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The Journal of Neuroscience : the... Oct 2014Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required...
Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior.
Topics: Animals; Cues; Dopamine; Dopamine Antagonists; Excitatory Postsynaptic Potentials; Male; Microinjections; Nucleus Accumbens; Random Allocation; Rats; Rats, Long-Evans; Reaction Time; Reward
PubMed: 25339748
DOI: 10.1523/JNEUROSCI.3492-14.2014 -
The International Journal of... Sep 2010Although dopamine D(3) receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are... (Comparative Study)
Comparative Study
Although dopamine D(3) receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are limited and their effects have never been examined in primates. Accordingly, we characterized the actions of the D(3) receptor antagonist, S33138, in rats and rhesus monkeys using a suite of procedures in which cognitive performance was disrupted by several contrasting manipulations. S33138 dose-dependently (0.01-0.63 mg/kg s.c.) blocked a delay-induced impairment of novel object recognition in rats, a model of visual learning and memory. Further, S33138 (0.16-2.5 mg/kg s.c.) similarly reduced a delay-induced deficit in social novelty discrimination in rats, a procedure principally based on olfactory cues. Adult rhesus monkeys were trained to perform cognitive procedures, then chronically exposed to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which produced cognitive impairment without motor disruption. In an attentional set-shifting task of cognitive flexibility involving an extra-dimensional shift, deficits were reversed by S33138 (0.04 and 0.16 mg/kg p.o.). S33138 also significantly improved accuracy (0.04 and 0.16 mg/kg p.o.) at short (but not long) delays in a variable delayed-response task of attention and working memory. Finally, in a separate set of experiments performed in monkeys displaying age-related deficits, S33138 significantly (0.16 and 0.63 mg/kg p.o.) improved task accuracies for long delay intervals in a delayed matching-to-sample task of working memory. In conclusion, S33138 improved performance in several rat and primate procedures of cognitive impairment. These data underpin interest in D(3) receptor blockade as a strategy for improving cognitive performance in CNS disorders like schizophrenia and Parkinson's disease.
Topics: Acetanilides; Animals; Benzopyrans; Cognition Disorders; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Macaca mulatta; Male; Rats; Rats, Wistar; Receptors, Dopamine D3; Species Specificity
PubMed: 20663270
DOI: 10.1017/S1461145710000775 -
Learning & Memory (Cold Spring Harbor,... Jul 2008Pavlovian stimuli previously paired with food can markedly elevate the rate of food-reinforced instrumental responding. This effect, termed Pavlovian-instrumental...
Pavlovian stimuli previously paired with food can markedly elevate the rate of food-reinforced instrumental responding. This effect, termed Pavlovian-instrumental transfer (PIT), depends both on general activating and specific cueing properties of Pavlovian stimuli. Recent evidence suggests that the general activating properties of Pavlovian stimuli are mediated by mesoaccumbens dopamine systems; however, the role of NAC dopamine D1 and D2 receptors is still unknown. Here we examined the effects of a selective dopamine D1 and D2 receptor blockade in the shell and core subregion of the NAC on general PIT. Rats were trained to press a single lever for food, and the effect of a single Pavlovian stimulus previously associated with the same food on performance of that lever was measured in extinction. Results reveal that PIT, that is, the increase in instrumental responding during presentation of the Pavlovian stimulus, was reduced by microinjections of the dopamine D1 receptor antagonist SCH-23390 and, less pronounced, by microinjections of the dopamine D2 receptor antagonist raclopride into the NAC core or shell, respectively. Our data suggest that dopamine D1 and D2 receptors in the NAC core and shell mediate the general activating effects of Pavlovian stimuli on instrumental behavior.
Topics: Analysis of Variance; Animals; Behavior, Animal; Benzazepines; Conditioning, Classical; Conditioning, Operant; Dopamine Antagonists; Male; Microinjections; Nucleus Accumbens; Raclopride; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Transfer, Psychology
PubMed: 18626092
DOI: 10.1101/lm.978708 -
Neuroscience Letters Apr 2023Previous research has revealed a high degree of complexity of the conditioned response that appears after associating a context with the effects of the dopaminergic...
Previous research has revealed a high degree of complexity of the conditioned response that appears after associating a context with the effects of the dopaminergic antagonist haloperidol. Specifically, when a drug-free test is performed in the presence of the context, conditioned catalepsy is observed. However, if the test is extended over time, the opposite effect occurs, namely, a conditioned increase in locomotor activity. In this paper, we present the results of an experiment with rats that received repeated administration of haloperidol or saline before or after exposure to the context. Next, a drug-free test was performed to evaluate catalepsy and spontaneous locomotor activity. The results revealed, on the one hand, the expected conditioned response of catalepsy for those animals that received the drug prior to context exposure during conditioning. However, for the same group, an analysis of locomotor activity for an extended period of ten minutes after registering catalepsy revealed an increase in general activity and more faster movements compared to the control groups. These results are interpreted considering the possible temporal dynamics of the conditioned response that could induce changes in dopaminergic transmission responsible for the observed changes in locomotor activity.
