Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice

Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output.

Download Full-text

Type 1 dopamine receptor (D1R)-independent circadian food anticipatory activity in mice

PLoS ONE ◽

10.1371/journal.pone.0242897 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0242897

Author(s):

Dina R. Assali ◽

Michael Sidikpramana ◽

Andrew P. Villa ◽

Jeffrey Falkenstein ◽

Andrew D. Steele

Keyword(s):

Dorsal Striatum ◽

D1 Receptor ◽

Conditional Deletion ◽

Food Anticipatory Activity ◽

Significant Impairment ◽

Receptor Pharmacology ◽

Cell Type Specific ◽

Anticipatory Activity

Circadian rhythms are entrained by light and influenced by non-photic stimuli, such as feeding. The activity preceding scheduled mealtimes, food anticipatory activity (FAA), is elicited in rodents fed a limited amount at scheduled times. FAA is thought to be the output of an unidentified food entrained oscillator. Previous studies, using gene deletion and receptor pharmacology, implicated dopamine type receptor 1 (D1R) signaling in the dorsal striatum as necessary for FAA in mice. To further understand the role of D1R in promoting FAA, we utilized the Cre-lox system to create cell type-specific deletions of D1R, conditionally deleting D1R in GABA neurons using Vgat-ires-Cre line. This conditional deletion mutant had attenuated FAA, but the amount was higher than expected based on prior results using a constitutive knockout of D1R, D1R KODrago. This result prompted us to re-test the original D1R KODrago line, which expressed less FAA than controls, but only moderately so. To determine if genetic drift had diminished the effect of D1R deletion on FAA, we re-established the D1R KODrago knockout line from cryopreserved samples. The reestablished D1R KODrago-cryo had a clear impairment of FAA compared to controls, but still developed increased activity preceding mealtime across the 4 weeks of timed feeding. Finally, we tested a different deletion allele of D1R created by the Knockout Mouse Project. This line of D1R KOKOMP mice had a significant impairment in the acquisition of FAA, but eventually reached similar levels of premeal activity compared to controls after 4 weeks of timed feeding. Taken together, our results suggest that D1R signaling promotes FAA, but other dopamine receptors likely contribute to FAA given that mice lacking the D1 receptor still retain some FAA.

Download Full-text

Food as circadian time cue for appetitive behavior

F1000Research ◽

10.12688/f1000research.20829.1 ◽

2020 ◽

Vol 9 ◽

pp. 61 ◽

Cited By ~ 2

Author(s):

Ralph E. Mistlberger

Keyword(s):

Ketone Bodies ◽

Dorsal Striatum ◽

Brain Regions ◽

Circadian Clocks ◽

Feeding Time ◽

Dopaminergic Drugs ◽

Activity Rhythms ◽

Circadian Oscillators ◽

Food Anticipatory Activity ◽

Anticipatory Activity

Feeding schedules entrain circadian clocks in multiple brain regions and most peripheral organs and tissues, thereby synchronizing daily rhythms of foraging behavior and physiology with times of day when food is most likely to be found. Entrainment of peripheral clocks to mealtime is accomplished by multiple feeding-related signals, including absorbed nutrients and metabolic hormones, acting in parallel or in series in a tissue-specific fashion. Less is known about the signals that synchronize circadian clocks in the brain with feeding time, some of which are presumed to generate the circadian rhythms of food-anticipatory activity that emerge when food is restricted to a fixed daily mealtime. In this commentary, I consider the possibility that food-anticipatory activity rhythms are driven or entrained by circulating ghrelin, ketone bodies or insulin. While evidence supports the potential of these signals to participate in the induction or amount of food-anticipatory behavior, it falls short of establishing either a necessary or sufficient role or accounting for circadian properties of anticipatory rhythms. The availability of multiple, circulating signals by which circadian oscillators in many brain regions might entrain to mealtime has supported a view that food-anticipatory rhythms of behavior are mediated by a broadly distributed system of clocks. The evidence, however, does not rule out the possibility that multiple peripheral and central food-entrained oscillators and feeding-related signals converge on circadian oscillators in a defined location which ultimately set the phase and gate the expression of anticipatory activity rhythms. A candidate location is the dorsal striatum, a core component of the neural system which mediates reward, motivation and action and which contains circadian oscillators entrainable by food and dopaminergic drugs. Systemic metabolic signals, such as ghrelin, ketones and insulin, may participate in circadian food anticipation to the extent that they modulate dopamine afferents to circadian clocks in this area.

