Putative Dopamine Research Articles

CODA-RET reveals functional selectivity as a result of GPCR heteromerization

Here we present a novel method that combines protein complementation with resonance energy transfer to study conformational changes in response to activation of a defined G protein-coupled receptor heteromer, and we apply the approach to the putative dopamine D1-D2 receptor heteromer. Remarkably, the potency of the D2 receptor (D2R) agonist R(–)-Propylnorapomorphine (NPA) to change the Gαi conformation via the D2R protomer in the D1-D2 heteromer was enhanced 10-fold relative to that observed in the D2R homomer. In contrast, the potencies of the D2R agonists dopamine and quinpirole were the same in the homomer and heteromer. Thus, we have uncovered a molecular mechanism for functional selectivity, in which a drug acts differently at a GPCR protomer depending on the identity of the second protomer that participates in forming the signaling unit, opening the door to enhanced pharmacological specificity through targeting differences between homomeric and heteromeric signaling.

Dopamine D5 receptors are localized at asymmetric synapses in the rat hippocampus

Functional studies indicate that the dopamine D5 receptor is involved in synaptic transmission in the hippocampus. However, previous anatomical studies have detected D5 receptor labelling primarily on the soma and main dendrites of CA1 pyramidal cells and on dendritic spines in monkey but not in rats. In order to get a better understanding of putative dopamine function in the hippocampus, we quantified the D5 receptor immunoreactivity on the pyramidal cell somas and on spines and dendrites in stratum radiatum and stratum oriens in the hippocampal CA1 region of rats by quantitative immunofluorescence and immunogold electron microscopy. The quantitative immunogold results revealed a higher labelling density on dendritic spines, notably at their synaptic membranes, compared to pyramidal cell somas and dendrites. Hence, dopamine could have effects on spines as well as on somas and dendrites. The labelling density was similar on spines in stratum oriens and stratum radiatum, but the presence of labelling varied between the spines within each stratum, indicating that the effect of dopamine could be diverse between different spines.

Convergent Processing of Both Positive and Negative Motivational Signals by the VTA Dopamine Neuronal Populations

Dopamine neurons in the ventral tegmental area (VTA) have been traditionally studied for their roles in reward-related motivation or drug addiction. Here we study how the VTA dopamine neuron population may process fearful and negative experiences as well as reward information in freely behaving mice. Using multi-tetrode recording, we find that up to 89% of the putative dopamine neurons in the VTA exhibit significant activation in response to the conditioned tone that predict food reward, while the same dopamine neuron population also respond to the fearful experiences such as free fall and shake events. The majority of these VTA putative dopamine neurons exhibit suppression and offset-rebound excitation, whereas ∼25% of the recorded putative dopamine neurons show excitation by the fearful events. Importantly, VTA putative dopamine neurons exhibit parametric encoding properties: their firing change durations are proportional to the fearful event durations. In addition, we demonstrate that the contextual information is crucial for these neurons to respectively elicit positive or negative motivational responses by the same conditioned tone. Taken together, our findings suggest that VTA dopamine neurons may employ the convergent encoding strategy for processing both positive and negative experiences, intimately integrating with cues and environmental context.

Conjunctive Processing of Locomotor Signals by the Ventral Tegmental Area Neuronal Population

The ventral tegmental area (VTA) plays an essential role in reward and motivation. How the dopamine (DA) and non-DA neurons in the VTA engage in motivation-based locomotor behaviors is not well understood. We recorded activity of putative DA and non-DA neurons simultaneously in the VTA of awake mice engaged in motivated voluntary movements such as wheel running. Our results revealed that VTA non-DA neurons exhibited significant rhythmic activity that was correlated with the animal's running rhythms. Activity of putative DA neurons also correlated with the movement behavior, but to a lesser degree. More importantly, putative DA neurons exhibited significant burst activation at both onset and offset of voluntary movements. These findings suggest that VTA DA and non-DA neurons conjunctively process locomotor-related motivational signals that are associated with movement initiation, maintenance and termination.

