RESUMO
An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0â¯mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3â¯mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.
Assuntos
Antipsicóticos , Apomorfina , Agonistas de Dopamina , Atividade Motora , Quimpirol , Ratos Long-Evans , Risperidona , Animais , Apomorfina/farmacologia , Apomorfina/administração & dosagem , Risperidona/farmacologia , Risperidona/administração & dosagem , Quimpirol/farmacologia , Ratos , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Antipsicóticos/farmacologia , Antipsicóticos/administração & dosagem , Relação Dose-Resposta a Droga , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Animais Recém-Nascidos , Fatores Etários , Fatores SexuaisRESUMO
BACKGROUND: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. AIMS: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. METHODS: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. RESULTS: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. CONCLUSION: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.
Assuntos
Condicionamento Clássico , Agonistas de Dopamina , Medo , Generalização Psicológica , Quimpirol , Racloprida , Ratos Wistar , Receptores de Dopamina D2 , Animais , Medo/efeitos dos fármacos , Masculino , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Quimpirol/farmacologia , Agonistas de Dopamina/farmacologia , Ratos , Generalização Psicológica/efeitos dos fármacos , Racloprida/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologiaRESUMO
The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D2Rs in the regulation of limbic information flow.
Assuntos
Prosencéfalo Basal , Agonistas de Dopamina , Relação Dose-Resposta a Droga , Microinjeções , Quimpirol , Ratos Sprague-Dawley , Receptores de Dopamina D2 , Animais , Quimpirol/farmacologia , Masculino , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/efeitos dos fármacos , Ratos , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiologia , Estimulação Elétrica , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiologiaRESUMO
Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Percepção do Tempo , Feminino , Masculino , Animais , Percepção do Tempo/fisiologia , Percepção do Tempo/efeitos dos fármacos , Humanos , Caracteres Sexuais , Dopamina/metabolismo , Ratos , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia , Quimpirol/farmacologia , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Adulto , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Benzazepinas/farmacologia , Adulto Jovem , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Memória de Curto Prazo/fisiologia , Memória de Curto Prazo/efeitos dos fármacosRESUMO
RATIONALE: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia. OBJECTIVE: The current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use. METHODS: Neonatal treatment of animals with the dopamine D2-like receptor agonist quinpirole (NQ) from postnatal day (P)1-21 produces a lifelong increase in D2 receptor sensitivity, showing relevance to psychosis and comorbid tobacco use disorder. Following an 8-day conditioning paradigm, brain tissue in the mesolimbic pathway was analyzed for several plasticity markers, including brain derived neurotrophic factor (BDNF), phosphorylated p70 ribosomal S6 kinase (phospho-p70S6K), and cadherin-13 (Cdh13). RESULTS: Pretreatment with CDPPB was effective to block enhanced nicotine conditioned place preference observed in NQ-treated animals. Pretreatment was additionally effective to block the nicotine-induced increase in BDNF and sex-dependent increases in cadherin-13 in the ventral tegmental area (VTA), as well as increased phospho-p70S6K in the nucleus accumbens (NAcc) shell found in NQ-treated animals. CONCLUSION: In conjunction with prior work, the current study suggests positive allosteric modulation of the mGlu5 receptor, an emerging target for schizophrenia therapeutics, may be effective for the treatment of comorbid nicotine abuse in psychosis.
Assuntos
Benzamidas , Nicotina , Receptor de Glutamato Metabotrópico 5 , Recompensa , Animais , Nicotina/farmacologia , Masculino , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Receptor de Glutamato Metabotrópico 5/metabolismo , Ratos , Plasticidade Neuronal/efeitos dos fármacos , Fumar Cigarros , Feminino , Quimpirol/farmacologia , Pirazóis/farmacologia , Ratos Sprague-Dawley , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sistema Límbico/metabolismo , Sistema Límbico/efeitos dos fármacos , Animais Recém-Nascidos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacosRESUMO
Perinatal testosterone, or its metabolite estradiol, organize the brain toward a male phenotype. Male rodents with insufficient testosterone during this period fail to display sexual behavior and partner preference for receptive females in adulthood. However, cohabitation with non-reproductive conspecifics under the influence of a D2 agonist facilitates the expression of conditioned partner preference via Pavlovian learning in gonadally intact male rats. In the present experiment, three groups of neonatal PD1 males (N = 12/group) were either gonadectomized (GDX), sham-GDX, or left intact and evaluated for social preferences and sexual behaviors as adults. We then examined whether the effects of GDX could be reversed by conditioning the males via cohabitation with receptive females under the effects of the D2 agonist quinpirole (QNP) or saline, along with the size of some brain regions, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA), suprachiasmatic nucleus (SCN), posterior dorsal medial amygdala (MeApd) and ventromedial hypothalamus (VMH). Results indicated that neonatal GDX resulted in the elimination of male-typical sexual behavior, an increase in same-sex social preference, and a reduction of the area of the SDN-POA. However, GDX-QNP males that underwent exposure to receptive females in adulthood increased their social preference for females and recovered the size in the SDN-POA. Although neonatal GDX impairs sexual behavior and disrupts partner preference and brain dimorphism in adult male rats, Pavlovian conditioning under enhanced D2 agonism ameliorates the effects on social preference and restores brain dimorphism in the SDN-POA without testosterone.