Download Full-text

Type 1 dopamine receptor (D1R)-independent circadian food anticipatory activity in mice

10.1101/2020.11.12.379545 ◽

2020 ◽

Author(s):

Dina R. Assali ◽

Michael Sidikpramana ◽

Andrew P. Villa ◽

Jeffrey Falkenstein ◽

Andrew D. Steele

Keyword(s):

Dorsal Striatum ◽

D1 Receptor ◽

Conditional Deletion ◽

Food Anticipatory Activity ◽

Significant Impairment ◽

Receptor Pharmacology ◽

Cell Type Specific ◽

Anticipatory Activity

ABSTRACTCircadian rhythms are entrained by light and influenced by non-photic stimuli, such as feeding. The activity preceding scheduled mealtimes, food anticipatory activity (FAA), is elicited in rodents fed a limited amount at scheduled times. FAA is thought to be the output of an unidentified food entrained oscillator. Previous studies, using gene deletion and receptor pharmacology, implicated dopamine type receptor 1 (D1R) signaling in the dorsal striatum as necessary for FAA in mice. To further understand the role of D1R in promoting FAA, we utilized the Cre-lox system to create cell type-specific deletions of D1R. We were unsuccessful in obtaining conditional deletion of D1R when using transgenically driven D1R-Cre. We then created a conditional deletion of D1R in GABA neurons using Vgat-ires-Cre line, which had attenuated FAA, but the amount was higher than expected based on prior results using a constitutive knockout of D1R, D1R KODrago. This result prompted us to re-test the original D1R KODrago line, which expressed less FAA than controls, but only moderately so. To determine if genetic drift had diminished the effect of D1R deletion on FAA, we re-established the D1R KODrago knockout line from cryopreserved samples. The reestablished D1R KODrago-cryo had a clear impairment of FAA compared to controls, but still developed increased activity preceding mealtime across the 4 weeks of timed feeding. Finally, we tested a different deletion allele of D1R created by the Knockout Mouse Project. This line of D1R KOKOMP mice had a significant impairment in the acquisition of FAA, but eventually reached similar levels of premeal activity compared to controls after 4 weeks of timed feeding. Taken together, our results suggest that D1R signaling promotes FAA, but other dopamine receptors likely contribute to FAA given that mice lacking the D1 receptor still retain some FAA.

Download Full-text

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Select Signaling Proteins Following Sub-Chronic Administration in the Rat

Current Molecular Pharmacology ◽

10.2174/1874467213666200910091007 ◽

2020 ◽

Vol 13 ◽

Author(s):

Ritesh Daya ◽

Joella Ho ◽

Sharon Thomson ◽

Jayant Bhandari ◽

Ram K. Mishra

Keyword(s):

Frontal Cortex ◽

Mechanism Of Action ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Dorsal Striatum ◽

D2 Receptors ◽

Dopamine D2 ◽

Therapeutic Mechanism ◽

Clinical Models ◽

G Protein Coupled

Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)- pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of Prolyl-Leucyl-Glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. Objective: in this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in preclinical models of schizophrenia. Method: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin-3), and phosphorylated mitogenactivated protein kinase (MAPKs), namely, extracellular signal-regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore PAOPA’s therapeutic mechanism of action for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggestive of a role for PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. Conclusion: While further studies are required to elucidate PAOPA’s mechanism of action, this study builds on prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

Download Full-text

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Biochemical Society Transactions ◽

10.1042/bst20150276 ◽

2016 ◽

Vol 44 (2) ◽

pp. 595-600 ◽

Cited By ~ 20

Author(s):

Verònica Casadó-Anguera ◽

Jordi Bonaventura ◽

Estefanía Moreno ◽

Gemma Navarro ◽

Antoni Cortés ◽

...

Keyword(s):

Structural Model ◽

Dopamine D2 Receptor ◽

Ex Vivo ◽

D2 Receptor ◽

Drug Dosage ◽

D1 Receptor ◽

Structural Basis ◽

Dopamine D2 ◽

Allosteric Mechanisms ◽

Adenosine A2a

Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D1 receptor (D1R)–dopamine D3 receptor (D3R) and adenosine A2A receptor (A2AR)–dopamine D2 receptor (D2R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A2AR–D2R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing the ex vivo expression of A2AR–D2R heteromers. The ability of A2AR agonists to decrease the affinity of D2R agonists has been reported and, on the basis of this interaction, A2AR antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A2AR–D2R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine.

Download Full-text

Pituitary Lactotroph Adenomas Develop after Prolonged Lactotroph Hyperplasia in Dopamine D2 Receptor-Deficient Mice1

Endocrinology ◽

10.1210/endo.140.11.7118 ◽

1999 ◽

Vol 140 (11) ◽

pp. 5348-5355 ◽

Cited By ~ 75

Author(s):

Sylvia L. Asa ◽

Michele A. Kelly ◽

David K. Grandy ◽

Malcolm J. Low

Keyword(s):