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D(2) autoreceptors and subsequent activation of G protein-gated inwardly rectifying K(+) (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D(2) receptor/GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA(B) receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca(2+) with BAPTA augments D(2) inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP(3))-induced intracellular Ca(2+) release and Ca(2+)/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D(2), but not GABA(B), receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP(3) generation leads to cross-desensitization of D(2)/GIRK-mediated responses. We propose that enhancement of D(2) receptor-mediated autoinhibition via attenuation of a Ca(2+)-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.

Appetitive and aversive coding by the primate dorsal raph? nucleus

Event Abstract Back to Event Appetitive and aversive coding by the primate dorsal raphé nucleus Kae Nakamura1* 1 Kansai Medical University, Japan There is considerable evidence that the serotonin system is involved in reward-related behaviors. However, unlike the dopamine system, which has been discussed in relation to reward prediction error, the exact role of serotonin in the cognitive and motivational behavior has not been well understood. We therefore measured single neurons’ activity in the primate dorsal raphé nucleus (DRN), a major source of serotonin, while animals performed saccade tasks in which the position of the target indicated the size of an upcoming reward. We also recorded from putative dopamine neurons using the same tasks in the same animals. We found that many DRN neurons exhibited tonic modulation in activity in response to reward-related cues and reward outcomes, lasting throughout multiple phases of a behavioral task with either large- or small-reward preference. A positive correlation between activity after task initiation and activity after the value of the trial was revealed indicated that the DRN tracked progress toward future rewards in a consistent manner. Conversely, the putative dopamine neurons showed phasic responses to reward-indicating cues that preferred only large rewards, and were modulated only after the unexpected reversal of the position–reward contingency, which supported the reward prediction error signal hypothesis of dopamine. We further examined whether DRN neurons code aversive signals using a pavlovian conditioning task in which visual cues indicated upcoming rewards or aversive airpuffs. The DRN neurons again exhibited modulation in tonic activity depending on the expected appetitive or aversive events. These data suggest that the DRN neurons influence behavior in an adaptive manner based on tonic signals representing the worth of future motivational outcomes. Keywords: decision-making, DRN neurons Conference: XI International Conference on Cognitive Neuroscience (ICON XI), Palma, Mallorca, Spain, 25 Sep - 29 Sep, 2011. Presentation Type: Symposium: Oral Presentation Topic: Symposium 15: Serotonin, motivation and action in learning and decision-making Citation: Nakamura K (2011). Appetitive and aversive coding by the primate dorsal raphé nucleus. Conference Abstract: XI International Conference on Cognitive Neuroscience (ICON XI). doi: 10.3389/conf.fnhum.2011.207.00559 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 Nov 2011; Published Online: 28 Nov 2011. * Correspondence: Dr. Kae Nakamura, Kansai Medical University, Osaka, Japan, nakamkae@takii.kmu.ac.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Kae Nakamura Google Kae Nakamura Google Scholar Kae Nakamura PubMed Kae Nakamura Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Overcoming qEEG Abnormalities and Reward Gene Deficits during Protracted Abstinence in Male Psychostimulant and Polydrug Abusers Utilizing Putative Dopamine D2 Agonist Therapy: Part 2

