Dopaminergic Influence Research Articles

Morphological changes in gray matter volume correlate with catechol-O-methyl transferase gene Val158Met polymorphism in first-episode treatment-naïve patients with schizophrenia.

The catechol-O-methyltransferase (COMT) gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene, Val158/158Met, has been proposed to influence gray matter volume (GMV). However, the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study, we explored the relationship between the Val158Met polymorphism of the COMT gene and the GMV/cortical thickness/cortical surface area in 150 first-episode treatment-naïve patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual, medial temporal, parietal, and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover, a diagnosis × genotype interaction was found for the GMV of the left precuneus, and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition, a pattern of increased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia, and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area.

Lack of association of COMT Val158Met polymorphism with attention and executive function in patients with schizophrenia

To explore the association of a functional polymorphism Val158Met of COMT gene and attention and executive function in first-episode treatment-naive patients with schizophrenia and healthy controls. Trail making test (TMT) and clinical performances were evaluated in 103 first-episode treatment-naive patients with schizophrenia and 99 healthy controls. Polymorphism of COMT Val158Met was analyzed using polymerase chain reaction-restriction fragment length polymorphism method. A general linear model was used to investigate the effect of genotype subgroups on the attention and executive function. There was a significant difference between control subjects and patients with schizophrenia on the TMT-A and B. However, no significant difference among Val/Val, Val/Met and Met/Met on the TMT-A and B in control subjects and patients with schizophrenia was detected. The association among COMT Met variant and trail making testing (attention and executive function) has been replicated. However, no association of COMT Met variant with disruption of dopaminergic influence on neurocognitive function was detected. This may be due to the heterogeneity of population.

Dopamine-Modulated Recurrent Corticoefferent Feedback in Primary Sensory Cortex Promotes Detection of Behaviorally Relevant Stimuli

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D1/D5 receptor distributions display a layer-dependent organization, suggesting specific functions in the cortical circuitry. However, the circuit effects of dopaminergic neurotransmission in sensory cortex and their possible roles in perception, learning, and memory are largely unknown. Here, we investigated layer-specific circuit effects of dopaminergic neuromodulation using current source density (CSD) analysis in AI of Mongolian gerbils. Pharmacological stimulation of D1/D5 receptors increased auditory-evoked synaptic currents in infragranular layers, prolonging local thalamocortical input via positive feedback between infragranular output and granular input. Subsequently, dopamine promoted sustained cortical activation by prolonged recruitment of long-range corticocortical networks. A detailed circuit analysis combining layer-specific intracortical microstimulation (ICMS), CSD analysis, and pharmacological cortical silencing revealed that cross-laminar feedback enhanced by dopamine relied on a positive, fast-acting recurrent corticoefferent loop, most likely relayed via local thalamic circuits. Behavioral signal detection analysis further showed that activation of corticoefferent output by infragranular ICMS, which mimicked auditory activation under dopaminergic influence, was most effective in eliciting a behaviorally detectable signal. Our results show that D1/D5-mediated dopaminergic modulation in sensory cortex regulates positive recurrent corticoefferent feedback, which enhances states of high, persistent activity in sensory cortex evoked by behaviorally relevant stimuli. In boosting horizontal network interactions, this potentially promotes the readout of task-related information from cortical synapses and improves behavioral stimulus detection.

Dopaminergic influences on executive function and impulsive behaviour in impulse control disorders in Parkinson's disease

The development of impulse control disorders (ICDs) in Parkinson's disease (PD) may arise from an interaction among cognitive impairment, impulsive responding and dopaminergic state. Dopaminergic state may be influenced by pharmacologic or genotypic (catechol-O-methyltransferase; COMT) factors. We sought to investigate this interaction further by comparing those with (n=35) and without (n=55) ICDs on delay-discounting in different pharmacologic conditions (ON or OFF dopaminergic medication) and on response inhibition as well as aspects of executive functioning in the ON state. We then undertook an exploratory sub-group analysis of these same tasks when the overall PD group was divided into different allelic variants of COMT (val/val vs. met/met). A healthy control group (HC; n=20) was also included. We found that in those with PD and ICDs, 'cognitive flexibility' (set shifting, verbal fluency, and attention) in the ON medication state was not impaired compared with those without ICDs. In contrast, our working memory, or 'cognitive focus', task was impaired in both PD groups compared with the HC group when ON. During the delay-discounting task, the PD with ICDs group expressed greater impulsive choice compared with the PD group without ICDs, when in the ON, but not the OFF, medication state. However, no group difference on the response inhibition task was seen when ON. Finally, the met homozygous group performed differently on tests of executive function compared with the val homozygous group. We concluded that the disparity in levels of impairment among different domains of executive function and impulsive decision-making distinguishes those with ICD in PD from those without ICD, and may in part be affected by dopaminergic status. Both pharmacologic and genotypic influences on dopaminergic state may be important in ICD.