Dopamine D2 Receptor ◽

D2 Receptor ◽

Distant Metastases ◽

Normal Female ◽

Cellular Mechanisms ◽

Fiber Network ◽

Female Mice ◽

Dopamine D2 ◽

Deficient Mice ◽

Pituitary Lactotroph

Abstract Tuberoinfundibular dopamine tonically inhibits PRL expression and secretion from the pituitary gland by the activation of dopamine D2 receptors (D2R) localized on lactotrophs. Mutant female mice that lack D2Rs have persistent hyperprolactinemia but also develop extensive hyperplasia of pituitary lactotrophs and peliosis of the adenohypophysis at 9 to 12 months of age, while age-matched male D2R-deficient mice have no morphologic adenohypophysial lesion. We now report that both female and male D2R-deficient mice 17 to 20 months of age develop pituitary lactotroph adenomas. Of 12 aged female mice examined, all developed monohormonal PRL-immunoreactive neoplasms that had a characteristic juxtanuclear Golgi pattern of PRL staining and loss of the reticulin fiber network. Several of these adenomas were 50-fold larger than normal glands with marked suprasellar extension and invasion of brain but no gross evidence of distant metastases. They also had striking peliosis that was more marked than the lesion seen in the hyperplastic pituitaries of the younger females. These findings demonstrate that a chronic loss of neurohormonal dopamine inhibition promotes the hyperplasia-neoplasia sequence in adenohypophysial lactotrophs. Our results are analogous to previous data indicating that protracted stimulation of adenohypophysial cells by hormones or growth factors results in proliferation with initial hyperplasia followed by the development of neoplasia. Six aged male D2R-deficient mice had slightly enlarged anterior pituitaries similar in size to normal female glands. However, each case exhibited multifocal, microscopic lactotroph adenomas with strong nuclear immunoreactivity for estrogen receptors and Pit-1 transcription factor. The unexpected development of adenomas in males without preexisting or concomitant hyperplasia suggests that prolonged loss of dopamine inhibition may also cause neoplasia by distinct cellular mechanisms in male and female animals.

Download Full-text

Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse

Cerebral Cortex ◽

10.1093/cercor/bhaa354 ◽

2020 ◽

Author(s):

Isabel Espadas ◽

Oscar Ortiz ◽

Patricia García-Sanz ◽

Adrián Sanz-Magro ◽

Samuel Alberquilla ◽

...

Keyword(s):

Synaptic Plasticity ◽

Associative Learning ◽

Dopamine Receptors ◽

Learning And Memory ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Long Term Potentiation ◽

D1 Receptor ◽

Term Potentiation

Abstract Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2−/−) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.

Download Full-text

Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice

Psychopharmacology ◽

10.1007/s00213-006-0579-9 ◽

2006 ◽

Vol 191 (3) ◽

pp. 567-578 ◽

Cited By ~ 48

Author(s):

Siobhan Robinson ◽

Aundrea J. Rainwater ◽

Thomas S. Hnasko ◽

Richard D. Palmiter

Keyword(s):

Instrumental Conditioning ◽

Dorsal Striatum ◽

Dopamine Signaling ◽

Deficient Mice

Download Full-text

D1 and D2 dopaminergic systems in the rat basolateral amygdala are involved in anxiogenic-like effects induced by histamine

Journal of Psychopharmacology ◽

10.1177/0269881111405556 ◽

2011 ◽

Vol 26 (4) ◽

pp. 564-574 ◽

Cited By ~ 22

Author(s):

Maryam Bananej ◽

Ahmad Karimi-Sori ◽

Mohammad Reza Zarrindast ◽

Shamseddin Ahmadi

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Basolateral Amygdala ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Dopamine D1 Receptor ◽

D1 Receptor ◽

Dopamine D2 ◽

D1 And D2 Receptors ◽

Male Wistar Rats

Involvement of the dopamine receptors in the basolateral amygdala (BLA) in the effects of histamine on anxiety-like behaviors of the elevated plus maze in male Wistar rats was investigated. The results showed that bilateral intra-BLA injections of histamine (2.5, 5 and 7.5 µg/rat) induced an anxiogenic-like effect, revealed by decreases in percentage of open arm time (%OAT) and open arm entries (%OAE). Intra-BLA administration of dopamine D1 receptor agonist, SKF38393 (0.25 µg/rat), and dopamine D2 receptor agonist, quinpirole (0.03 and 0.05 µg/rat), decreased %OAT but not %OAE. Conversely, intra-BLA administration of dopamine D1 receptor antagonist, SCH23390 (0.5 and 1 µg/rat), and dopamine D2 receptor antagonist, sulpiride (0.3 and 0.5 µg/rat), increased %OAT and %OAE, suggesting an anxiolytic-like effect for both drugs. Interestingly, co-administration of a silent dose of SCH23390 or sulpiride prevented anxiogenic-like effects of SKF38393 and quinpirole, respectively. Conjoint administration of a sub-effective dose of SKF38393 (0.125 µg/rat) or quinpirole (0.01 µg/rat) along with lower doses of histamine (1 and 2.5 µg/rat) induced anxiolytic-like effects. On the other hand, intra-BLA pretreatment with a silent dose of SCH23390 (0.25 µg/rat) or sulpiride (0.1 µg/rat) prevented the anxiogenic-like effect of higher doses of histamine (5 and 7.5 µg/rat). No significant change was observed in total closed arm entries, as an index for motor activity of the animals. It can be concluded that the dopamine D1 and D2 receptors in the BLA may be involved in the anxiogenic-like effects induced by histamine.

Download Full-text