Background: It is well established that in both food- and drug-addicted individuals there is “dopamine resistance” associated with the DRD2 gene A1 allele. Based on earlier studies, evidence is emerging wherein the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may play a significant role in the recovery of individuals with reward deficiency syndrome, including those addicted to psychoactive chemicals. Findings: Positive outcomes demonstrated by quantitative electroencephalographic (qEEG) imaging in a randomized, triple-blind, placebo-controlled, crossover study involving oral Synaptose Complex KB220Z™ showed an increase of alpha waves and low beta wave activity in the parietal brain region. Using t statistics, significant differences observed between placebo and Synaptose Complex KB220Z™ consistently occurred in the frontal regions after week 1 and then again after week 2 of analyses (P = 0.03). This is the first report to demonstrate involvement of the prefrontal cortex in the qEEG response to a natural putative D2 agonist (Synaptose Complex KB220Z™), especially evident in dopamine D2 A1 allele subjects. Independently, we have further supported this finding with an additional study of 3 serious polydrug abusers undergoing protracted abstinence who carried the DRD2 A1 allele. Significant qEEG differences were found between those who received 1 dose of placebo compared with those who were administered Synaptose Complex KB220Z™. Synaptose Complex KB220Z™ induced positive regulation of the dysregulated electrical activity of the brain in these addicts. The results are indicative of a phase change from low amplitude or low power in the brain to a more regulated state by increasing an average of 6.169 mV2 across the prefrontal cortical region. In the first experiment we found that while 50% of the subjects carried the DRD2 A1 allele, 100% carried ≥ 1 risk allele. Specifically, based on the proposed addiction risk score for these 14 subjects, 72% had moderate-to-severe addiction risk. Similar findings were obtained by repeating the experiment in 3 additional currently abstinent polydrug abusers carrying the DRD2 A1 allele. Conclusion: This seminal work will provide important information that may ultimately lead to significant improvement in the recovery of individuals with psychostimulant and polydrug abuse problems, specifically those with genetically induced dopamine deficiency. Based on this small sample size, we are proposing that with necessary large populations supporting these initial results, and possibly even additional candidate genes and single nucleotide polymorphisms, we may eventually have the clinical ability to classify severity according to genotype and possession of risk alleles, along with offering a safe, nonaddicting, natural dopaminergic receptor agonist that potentially upregulates instead of downregulates dopaminergic receptors, preferably the D2 subtype.

Analysis of the actions of the novel dopamine receptor‐directed compounds (S)‐OSU6162 and ACR16 at the D2 dopamine receptor

BACKGROUND AND PURPOSE; The two phenylpiperidines, OSU6162 and ACR16, have been proposed as novel drugs for the treatment of brain disorders, including schizophrenia and Huntington's disease, because of their putative dopamine stabilizing effects. Here we evaluated the activities of these compounds in a range of assays for the D(2) dopamine receptor in vitro. The affinities of these compounds for the D(2) dopamine receptor were evaluated in competition with [(3) H]spiperone and [(3) H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [(35) S]GTPγS binding. Both compounds had low affinities for inhibition of [(3) H]spiperone binding (pK(i) vs. [(3) H]spiperone, ACR16: <5, OSU6162: 5.36). Neither compound was able to stimulate [(35) S]GTPγS binding when assayed in the presence of Na(+) ions, but if the Na(+) ions were removed, both compounds were low-affinity, partial agonists (E(max) relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [(35) S]GTPγS binding indicated Schild slopes of ∼0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [(3) H]NPA dissociation from D(2) dopamine receptors, indicating some allosteric effects of this compound. The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D(2) dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro-in vivo correlation for agonist efficacy needs to be further addressed. This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.

Pavlovian-Instrumental Interaction in ‘Observing Behavior’

Subjects typically choose to be presented with stimuli that predict the existence of future reinforcements. This so-called ‘observing behavior’ is evident in many species under various experimental conditions, including if the choice is expensive, or if there is nothing that subjects can do to improve their lot with the information gained. A recent study showed that the activities of putative midbrain dopamine neurons reflect this preference for observation in a way that appears to challenge the common prediction-error interpretation of these neurons. In this paper, we provide an alternative account according to which observing behavior arises from a small, possibly Pavlovian, bias associated with the operation of working memory.

Putative γ‐aminobutyric acid neurons in the ventral tegmental area have a similar pattern of plasticity as dopamine neurons during appetitive and aversive learning