Topics: Rats; Animals; Haloperidol; Rats, Wistar; Catalepsy; Dopamine Antagonists; Locomotion
PubMed: 36906082
DOI: 10.1016/j.neulet.2023.137174 -
PloS One 2018Dopamine antagonist drugs have profound effects on locomotor activity. In particular, the administration of the D2 antagonist haloperidol produces a state that is...
Dopamine antagonist drugs have profound effects on locomotor activity. In particular, the administration of the D2 antagonist haloperidol produces a state that is similar to catalepsy. In order to confirm whether the modulation of the dopaminergic activity produced by haloperidol can act as an unconditioned stimulus, we carried out two experiments in which the administration of haloperidol was repeatedly paired with the presence of distinctive contextual cues that served as a Conditioned Stimulus. Paradoxically, the results revealed a dose-dependent increase in locomotor activity following conditioning with dopamine antagonist (Experiments 1) that was susceptible of extinction when the conditioned stimulus was presented repeatedly by itself after conditioning (Experiment 2). These data are interpreted from an associative perspective, considering them as a result of a classical conditioning process.
Topics: Animals; Behavior, Animal; Conditioning, Classical; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Haloperidol; Locomotion; Male; Rats; Rats, Wistar; Time Factors
PubMed: 30281607
DOI: 10.1371/journal.pone.0200178 -
Reproductive Biology and Endocrinology... Apr 2010It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic...
BACKGROUND
It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic gonadotropin, which are not effective in many frogs. There is a need for simple, cost-effective alternative techniques to induce spawning.
METHODS
Our new method is based on the injection of a combination of a gonadotropin-releasing hormone (GnRH) agonist and a dopamine antagonist. We have named this formulation AMPHIPLEX, which is derived from the combination of the words amphibian and amplexus. This name refers to the specific reproductive behavior of frogs when the male mounts and clasps the female to induce ovulation and to fertilize the eggs as they are laid.
RESULTS
We describe the use of the method and demonstrate its applicability for captive breeding in 3 different anuran families. We tested several combinations of GnRH agonists with dopamine antagonists using Lithobates pipiens. The combination of des-Gly10, D-Ala6, Pro-LHRH (0.4 microrams/g body weight) and metoclopramide (10 micrograms/g BWt. MET) was most effective. It was used in-season, after short-term captivity and in frogs artificially hibernated under laboratory conditions. The AMPHIPLEX method was also effective in 3 Argentinian frogs, Ceratophrys ornata, Ceratophrys cranwelli and Odontophrynus americanus.
CONCLUSION
Our approach offers some advantages over other hormonally-based techniques. Both sexes are injected only once and at the same time, reducing handling stress. AMPHIPLEX is a new reproductive management tool for captive breeding in Anura.
Topics: Animals; Anura; Dopamine Antagonists; Drug Combinations; Female; Gonadotropin-Releasing Hormone; Injections; Male; Metoclopramide; Ovulation Induction; Seasons; Species Specificity
PubMed: 20398399
DOI: 10.1186/1477-7827-8-36 -
Journal of Chemical Neuroanatomy Nov 1996The study was designed to determine whether dopaminergic neurotransmission in the retina can operate via volume transmission. In double immunolabelling experiments, a...
The study was designed to determine whether dopaminergic neurotransmission in the retina can operate via volume transmission. In double immunolabelling experiments, a mismatch as well as a match was demonstrated in the rat retina between tyrosine hydroxylase (TH) and dopamine (DA) immunoreactive (ir) terminals and cell bodies and dopamine D2 receptor-like ir cell bodies and processes. The match regions were located in the inner nuclear and plexiform layers (D2 ir cell bodies plus processes). The mismatch regions were located in the ganglion cell layer, the outer plexiform layer, and the outer segment of the photoreceptor layer, where very few TH ir terminals can be found in relation to the D2 like ir processes. In similar experiments analyzing D1 receptor like ir processes versus TH ir nerve terminals, mainly a mismatch in their distribution could be demonstrated, with the D1 like ir processes present in the outer plexiform layer and the outer segment where a mismatch in D2 like receptors also exists. The demonstration of a mismatch between the localization of the TH terminal plexus and the dopamine D2 and D1 receptor subtypes in the outer plexiform layer, the outer segment and the ganglion cell layer (only D2 immunoreactivity (IR)) suggests that dopamine, mainly from the inner plexiform layer, may reach the D2 and D1 mismatch receptors via diffusion in the extracellular space. After injecting dopamine into the corpus vitreum, dopamine diffuses through the retina, and strong catecholamine (CA) fluorescence appears in the entire inner plexiform layer and the entire outer plexiform layer, representing the match and mismatch DA receptor areas, respectively. The DA is probably bound to D1 and D2 receptors in both plexiform layers, since the DA receptor antagonist chlorpromazine fully blocks the appearance of the DA fluorescence, while only a partial blockade is found after haloperidol treatment which mainly blocks D2 receptors. These results indicate that the amacrine and/or interplexiform DA cells, with sparse branches in the outer plexiform layer, can operate via volume transmission in the rat retina to influence the outer plexiform layer and the outer segment, as well as other layers of the rat retina such as the ganglion cell layer.
