-
Drug Design, Development and Therapy 2021Depressive episodes, the most frequent episodes in bipolar disorder, contribute in large part to poor functional outcomes. Very few treatments, however, have been... (Review)
Review
Depressive episodes, the most frequent episodes in bipolar disorder, contribute in large part to poor functional outcomes. Very few treatments, however, have been approved by the Food and Drug Administration for the treatment of bipolar depression. Cariprazine, a broad-spectrum dopamine antagonist/partial agonist with dopamine D3/D2 (preferring D3) and serotonin 5-HT1A receptor partial agonist properties, was recently approved. A review of the literature suggests that it is an effective and well-tolerated treatment for bipolar depression.
Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Depression; Dopamine Antagonists; Drug Partial Agonism; Humans; Piperazines
PubMed: 34012253
DOI: 10.2147/DDDT.S240860 -
The Journal of Neuroscience : the... Nov 2017Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to...
Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is also minimal in the shell in part due to elevated acetylcholinesterase activity. This distinctive modulation of DA transmission in the shell may have functional implications in the acquisition of reward-motivated behaviors and reward seeking.
Topics: Animals; Cholinergic Antagonists; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nucleus Accumbens; Organ Culture Techniques; Receptors, Dopamine; Receptors, Nicotinic
PubMed: 29030431
DOI: 10.1523/JNEUROSCI.0596-17.2017 -
Translational Psychiatry Nov 2019D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine...
D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine synthase (MS). We evaluated the impact of D4R expression on folate-dependent phospholipid methylation (PLM) and MS activity, as well as cellular redox and methylation status, in transfected CHO cells expressing human D4R variants containing 2, 4, or 7 exon III repeats (D4.2R, D4.4R, D4.7R). Dopamine had no effect in non-transfected CHO cells, but increased PLM to a similar extent for both D4.2R- and D4.4R-expressing cells, while the maximal increase was for D4.7R was significantly lower. D4R expression in CHO cells decreased basal MS activity for all receptor subtypes and conferred dopamine-sensitive MS activity, which was greater with a higher number of repeats. Consistent with decreased MS activity, D4R expression decreased basal levels of methylation cycle intermediates methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), as well as cysteine and glutathione (GSH). Conversely, dopamine stimulation increased GSH, SAM, and the SAM/SAH ratio, which was associated with a more than 2-fold increase in global DNA methylation. Our findings illustrate a profound influence of D4R expression and activation on MS activity, coupled with the ability of dopamine to modulate cellular redox and methylation status. These previously unrecognized signaling activities of the D4R provide a unique link between neurotransmission and metabolism.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; DNA Methylation; Dopamine Agonists; Dopamine Antagonists; Humans; Methionine; Phospholipids; Receptors, Dopamine D4; Signal Transduction; Transfection; Tumor Cells, Cultured
PubMed: 31719518
DOI: 10.1038/s41398-019-0630-3 -
Biological & Pharmaceutical Bulletin 2021The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious...
The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.
Topics: Animals; Benzazepines; Catalepsy; Corpus Striatum; Dopamine Antagonists; Mice, Inbred C57BL; Mice, Transgenic; Prefrontal Cortex; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Mice
PubMed: 33642553
DOI: 10.1248/bpb.b20-01006 -
The International Journal of... Nov 2021Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments.
METHODS
We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist.
RESULTS
Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients.
CONCLUSION
Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.
Topics: Adult; Amphetamine-Related Disorders; Central Nervous System Stimulants; Cocaine-Related Disorders; Computer Simulation; Corpus Striatum; Cross-Over Studies; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Double-Blind Method; Feedback; Humans; Male; Pramipexole; Receptors, Dopamine D2; Receptors, Dopamine D3; Reinforcement, Psychology; Reward
PubMed: 34197589
DOI: 10.1093/ijnp/pyab041 -
Neurology Aug 2015To evaluate the appropriateness of dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases after implementation of an...
OBJECTIVE
To evaluate the appropriateness of dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases after implementation of an automated prescription alert system.
METHODS
We examined dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases and physician response to an automated drug contraindication alert system at Barnes-Jewish Hospital from 2009 to 2013. A detailed review of patient medical records was performed for all alert events generated when a physician prescribed a dopamine receptor antagonist concurrently with a dopamine receptor agonist in hospitalized patients. Two movement disorders neurologists determined the appropriateness of each prescription, based on patient medical history, through consensus. Physician response to alert was compared by indication for the prescription and physician specialty.
RESULTS
Of 237 orders, 197 (83.1%) prescriptions for dopamine receptor antagonists were considered inappropriate. The prevalence of inappropriate dopamine receptor antagonist prescriptions per levodopa prescriptions was 16.10% (95% confidence interval 9.47, 22.73) in psychiatry, 7.51% (6.16, 8.86) in general medicine, 6.14% (4.49, 7.79) in the surgical specialties, and 0.85% (0.46, 1.25) in the neurologic/neurosurgical specialties. Of the inappropriate prescriptions, 146 (74.1%) were continued despite the alert. The strongest predictor of discontinuation of dopamine receptor antagonist medications was use of the medication to treat nausea or emesis (p < 0.001).