Dopamine influences affective, motor and cognitive processing, and multiple forms of learning and memory. This multifaceted functionality, which operates across long temporal windows, is broader than the narrow and temporally constrained role often ascribed to dopamine neurons as reward prediction error detectors. Given the modulatory nature of dopamine neurotransmission, that dopamine release is activated by both aversive and appetitive stimuli, and that dopamine receptors are often localized extrasynaptically, a role for dopamine in transmitting precise error signals has been questioned. Here we recorded from ventral tegmental area (VTA) neurons, while exposing rats to novel stimuli that were predictive of an appetitive or aversive outcome in the same behavioral session. The VTA contains dopamine and -aminobutyric acid (GABA) neurons that project to striatal and cortical regions and are strongly implicated in learning and affective processing. The response of VTA neurons, regardless of whether they had putative dopamine or GABA waveforms, transformed flexibly as animals learned to associate novel stimuli from different sensory modalities to appetitive or aversive outcomes. Learning the appetitive association led to larger excitatory VTA responses, whereas acquiring the aversive association led to a biphasic response of brief excitation followed by sustained inhibition. These responses shifted rapidly as outcome contingencies changed. These data suggest that VTA neurons interface sensory information with representational memory of aversive and appetitive events. This pattern of plasticity was not selective for putative dopamine neurons and generalized to other cells, suggesting that the temporally precise information transfer from the VTA may be mediated by faster acting GABA neurons.

Spontaneous Electrical Activity in the Nervous System and its Modification by Biogenic Amines in the Silkworm &lt;i&gt;Bombyx Mori &lt;/i&gt;(L)

The present study was carried out to examine the effects of biogenic amines on the spontaneous electrical activity of the nervous system in the silkworm Bombyx mori. The activity recorded from different segments of the ventral nerve cord differed in the frequency and number of spike categories firing. The activity was highest between the subesophageal ganglion and 1st thoracic ganglion. Lower activity was recorded in the thoracic part of the cord and the activity increased in the abdominal cord. More or less the same level of activity was recorded from all the abdominal segments of the cord. The above trend was the same from the 1st day to the 7th day of the 5th instar of the silkworm. However, the overall level of activity increased from the 1st day to the 7th day in tune with the increasing complexity of the peripheral nervous system in the silkworm as the 5th instar progressed. Treatment of the cord with solutions of putative neurotransmitter substances, viz. epinephrine (EP), norepinephrine (NEP), dopamine (DA) and 5-hydroxytryptamine (5-HT) at different concentrations from 1x10-8 M to 1x10-4 M showed elevation at lower concentrations anddecrease at 1x10-4 M. The concentration at which maximum elevation could be elicited varied between the above transmitters. Biochemical analyses revealed the presence of these biogenic amines in the silkworm nervous system. Thus the possibility remains that one or more of these substances could act as neurotransmitters in the silkworm nervous system.Keywords: Silkworm; 5th Instar; Spontaneous electrical activity;Biogenic amines; Neurotransmitters.

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Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of α7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2 h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective α7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178–1.78 mg/kg) and the compound effect was found to be absent in homozygous α7 KO animals. Together, these data indicate that selective interaction with α7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective α7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.

Dopamine Signaling Differences in the Nucleus Accumbens and Dorsal Striatum Exploited by Nicotine

The dorsal striatum and the nucleus accumbens (NAc) shell of the ventral striatum have similar cellular components and are both richly innervated by dopamine neurons. Despite similarities that extend throughout the striatum, only the NAc shell has a conspicuous increase in basal dopamine upon the initial administration of psychostimulant drugs such as nicotine. As measured by microdialysis, the elevated dopamine in the NAc shell is considered an identifying functional characteristic of addictive drugs. To examine this general functional difference between nicotine's action on the dorsolateral striatum and NAc shell, we directly monitored dopamine release in rat striatal slices using fast-scan cyclic voltammetry. In addition, we separately monitored the in vivo unit firing activity of putative midbrain dopamine neurons from freely moving rats using chronic multiple tetrodes. Nicotine administration increased the firing frequency of dopamine neurons and specifically increased the number and the length of phasic burst firing. The frequency dependence for dopamine release in the dorsolateral striatum and NAc shell is fundamentally different, enabling mainly the NAc shell to capitalize on the nicotine-induced phasic burst firing by dopamine neurons. Although nicotine decreased low-frequency (tonic) dopamine release in both areas, the increased ratio of phasic bursts relative to tonic firing caused by nicotine boosted the basal dopamine concentration predominantly in the NAc shell. By favoring release from bursts while depressing release from tonic signals, nicotine spreads the range of dopamine signaling and effectively increases the signal-to-noise relationship along dopamine afferents.