Assaying the Effect of Levodopa on the Evaluation of Risk in Healthy Humans

In humans, dopamine is implicated in reward and risk-based decision-making. However, the specific effects of dopamine augmentation on risk evaluation are unclear. Here we sought to measure the effect of 100 mg oral levodopa, which enhances synaptic release of dopamine, on choice behaviour in healthy humans. We use a paradigm without feedback or learning, which solely isolates effects on risk evaluation. We present two studies (n = 20; n = 20) employing a randomised, placebo-controlled, within-subjects design. We manipulated different dimensions of risk in a controlled economic paradigm. We test effects on risk-reward tradeoffs, assaying both aversion to variance (the spread of possible outcomes) and preference for relative losses and gains (asymmetry of outcomes - skewness), dissociating this from potential non-specific effects on choice randomness using behavioural modelling. There were no systematic effects of levodopa on risk attitudes, either for variance or skewness. However, there was a drift towards more risk-averse behaviour over time, indicating that this paradigm was sensitive to detect changes in risk-preferences. These findings suggest that levodopa administration does not change the evaluation of risk. One possible reason is that dopaminergic influences on decision making may be due to changing the response to reward feedback.

A unifying perspective on neuromodulatory effects on signal transmission and plasticity in D1-dominant MSN neurons

How could phasic variations in dopamine level affect the learning outcome of a spiking neural network? How may neuromodulation affect the network's instantaneous response to simultaneously arriving glutamatergic inputs? How may this depend on the brain regions involved? In our spiking phenomenological model for signal transmission across the synapse and along the dendritic tree, we propose a new approach for the influence of dopamine-like neuromodulators on the ascribed aspects, which unifies diverging views on its role in (reinforcement) learning and (attentional) contrast. We call into question the common practice of simulating dopaminergic influence on an STDP rule as a third factor, and instead show how an instantaneous effect of a dopamine-like neuromodulator on postsynaptic activity can also lead to reinforced learning outcomes. As the phasic change of neuromodulator needs to be present during glutamatergic transmission in our model, we do not account for delayed reward as stated in the distal reward problem. Instead, we assume an involvement of hippocampus and cortical working memory for long delays of reward. However, as our transmission-based model does not interfere with the standard two-factor STDP rule, it may be freely combined with existing extensions to STDP if needed.

Dopamine Modulates Reward-Related Vigor

Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects' responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence.

810 – Zolpidem-induced galactorrhea via gabaergic inhibition of dopamine: a case report

Objective To discuss a case of zolpidem-induced galactorrhea. Introduction The prevalence of insomnia can be as high as 32 to 33%. Non-benzodiazepines (such as zolpidem) have become more commonly used to treat insomnia. Case report The patient is a 29-year-old woman with a history of (PTSD) who presented with PTSD associated insomnia. She was started on zolpidem 5 mg po qhs. Two months after the initiation of zolpidem treatment, the patient presented with breast tenderness and galactorrhea. Zolpidem was discontinued and the galactorrhea resolved after two weeks. A serum prolactin level drawn shortly after discontinuation of zolpidem was 15.67 mg/ml. Discussion Zolpidem has a high affinity at the α1 containing GABAA receptors, with reduced affinity for those containing the α2- and α3- GABAA receptor subunits and minimal affinity for α5 receptor subunit. Psychotropic drugs have been well recognized to produce hyperprolactinemia. However, there has been no reported case of zolpidem-induced hyperprolactinemia. Specifically, zolpidem has been noted to activate GABAergic neurons within the ventral tegmental area (VTA), where there is a sizable population of GABAergic neurons. These GABAergic neurons regulate the firing of dopaminergic counterparts, also located in the VTA, which send projections throughout the brain. This inhibition results in a decrease in the dopaminergic inhibitory influence on prolactin and an increase in prolactin releasing factors which act on the anterior pituitary, leading to hyperprolactinemia and thus galactorrhea. Conclusion Pharmacologically induced hyperprolactinemia may be a problem of underestimated prevalence due to the lack of externally visible symptoms.