CONCLUSIONS
Despite successfully identifying instances when dopamine antagonists were prescribed to patients with dopamine-requiring diseases, the alert system modestly affected physician prescribing behavior, highlighting the need for improved education of health care providers.
Topics: Aged; Aged, 80 and over; Dopamine Antagonists; Drug Prescriptions; Female; Hospitalization; Humans; Levodopa; Male; Medical Order Entry Systems; Medication Errors; Middle Aged; Physician's Role; Retrospective Studies; Treatment Outcome
PubMed: 26092916
DOI: 10.1212/WNL.0000000000001745 -
The Journal of Neuroscience : the... Feb 2019The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control...
The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aDLS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopamine-dependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (0, 5, 10, and 15 μg/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control. Over the course of addictive drug exposure, there is a transition in the control over drug seeking from ventral to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms, but it is unclear whether this is causally involved in the development of compulsive drug seeking. We tested the hypothesis that individual differences in the reliance of alcohol seeking on aDLS dopamine predicts and underlies the emergence of compulsive alcohol seeking. We identified individual differences in the reliance of well established alcohol seeking, but not taking behavior, on aDLS mechanisms and also showed that this predicted the subsequent development of compulsive alcohol-seeking behavior. Thus, those individuals in whom alcohol seeking depended on aDLS mechanisms were vulnerable subsequently to display compulsivity.
Topics: Alcoholism; Animals; Compulsive Behavior; Corpus Striatum; Dopamine; Dopamine Antagonists; Drug-Seeking Behavior; Flupenthixol; Male; Rats; Reward
PubMed: 30617206
DOI: 10.1523/JNEUROSCI.2615-18.2018 -
The Journal of Neuroscience : the... Feb 2017Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate...
Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology [D receptor (D2R) antagonist amisulpride] in humans with resting-state functional magnetic resonance imaging and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the twofold clustering did not differ significantly between groups, blocking D2Rs significantly changed the composition of the sixfold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectivity patterns of individual OFC subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks. A key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the orbitofrontal cortex (OFC). We show that blockade of dopamine D receptors has profound effects on the functional connectivity patterns of the OFC, yielding altered connectivity-based subdivisions of this region. Our results suggest that dopamine changes the connectional configuration of the OFC, possibly leading to transitions between different operating modes that favor either sensory input or recurrent processing in the prefrontal cortex. More generally, our findings support a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks and may have clinical implications for understanding the actions of antipsychotic agents.
Topics: Amisulpride; Dopamine; Dopamine Antagonists; Double-Blind Method; Humans; Magnetic Resonance Imaging; Male; Nerve Net; Prefrontal Cortex; Random Allocation; Receptors, Dopamine D2; Sulpiride
PubMed: 28069917
DOI: 10.1523/JNEUROSCI.2827-16.2016 -
Scientific Reports May 2022According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when...
According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.
Topics: Animals; Behavior, Animal; Benzazepines; Cocaine; Dopamine Antagonists; Dose-Response Relationship, Drug; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Self Administration
PubMed: 35610298
DOI: 10.1038/s41598-022-12798-x -
Psychopharmacology Apr 2017Dopamine (DA) plays a central role in reward processing. Accumulating evidence suggests that social interaction and social stimuli have rewarding properties that...
RATIONALE
Dopamine (DA) plays a central role in reward processing. Accumulating evidence suggests that social interaction and social stimuli have rewarding properties that activate the DA reward circuits. However, few studies have attempted to investigate how DA is involved in the processing of social stimuli.
OBJECTIVES
In this study, we investigated the effects of pharmacological manipulations of DA D1 and D2 receptors on social vs. nonsocial visual attention preference in macaques.
METHODS
Japanese macaques were subjected to behavioral tests in which visual attention toward social (monkey faces with and without affective expressions) and nonsocial stimuli was examined, with D1 and D2 antagonist administration.
RESULTS
The macaques exhibited significantly longer durations of gazing toward the images with social cues than did those with nonsocial cues. Both D1 and D2 antagonist administration decreased duration of gazing toward the social images with and without affective valences. In addition, although D1 antagonist administration increased the duration of gazing toward the nonsocial images, D2 antagonism had no effect.
CONCLUSIONS
These results suggest that both D1 and D2 receptors may have roles in the processing of social signals but through separate mechanisms.
Topics: Animals; Attention; Dopamine Antagonists; Facial Expression; Facial Recognition; Macaca; Male; Receptors, Dopamine D1; Receptors, Dopamine D2; Social Behavior; Social Environment; Visual Perception
PubMed: 28154891
DOI: 10.1007/s00213-017-4544-6