In vitro and in vivo evaluation of [18F]FHTP as a potential dopamine D4 receptor PET imaging agent

3-(4-[18F]fluorobenzyl)-8-hydroxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one ([18F]FHTP) was in vitro and in vivo evaluated as a putative dopamine D4 receptor radioligand. Its inhibition constant (Ki) for cloned human dopamine D4.2 receptor was determined to be 2.9 nM and it displayed a 2000-fold D4-selectivity over the D2long subtype. Its partition coefficient (logP) was measured to be 1.11. Biodistribution, blocking distribution and metabolism studies in rats demonstrated that the specific distribution of [18F]FHTP in brain regions, suggesting that [18F]FHTP may be a suitable PET imaging agent for in vivo studies of the dopamine D4 receptor.

Critical review of ropinirole and pramipexole - putative dopamine D3-receptor selective agonists - for the treatment of RLS

Ropinirole hydrochloride (REQUIP, ADARTREL) and pramipexole dihydrochloride (MIRAPEX, SIFROL) are two putative dopamine D(3) receptor subtype-selective agonists recently approved by the FDA for the treatment of 'restless legs syndrome' (RLS). RLS is a difficult to define condition that is possibly more prevalent than previously thought. Direct-to-consumer advertising has raised public and professional awareness of RLS, but questions, even skepticism about the very existence of the condition, persist. The drugs have adverse effects that can negatively impact on quality of life and thus, as true for all drugs, require consideration of the benefit : risk ratio. We review the definition, diagnostic criteria, pathophysiology, and treatment of RLS, and assess the clinical and preclinical evidence for a pharmacologic rationale for D(3) agonism in general and of the claimed D(3) selectivity of ropinirole and pramipexole in particular.

Two Distinct Dopamine D2 Receptor Genes in the European Eel: Molecular Characterization, Tissue-Specific Transcription, and Regulation by Sex Steroids

Two full-length cDNA encoding putative dopamine D2-like receptors were cloned from the brain of female European eel. The deduced protein sequences, termed D2A- and D2B-R, exhibit closer phylogenetic relationships to vertebrate D2 receptors compared with D3 and D4 or D1 receptors. The two protein sequences share 100% identity within the transmembrane domains containing the highly conserved amino acids involved in dopamine binding. Accordingly, an apparent single population of sites on eel brain membranes bound [(3)H]spiperone, a D2-R-specific antagonist, with a K(d) of 0.2 +/- 0.04 nM. However, D2A- and D2B-R significantly differ within the amino terminus and the third intracellular loop. As analyzed by quantitative PCR and in situ hybridization, both receptor transcripts were found, with different relative abundance, in the majority of brain areas and in the pituitary, whereas in the retina, olfactory epithelium, spinal cord, and adipose tissue, only D2A-R gene was expressed. Because sex steroid hormones recently have been shown to regulate eel brain dopamine systems, we analyzed the effect of steroids on the amount of D2-R transcripts by quantitative PCR and in situ hybridization. In eels treated with testosterone, the gene expression of the D2B-R, but not D2A-R, was increased in a region-dependent manner. The effect of testosterone on D2B-R transcript levels was mimicked by dihydrotestosterone, a nonaromatizable androgen, whereas estradiol had no stimulatory action, evidencing an androgen receptor-dependent mechanism. Although functionality of the two receptors awaits determination of D2-R proteins, we hypothesize that differences in the tissue expression pattern and hormonal regulation of eel D2A- and D2B-R gene expression could represent selective forces that have contributed to the conservation of the duplicated D2-R.

Tripartite mechanism of extinction suggested by dopamine neuron activity and temporal difference model.