Learning‐dependent plasticity in human auditory cortex during appetitive operant conditioning

Animal experiments provide evidence that learning to associate an auditory stimulus with a reward causes representational changes in auditory cortex. However, most studies did not investigate the temporal formation of learning-dependent plasticity during the task but rather compared auditory cortex receptive fields before and after conditioning. We here present a functional magnetic resonance imaging study on learning-related plasticity in the human auditory cortex during operant appetitive conditioning. Participants had to learn to associate a specific category of frequency-modulated tones with a reward. Only participants who learned this association developed learning-dependent plasticity in left auditory cortex over the course of the experiment. No differential responses to reward predicting and nonreward predicting tones were found in auditory cortex in nonlearners. In addition, learners showed similar learning-induced differential responses to reward-predicting and nonreward-predicting tones in the ventral tegmental area and the nucleus accumbens, two core regions of the dopaminergic neurotransmitter system. This may indicate a dopaminergic influence on the formation of learning-dependent plasticity in auditory cortex, as it has been suggested by previous animal studies.

Differential ROS production in non‐neuronal brain cell subsets in response to Methamphetamine

The production of Reactive Oxygen Species (ROS) leads to neurodegeneration in Meth abusers. We examined the contribution of ROS from non‐neuronal cells that affect local immunity and neuron survival in the brain. Using astrocyte (C8S), microglia (BV2) and macrophage (THP1) cell lines we show direct and differential effects of Meth on ROS pathways. Basal levels of H2O2 from macrophages and microglia (MM) were higher than those released by astrocytes. Meth reduced H2O2 in MM, but increased it in astrocytes, in a dose‐dependent manner. Rotenone, Superoxide Dysmutase and Antimycin A further reduced ROS in MM but increased it in astrocytes. This indicates that 1) mitochondria are important sources of H2O2 in MM, 2) superoxide is released to the extracellular space by astrocytes and 3) astrocytes have more tightly coupled mitochondria. In the presence of PMA, Meth highly exacerbated H2O2 production in astrocytes (> 400%) in a dose‐dependent manner, but MM cells produced less H2O2 at higher Meth dose. This indicates 4) a role of Meth downstream of the PKC feedback‐activation of NADPH oxidase (NOX) in astrocytes, and not in MM. Our data suggest that Meth directly enhances NOX‐generated ROS in astrocytes and reduces mitochondrial ROS in all cells, in an environment that excludes dopaminergic influence.

Effects of Intrastriatal and Systemic Microinjections of Nicotine on Motor Behavior and Its Motor and Postural Components in Dogs

In chronic experiments in dogs on a model of instrumental avoidance reflex we have found that intrastriatal and/or systemic injection of nicotine causes a significant prolonged increase of motor excitability. By decrease of latent period of instrumental reflex, an increase of amplitude of reflex was shown and, in some cases, by increase of conditional flexion maintenance time. An interesting feature of instrumental reflex in our investigations was both strengthening of cholinergic influence and strengthening of dopaminergic influence. The former is shown by sharp strengthening of tonic component of answer, the latter--by increase of answer amplitude and decrease of its latency, increase of general excitability.

Neural correlates of sleepiness induced by catecholamine depletion

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep–wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups. The CD-induced prolactin increase significantly correlated with CD-induced sleepiness but not with CD-induced mood and anxiety symptoms. CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep.

Acute stress alters auditory selective attention in humans independent of HPA: a study of evoked potentials.

BackgroundAcute stress is a stereotypical, but multimodal response to a present or imminent challenge overcharging an organism. Among the different branches of this multimodal response, the consequences of glucocorticoid secretion have been extensively investigated, mostly in connection with long-term memory (LTM). However, stress responses comprise other endocrine signaling and altered neuronal activity wholly independent of pituitary regulation. To date, knowledge of the impact of such “paracorticoidal” stress responses on higher cognitive functions is scarce.We investigated the impact of an ecological stressor on the ability to direct selective attention using event-related potentials in humans. Based on research in rodents, we assumed that a stress-induced imbalance of catecholaminergic transmission would impair this ability.Methodology/Principal FindingsThe stressor consisted of a single cold pressor test. Auditory negative difference (Nd) and mismatch negativity (MMN) were recorded in a tonal dichotic listening task. A time series of such tasks confirmed an increased distractibility occuring 4–7 minutes after onset of the stressor as reflected by an attenuated Nd. Salivary cortisol began to rise 8–11 minutes after onset when no further modulations in the event-related potentials (ERP) occurred, thus precluding a causal relationship.This effect may be attributed to a stress-induced activation of mesofrontal dopaminergic projections. It may also be attributed to an activation of noradrenergic projections. Known characteristics of the modulation of ERP by different stress-related ligands were used for further disambiguation of causality. The conjuncture of an attenuated Nd and an increased MMN might be interpreted as indicating a dopaminergic influence. The selective effect on the late portion of the Nd provides another tentative clue for this.Conclusions/SignificancePrior studies have deliberately tracked the adrenocortical influence on cognition, as it has proven most influential with respect to LTM. However, current cortisol-optimized study designs would have failed to detect the present findings regarding attention.