Topics: Animals; Diffusion; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Immunohistochemistry; Male; Microinjections; Nerve Endings; Neurons; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Retina; Synaptic Transmission; Tyrosine 3-Monooxygenase; Vitreous Body
PubMed: 9001947
DOI: 10.1016/s0891-0618(96)00176-7 -
PloS One 2019Autosomal dominant polycystic kidney disease (ADPKD) is caused mostly by mutations in polycystin-1 or polycystin-2. Fluid flow leads to polycystin-dependent calcium...
Autosomal dominant polycystic kidney disease (ADPKD) is caused mostly by mutations in polycystin-1 or polycystin-2. Fluid flow leads to polycystin-dependent calcium influx and nuclear export of histone deacetylase 5 (HDAC5), which facilitates the maintenance of renal epithelial architecture by de-repression of MEF2C target genes. Here, we screened a small-molecule library to find drugs that promotes nuclear export of HDAC5. We found that dopamine receptor antagonists, domperidone and loxapine succinate, stimulate export of HDAC5, even in Pkd1-/-cells. Domperidone targets Drd3 receptor to modulate the phosphorylation of HDAC5. Domperidone treatment increases HDAC5 phosphorylation likely by reducing protein phosphatase 2A (PP2A) activity, thus shifting the equilibrium towards HDAC5-P and export from the nucleus. Treating Pkd1-/-mice with domperidone showed significantly reduced cystic growth and cell proliferation. Further, treated mice displayed a reduction in glomerular cyst and increased body weight and activity. These results suggest that HDAC5 nucleocytoplasmic shuttling may be modulated to impede disease progression in ADPKD and uncovers an unexpected role for a class of dopamine receptors in renal epithelial morphogenesis.
Topics: Active Transport, Cell Nucleus; Animals; Cell Proliferation; Domperidone; Dopamine Antagonists; Drug Evaluation, Preclinical; Epithelial Cells; Histone Deacetylases; Kidney; Mice; Polycystic Kidney, Autosomal Dominant
PubMed: 31059522
DOI: 10.1371/journal.pone.0216220 -
Psychopharmacology Jul 2016Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission.
RATIONALE
Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission.
OBJECTIVES
The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats that differ in individual levels of alcohol intake.
METHODS
The effects of the dopamine D1 receptor agonist SKF 82958, the dopamine D1 receptor antagonist SCH 23390, the dopamine D2 receptor agonist sumanirole and the dopamine D2 receptor antagonist L741,626 on alcohol consumption and preference were assessed at different time points after treatment in subgroups of low and high alcohol drinking rats (LD and HD) using an intermittent alcohol access paradigm.
RESULTS
SKF 82958 decreased alcohol intake and alcohol preference throughout the 24-h session. Sumanirole decreased alcohol intake during the first 2 h, but increased alcohol intake during the remainder of the session. The effects of SKF 82958 and sumanirole on alcohol intake and alcohol preference were comparable in LD and HD. By contrast, the dopamine receptor antagonists SCH 23390 and L741,626 did not alter alcohol consumption in either group at any time point.
CONCLUSIONS
These data indicate that stimulation of dopamine D1 receptors reduces alcohol intake, but that endogenous dopamine does not play a primary role in alcohol consumption. Moreover, the difference in alcohol consumption between LD and HD does not involve altered dopamine signaling.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Alcohol Drinking; Analysis of Variance; Animals; Benzazepines; Benzimidazoles; Disease Models, Animal; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Rats; Receptors, Dopamine D1
PubMed: 27236784
DOI: 10.1007/s00213-016-4330-x -
Neuropharmacology Feb 2014Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown...
Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown that a 4-day, low-dose nicotine (0.06 mg/kg) pretreatment enhances locomotor and penile response to the D2-like agonist, quinpirole (0.4 mg/kg), in adolescent but not adult rats. The present study is designed to determine mechanisms underlying this effect. Nicotine enhancement of adolescent quinpirole-induced locomotion was mediated by D2 receptors (D2Rs) since it was blocked by the D2R antagonist, L-741,626, but not by the D3R and D4R antagonists, NGB 2904 and L-745,870. Enhancement of quinpirole-induced erectile response was blocked by both L-741,626 and NGB 2904, indicating involvement of D3Rs. Whereas D2R binding was unaffected by adolescent nicotine pretreatment, effector coupling in the striatum was increased, as determined by GTPγS binding. Nicotine pretreatment enhanced quinpirole-induced c-fos mRNA expression in the hypothalamic paraventricular and supraoptic nuclei in adolescents only. Adolescent nicotine pretreatment enhanced c-fos mRNA expression in corticotropin releasing factor (CRF) cells of the paraventricular nucleus, and enhancement of penile erection was blocked by the CRF-1 receptor antagonist, CP 376,396. These findings suggest that adolescent dopamine and CRF systems are vulnerable to alteration by nicotine. This is the first evidence for a role of CRF in adolescent erectile response.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Hypothalamus; Male; Motor Activity; Nicotine; Penile Erection; Proto-Oncogene Proteins c-fos; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2
PubMed: 24157491
DOI: 10.1016/j.neuropharm.2013.10.012