Extinction of behavior enables adaptation to a changing world and is crucial for recovery from disorders such as phobias and drug addiction. However, the brain mechanisms underlying behavioral extinction remain poorly understood. Midbrain dopamine (DA) neurons appear to play a central role in most acquisition processes of appetitive conditioning. Here, we show that the responses of putative DA neurons to conditioned reward predicting cues also dynamically encode two classical features of extinction: decrement in amplitude of previously learned excitatory responses and rebound of responding on subsequent retesting (spontaneous recovery). Crucially, this encoding involves development of inhibitory responses in the DA neurons, reflecting new, extinction-specific learning in the brain. We explored the implications of this finding by adding such inhibitory inputs to a standard temporal difference model of DA cell activity. We found that combining extinction-triggered plasticity of these inputs with a time-dependent spontaneous decay of weights, equivalent to a forgetting process as described in classical behavioral extinction literature, enabled the model to simulate several classical features of extinction. A key requirement to achieving spontaneous recovery was differential rates of spontaneous decay for weights representing original conditioning and for subsequent extinction learning. A testable prediction of the model is thus that differential decay properties exist within the wider circuits regulating DA cell activity. These findings are consistent with the hypothesis that extinction processes at both cellular and behavioral levels involve a dynamic interaction between new (inhibitory) learning, forgetting, and unlearning.

Cyclooxygenase‐2 deficiency modifies the neurochemical effects, motor impairment and co‐morbid anxiety provoked by paraquat administration in mice

Parkinson's disease and other motor disorders of midbrain basal ganglia dopaminergic functioning are often characterized by alterations of brainstem and limbic systems with accompanying co-morbid anxiety and depressive symptoms. Accumulating evidence suggests that inflammatory processes may play an important role in such neurodegenerative and psychiatric pathology. In this regard, inhibition of the inflammatory enzyme cyclooxygenase-2 (COX-2) was reported to limit the impact of stressors as well as the neurodegenerative effects of dopaminergic toxins. The present investigation assessed the impact of the putative dopamine toxin paraquat (a widely used herbicide) upon motor functioning, behavioural indices of anxiety-like states and central monoamine levels and whether these effects were altered in mice lacking COX-2. Indeed, paraquat did induce motor impairment and altered dopamine utilization within the striatum, and COX-2 deletion moderately attenuated these effects. Conversely, COX-2 deficiency enhanced the impact of paraquat upon indices of anxiety (open field exploration) and on serotonergic, noradrenergic and dopaminergic alterations within two brain regions implicated in stressor-related pathologies, namely the dorsal hippocampus and medial prefrontal cortex. These results suggest that COX-2 might differentially influence the motor and psychiatric symptoms associated with environmental toxin exposure. Furthermore, these data indicate that the neurochemical impact of paraquat is not restricted to the nigrostriatal dopamine pathway but also involves stressor-sensitive limbic regions. It is possible that COX-2 may play a dual role by contributing to the motor impairment induced by paraquat, but acting to moderate the effects of paraquat upon processes aligned with anxiety and depression.

Reward-Dependent Modulation of Neuronal Activity in the Primate Dorsal Raphe Nucleus

The dopamine system has been thought to play a central role in guiding behavior based on rewards. Recent pharmacological studies suggest that another monoamine neurotransmitter, serotonin, is also involved in reward processing. To elucidate the functional relationship between serotonin neurons and dopamine neurons, we performed single-unit recording in the dorsal raphe nucleus (DRN), a major source of serotonin, and the substantia nigra pars compacta, a major source of dopamine, while monkeys performed saccade tasks in which the position of the target indicated the size of an upcoming reward. After target onset, but before reward delivery, the activity of many DRN neurons was modulated tonically by the expected reward size with either large- or small-reward preference, whereas putative dopamine neurons had phasic responses and only preferred large rewards. After reward delivery, the activity of DRN neurons was modulated tonically by the received reward size with either large- or small-reward preference, whereas the activity of dopamine neurons was not modulated except after the unexpected reversal of the position-reward contingency. Thus, DRN neurons encode the expected and received rewards, whereas dopamine neurons encode the difference between the expected and received rewards. These results suggest that the DRN, probably including serotonin neurons, signals the reward value associated with the current behavior.