (MSN) in the striatopalladal (indirect) pathway and excite MSNs in the striatonigral (direct) pathway. It has long been hypothesized that the effect of dopamine (DA) depletion caused by the loss of SNc cells in PD is to change the “balance” between the pathways to favor the indirect pathway. Originally, “balance” was understood to mean equal firing rates, but now it is understood that the level of DA affects the patterns of firing in the two pathways too. There are dense 5-HT projections to the striatum from the dorsal raphe nucleus and it is known that increased 5-HT in the striatum facilitates DA release from DA terminals. The direct pathway excites various cortical nuclei and some of these nuclei send inhibitory projections to the DRN. Our hypothesis is that this feedback circuit from the striatum to the cortex to the DRN to the striatum serves to stabilize the balance between the direct and indirect pathways, and this is confirmed by our model calculations. Our calculations also show that this circuit contributes to the stability of the dopamine concentration in the striatum as SNc cells die during Parkinson's disease progression (until late phase). There may be situations in which there are physiological reasons to “unbalance” the direct and indirect pathways, and we show that projections to the DRN from the cortex or other brain regions could accomplish this task.

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.

The AT1angiotensin II receptor blockade attenuates the development of amphetamine‐induced behavioral sensitization in a two‐injection protocol

It has been shown that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical, and neuroendocrine sensitization in rats. Dopaminergic neurotransmission in the nucleus accumbens and the caudate-putamen plays a critical role in the addictive properties of drugs of abuse. Angiotensin (Ang) II receptors are found on the soma and terminals of mesolimbic dopaminergic neurons and it has been shown that Ang II acting through its AT₁ receptors facilitates dopamine release. The hypothesis was tested that Ang II AT₁ receptors are involved in the neuroadaptative changes induced by a single exposure to amphetamine and that such changes are related to the development of behavioral and neurochemical sensitization. For this purpose, the study examined the expression of amphetamine-enhanced (0.5 mg kg⁻¹ i.p.) locomotor activity in animals pretreated with candesartan, an AT₁ blocker, (3 mg kg⁻¹ p.o. x 5 days), 3 weeks after an amphetamine injection (5 mg kg⁻¹ i.p.). Dopaminergic hyperreactivity was tested by measuring the 3H-DA release in vitro from caudate-putamen and nucleus accumbens slices, induced by K+ stimulus. It was confirmed the behavioral sensitization in the two-injection protocol and candesartan pretreatment attenuate this response. It was also found that AT₁ blockade pretreatment did not affect the locomotor response to dopamine agonists. In respect to the neurochemical sensitization tested using ex vivo 3H-DA release experiments it was found that AT₁ receptor pretreatment blunted the enhanced response induced by K+ stimulus. The results support the idea that the development of neuroadaptive changes induced by amphetamine involves brain AT₁ Ang II receptor activation.

In-vivo effects of the 1,2,4-piperazine derivatives MM5 and MC1, putative 5-HT agonists, on dopamine and serotonin release in rat prefrontal cortex

Two 1,2,4-substituted derivatives of piperazine were tested for their effect on dopamine and serotonin (5-HT) release in rat prefrontal cortex. Both compounds, 1-[4-(4-chinolin-2-yl-piperazin-1yl)-butyl]piperidin-2-on (MM5) and 1-[4-(2-methyl-4-chinolin-2-yl-piperazin-1-yl)-butyl]-8-azaspiro [4.5]decano-7,9-dion (MC1), produced hypothermia in mice and showed affinity for 5-HT1A receptors in-vitro. Like the selective 5-HT1A agonist 8-OH-DPAT (0.1 mg kg(-1)), MM5 given peripherally (30 mg kg(-1)) decreased the extracellular 5-HT level in rat prefrontal cortex, while MC1 suppressed 5-HT release at a higher dose (40 mg kg(-1)), but not at a lower one (30 mg kg(-1)). The effect of both compounds on 5-HT release was abolished by WAY 100635 (0.3 mg kg(-1)). MC1 (30 and 40 mg kg(-1)), but not MM5, raised cortical dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and extracellular homovanillic acid (HVA) levels. The effect of MC1 on dopamine release was reversed by neither WAY 100635 nor the non-selective 5-HT2 antagonist ritanserin (2 mg kg(-1)). However, ritanserin prevented the effect of the higher dose of MC1 on 5-HT release. The results of this study suggest that MM5 exhibits the profile of a 5-HT1A agonist devoid of dopaminergic activity. MC1 seems to possess moderate agonist activity at 5-HT1A and 5-HT2A receptors, while acting on 5-HT release in the rat prefrontal cortex. However, the facilitation of dopamine release by this compound does not seem to be related to its affinity for 5-HT1A and 5-HT2A receptors.

Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function

BackgroundNeurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc).ResultsDA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D2 autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D2 autoreceptors, quinpirole (1 μM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D2 receptor antagonist, sulpiride (5 μM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8–13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D2 autoreceptors. In addition, initial blockade of D2 autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8–13).ConclusionTaken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D2 autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.

Antidepressant treatment facilitates dopamine release and drug seeking behavior in a genetic animal model of depression

Anhedonia and lack of motivation are core symptoms of depression. In contrast, hyper-motivation and euphoria characterize intoxicated states. In order to explore the relationship between these two behavioral states we examined cocaine self-administration tasks in an animal model of depression [Flinders Sensitive Line (FSL) rats]. We found that FSL rats exhibit sub-sensitivity in their cocaine-seeking behavior, which was normalized following a chronic treatment with the antidepressant desipramine. However, when the cocaine dosage was increased, FSL rats demonstrated a similar cocaine-seeking behavior to that of controls. In light of dopamine's central role in modulating cocaine reinforcement, we examined dopaminergic neurotransmission in the nucleus accumbens, a brain region implicated in the rewarding and hedonic effects of substances of misuse. FSL rats exhibited low but dose-dependent increases in extracellular levels of dopamine in the nucleus accumbens after acute intravenous cocaine injection. Furthermore, by using the dopamine transporter blocker GBR-12909 we were able to demonstrate that the low extracellular dopamine levels, observed in FSL rats, were a consequence of low dopamine release in the nucleus accumbens, as opposed to the possibility of increased uptake. Treatment of FSL rats with the antidepressant desipramine raised cocaine- and GBR-12909-induced dopamine release to the level of controls. This treatment also resulted in increased cocaine-seeking behavior.