Neurons of the Dopaminergic/Calcitonin Gene-Related Peptide A11 Cell Group Modulate Neuronal Firing in the Trigeminocervical Complex: An Electrophysiological and Immunohistochemical Study

Activation of spinal trigeminal afferents innervating the cranial vasculature is likely to play a role in migraine, although some parts of the clinical presentation may have a dopaminergic basis. The A11 nucleus, located in the posterior hypothalamus, provides the only known source of descending dopaminergic innervation for the spinal gray matter. Extracellular recordings were made in the trigeminocervical complex (TCC) in response to electrical stimulation of the dura mater. Receptive fields were characterized by mechanical noxious and innocuous stimulation of the ipsilateral ophthalmic dermatome. Stimulation of the A11 significantly inhibited peri-middle meningeal artery dural and noxious pinch evoked firing of neurons in the TCC. This inhibition was reversed by the D(2) receptor antagonist eticlopride. Lesioning of the A11 significantly facilitated dural and noxious pinch and innocuous brush evoked firing from the TCC. In previous work using immunohistofluorescence, it was shown that D(1) and D(2) receptors were found in the rat TCC, and here we report, in addition, that D(4) and D(5) dopamine receptors are also present, whereas D(3) receptors are not. No dopamine receptors were present in the A11 nucleus itself. However, the A11 does contain dopamine and calcitonin gene-related peptide (CGRP) and, by this combination, is distinct from the neighboring CGRPergic subparafascicular nucleus. Exploration of dopaminergic influences and mechanisms in migraine may open up an almost untapped opportunity to pursue potential new therapeutic options for the disorder.

Influence of Dopaminergically Mediated Reward on Somatosensory Decision-Making

Author SummaryThe rewards one receives during decision-making has a profound impact on learning. Much recent interest has focused on the role of the neurotransmitter dopamine in the basal ganglia for influencing learning and behaviour. Here, we ask whether reward can influence low-level sensory processing, for instance in primary sensory cortex, and how dopamine mediates this process. We show in humans that dopamine level, as manipulated with a dopamine agonist and antagonist in a double-blind placebo-controlled design, is involved in reward modulation of primary somatosensory cortex. Higher anticipated reward improved tactile decisions, and receipt of visual reward signals reactivated primary somatosensory cortex for the judged hand as measured using functional neuroimaging. After receiving a higher reward on one trial, somatosensory activations and decisions were enhanced on the next trial, suggesting that reward outcome provides a form of teaching signal that may be fed back to task-relevant sensory cortex. All these behavioural and neural effects of reward on somatosensory decision-making were strongly modulated by the availability of dopamine as the mediating neurotransmitter. These findings raise the tantalising new possibility that reward manipulations in conjunction with dopaminergic drugs might be used to enhance pathologically deficient or lapsed sensory processes, analogous to how rewards can be used to shape or correct behaviour.

Dopaminergic influence on rat tongue function and limb movement initiation.

Altering dopamine synaptic transmission can affect both cranial and limb sensorimotor function, but often to a different degree of severity. We hypothesized that haloperidol has dose-dependent but differential effects on lingual forces, lingual movement rates, and limb movement initiation. We measured average and maximal lingual force, tongue press rate and cataleptic descent time in nine Fischer 344/Brown Norway rats in varied doses of haloperidol. Decreases in lingual force and temporal parameters and increases in cataleptic descent time were related to haloperidol dose. However, they were related to a different degree as the relationships were strong between average force and tongue press rate, moderate between maximal force and tongue press rate, moderate between average force and cataleptic descent time, and weak between maximal force and cataleptic descent time. Elucidating the relationships between the cranial and limb sensorimotor systems in the context of altered dopamine synaptic transmission may assist in developing therapies for conditions such as Parkinson's disease.