Mobilization of Calcium from Intracellular Stores Facilitates Somatodendritic Dopamine Release

Somatodendritic dopamine (DA) release in the substantia nigra pars compacta (SNc) shows a limited dependence on extracellular calcium concentration ([Ca(2+)](o)), suggesting the involvement of intracellular Ca(2+) stores. Here, using immunocytochemistry we demonstrate the presence of the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) that sequesters cytosolic Ca(2+) into the endoplasmic reticulum (ER), as well as inositol 1,4,5-triphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs) in DAergic neurons. Notably, RyRs were clustered at the plasma membrane, poised for activation by Ca(2+) entry. Using fast-scan cyclic voltammetry to monitor evoked extracellular DA concentration ([DA](o)) in midbrain slices, we found that SERCA inhibition by cyclopiazonic acid (CPA) decreased evoked [DA](o) in the SNc, indicating a functional role for ER Ca(2+) stores in somatodendritic DA release. Implicating IP(3)R-dependent stores, an IP(3)R antagonist, 2-APB, also decreased evoked [DA](o). Moreover, DHPG, an agonist of group I metabotropic glutamate receptors (mGluR1s, which couple to IP(3) production), increased somatodendritic DA release, whereas CPCCOEt, an mGluR1 antagonist, suppressed it. Release suppression by mGluR1 blockade was prevented by 2-APB or CPA, indicating facilitation of DA release by endogenous glutamate acting via mGluR1s and IP(3)R-gated Ca(2+) stores. Similarly, activation of RyRs by caffeine increased [Ca(2+)](i) and elevated evoked [DA](o). The increase in DA release was prevented by a RyR blocker, dantrolene, and by CPA. Importantly, the efficacy of dantrolene was enhanced in low [Ca(2+)](o), suggesting a mechanism for maintenance of somatodendritic DA release with limited Ca(2+) entry. Thus, both mGluR1-linked IP(3)R- and RyR-dependent ER Ca(2+) stores facilitate somatodendritic DA release in the SNc.

GDNF control of the glutamatergic cortico‐striatal pathway requires tonic activation of adenosine A2A receptors

Glial cell line-derived neurotrophic factor (GDNF) affords neuroprotection in Parkinson's disease in accordance with its ability to bolster nigrostriatal innervation. We previously found that GDNF facilitates dopamine release in a manner dependent on adenosine A(2A) receptor activation. As motor dysfunction also involves modifications of striatal glutamatergic innervation, we now tested if GDNF and its receptor system, Ret (rearranged during transfection) and GDNF family receptor alpha1 controlled the cortico-striatal glutamatergic pathway in an A(2A) receptor-dependent manner. GDNF (10 ng/mL) enhanced (by approximately 13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to approximately 30%) by the A(2A) receptor agonist CGS 21680 (10 nM) and prevented by the A(2A) receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GDNF family receptor alpha1 were located in 50% of rat striatal glutamatergic terminals (immunopositive for vesicular glutamate transporters-1/2), where they were found to be co-located with A(2A) receptors. Activation of the glutamatergic system upon in vivo electrical stimulation of the rat cortico-striatal input induced striatal Ret phosphorylation that was prevented by pre-treatment with the A(2A) receptor antagonist, MSX-3 (3 mg/kg). The results provide the first functional and morphological evidence that GDNF controls cortico-striatal glutamatergic pathways in a manner largely dependent on the co-activation of adenosine A(2A) receptors.

Ziprasidone-induced spontaneous orgasm

Neuroleptic treatment in schizophrenic patients has been associated with sexual dysfunction, including impotence and decreased libido. Spontaneous ejaculation without sexual arousal during typical antipsychotic treatment is a rare condition that has been described with zuclopentixol, trifluoperazine, and thiothixene. Here, we are reporting a case of spontaneous orgasm with ziprasidone in a bipolar patient. This patient began to repeatedly experience spontaneous sexual arousal and orgasm, which she had never experienced in the past. Ziprasidone might be causing an increase in sexual orgasm by 5-HT2 receptor antagonism, which preclinical evidence suggests that it facilitates dopamine release in the cortex.

5-HT6/7 Receptor Antagonists Facilitate Dopamine Release in the Cochlea via a GABAergic Disinhibitory Mechanism

In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume superfusion techniques we tested 5-HT(6) and 5-HT(7) receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic conditions using currently available and new 5-HT(6) and 5-HT(7) antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT(7) antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT(6) receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type of receptor. Moreover, the mixed 5-HT(6/7) antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement of an indirect neural mechanism through an inhibitory system. In the presence of the GABA(A) receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic inhibitory tone on dopaminergic nerve endings. The mixed 5-HT(7)/D(4) receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals in the cochlea may have a role in the treatment of sensorineural hearing loss.

How Mice Cope with Stressful Social Situations

Individuals differ greatly in their psychological responses to chronic stress. As a step toward understanding the neural basis for these individual differences, Krishnan et al. (2007) reveal molecular changes in the brain's reward circuits that make some mice resistant to the effects of social defeat.