44. Dopaminergic influence on the control of the maximum force with Parkinson’s patients

44. Dopaminergic influence on the control of the maximum force with Parkinson’s patients

Dopamine induced switch in the subthreshold dynamics of the striatal cholinergic interneurons: A numerical study

The striatum is a part of the basal ganglia, which are a group of nuclei in the brain associated with motor control, cognition and learning. Striatal cholinergic interneurons (AchNs) play a crucial role in these functions. AchNs are tonically active in vivo and in vitro, and are able to fire in the absence of synaptic inputs. AchNs respond to sensory stimuli and sensorimotor learning by transiently suppressing their firing activity. This pause is dopamine signal sensitive, but the neurophysiological mechanism of the dopaminergic influence is under debate. Both the regular spiking response as well as the pause response are influenced by the inwardly rectifying outward G kir , a slow hyperpolarization activated noninactivating G h , and calcium and calcium-dependent potassium conductances [Wilson, C., Goldberg, J., 2006. Origin of the slow afterhyperpolarization and slow rhythmic bursting in striatal cholinergic interneurons. J. Neurophysiol. 95(1), 196–204; Wilson, C., 2005. The mechanism of intrinsic amplification of hyperpolarizations and spontaneous bursting in striatal cholinergic interneurons. Neuron 45(4), 575–585]. Recent experimental evidence has shown that dopaminergic modulations on G h , G kir and calcium conductances influence the AchN's excitability [Deng, P., Zhang, Y., Xu, Z., 2007. Involvement of I( h) in dopamine modulation of tonic firing in striatal cholinergic interneurons. J. Neurosci. 27(12), 3148–3156; Aosaki, T., Kiuchi, K., Kawaguchi, Y., 1998. Dopamine D 1 -like receptor activation excites rat striatal large aspiny neurons in vitro. J. Neurosci. 18(14), 5180–5190]. We employed computational models of the AchN to analyze the conductance based dopaminergic changes. We analyzed the robustness of these subthreshold oscillations and how they are affected by dopaminergic modulation. Our results predict that these conductances allow the dopamine to switch the AchN between stable oscillatory and fixed-point behaviors. The present approach and results show that dopamine receptors ( D 1 and D 2 ) mediate opposing effects on this switch and therefore on the suprathreshold excitability as well. The switching effect of the dopaminergic signal is the major qualitative feature that can serve as a building block for higher network-level descriptions. To our knowledge this is the first paper that synthesizes the growing body of experimental literature about the dopaminergic modulation of the AchNs into a modelling framework.

Physiology of the Canine Anoestrus and Methods for Manipulation of Its Length

Progression from early to late anoestrus is characterized by the appearance of a larger number of gonadotrophin-releasing hormone (GnRH) pulses with a higher amplitude, an increase in the sensitivity of the pituitary to GnRH, an increase in ovarian responsiveness to gonadotrophins, and an increase in basal plasma follicle-stimulating hormone (FSH) concentration. A period of increased luteinizing hormone (LH) pulsatility has been observed shortly before the onset of pro-oestrus. Apart from these changes in the hypothalamus-pituitary-ovary axis, the initiation of a new follicular phase in the bitch is also stimulated by dopaminergic influences other than the accompanying plasma prolactin decrease. Metergoline, a drug which in a low dosage lowers the plasma prolactin concentration via a serotonin-antagonistic pathway, does not shorten the anoestrus; while bromocriptine, in a dosage insufficient to cause a decrease in the plasma prolactin concentration, does prematurely induce a follicular phase. These observations indicate that it is not the decrease in the plasma prolactin concentration, but another dopamine-agonistic influence that plays a crucial role in the transition to a new follicular phase. The dopamine-agonist induced oestrus is associated with a rapid rise in the basal plasma FSH concentration, similar to what is observed during the physiological late anoestrus. Administration of GnRH, eCG and oestrogens may also be used to induce oestrus but with variable results. Oestrus can be prevented surgically or medically, for which purpose progestagens are the most important drugs. The mechanism is still unclear, although it has been demonstrated that with continuing medroxyprogesterone acetate (MPA) treatment the FSH response to GnRH stimulation decreases and changes occur in the pulsatile release of the gonadotrophins. In general, LH pulses coincide with a FSH pulse, but during MPA treatment, LH pulses were observed while there was such a small increase in FSH that it was not recognized as significant FSH pulse.

Dopaminergic influence on the control of the maximum force with Parkinson's patients

Dopaminergic influence on the control of the maximum force with Parkinson's patients