Assuntos
Área Pré-Óptica , Caracteres Sexuais , Gravidez , Ratos , Animais , Masculino , Feminino , Área Pré-Óptica/metabolismo , Encéfalo , Quimpirol/farmacologia , Castração , Testosterona/farmacologia , Testosterona/metabolismoRESUMO
Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also with some serotonin 5-HT2B/7 effects. The present study examined the role of D2/3 receptors and 5-HT2B/7 receptors in amisulpride's discriminative stimulus. Selective agonists and antagonists of the above receptors were tested in adult, male C57BL/6 mice trained to discriminate 10â mg/kg amisulpride from vehicle in a two-lever drug discrimination assay. After acquisition of the two-lever discrimination, the amisulpride generalization curve yielded an ED50â =â 0.56â mg/kg (95% CI = 0.42-0.76â mg/kg). Substitution tests found that the D2/3 antagonist raclopride (62.7% Drug Lever Responding), D2/3 agonist quinpirole (56.6% DLR), 5-HT7 agonist LP-44 (50.1% DLR) and 5-HT7 antagonist SB-269970 (36.7% DLR) produced various degrees of partial substitution for the amisulpride stimulus, whereas the 5-HT2B agonist BW 723C86 (17.9% DLR) and 5-HT2B antagonist SB-204741 (21.1% DLR) yielded negligible amisulpride-like effects. In combination tests with amisulpride, quinpirole decreased percent responding from 98.3% to 57.0% DLR, LP-44 decreased percent responding from 97.6% to 76.7% DLR, and BW 723C86 reduced percent responding from 95.66% to 74.11% DLR. Taken together, the results from stimulus generalization and antagonism studies suggest that amisulpride has a complex discriminative cue that involves mainly mixed D2/3 receptor antagonist/agonist effects and, to a lesser degree, mixed 5-HT7 receptor agonist/antagonist and perhaps 5-HT2B receptor antagonist effects.
Assuntos
Antipsicóticos , Indóis , Piperazinas , Tetra-Hidronaftalenos , Tiofenos , Camundongos , Animais , Masculino , Antipsicóticos/farmacologia , Amissulprida/farmacologia , Quimpirol/farmacologia , Camundongos Endogâmicos C57BL , Relação Dose-Resposta a Droga , Aprendizagem por DiscriminaçãoRESUMO
Early and progressive dysfunctions of the dopaminergic system from the Ventral Tegmental Area (VTA) have been described in Alzheimer's Disease (AD). During the long pre-symptomatic phase, alterations in the function of Parvalbumin interneurons (PV-INs) are also observed, resulting in cortical hyperexcitability represented by subclinical epilepsy and aberrant gamma-oscillations. However, it is unknown whether the dopaminergic deficits contribute to brain hyperexcitability in AD. Here, using the Tg2576 mouse model of AD, we prove that reduced hippocampal dopaminergic innervation, due to VTA dopamine neuron degeneration, impairs PV-IN firing and gamma-waves, weakens the inhibition of pyramidal neurons and induces hippocampal hyperexcitability via lower D2-receptor-mediated activation of the CREB-pathway. These alterations coincide with reduced PV-IN numbers and Perineuronal Net density. Importantly, L-DOPA and the selective D2-receptor agonist quinpirole rescue p-CREB levels and improve the PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly to quinpirole, sumanirole - another D2-receptor agonist and a known anticonvulsant - not only increases p-CREB levels in PV-INs but also restores gamma-oscillations in Tg2576 mice. Conversely, blocking the dopaminergic transmission with sulpiride (a D2-like receptor antagonist) in WT mice reduces p-CREB levels in PV-INs, mimicking what occurs in Tg2576. Overall, these findings support the hypothesis that the VTA dopaminergic system integrity plays a key role in hippocampal PV-IN function and survival, disclosing a relevant contribution of the reduced dopaminergic tone to aberrant gamma-waves, hippocampal hyperexcitability and epileptiform activity in early AD.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Hipocampo , Interneurônios , Camundongos Transgênicos , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/patologia , Neurônios Dopaminérgicos/metabolismo , Interneurônios/metabolismo , Interneurônios/fisiologia , Parvalbuminas/metabolismo , Dopamina/metabolismo , Receptores de Dopamina D2/metabolismo , Masculino , Células Piramidais/metabolismo , Levodopa/farmacologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Degeneração Neural/metabolismo , Quimpirol/farmacologia , Ritmo Gama/fisiologia , Camundongos Endogâmicos C57BLRESUMO
Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D2 receptor (D2R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D2R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.
Assuntos
Transtorno Obsessivo-Compulsivo , Inibidores da Bomba de Prótons , Camundongos , Animais , Quimpirol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/etiologia , Neurônios , Concentração de Íons de HidrogênioRESUMO
Dopamine D2 receptor (D2R) is expressed in striatopallidal neurons and decreases forskolin-stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma-aminobutyric acid (GABA) release. Dopamine D3 receptor (D3R) mRNA is expressed in a population of striatal D2R-expressing neurons. Also, D3R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D2R and D3R colocalize in striatopallidal terminals and whether D3R modulates the D2R effect on forskolin-stimulated [3H]cAMP accumulation in pallidal synaptosomes and high K+ stimulated-[3H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D2R and D3R functions; thus, we study whether this system regulates its functional interaction. D2R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K+ decreases it. Both treatments increase the D2R inhibition of forskolin-stimulated [3H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D2R function. Quinpirole also activates D3R, potentiating D2R inhibition of cAMP accumulation in the ophiobolin A-treated synaptosomes. D2R and D3R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM-kinase II alfa (CaMKIIα) immunoprecipitates with D3R and increases after high K+ depolarization. In the presence of KN62, a CaMKIIα blocker, D3R potentiates D2R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D3R function regulation by CaMKIIα. Our data indicate that D3R potentiates the D2R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM-CaMKIIα system.
Assuntos
Calmodulina , Receptores de Dopamina D3 , Sesterterpenos , Receptores de Dopamina D3/metabolismo , Quimpirol/farmacologia , Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Colforsina , Receptores de Dopamina D2/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Adolescence is a phase of substantial changes in the brain, characterized by maturational remodeling of many systems. This remodeling allows functional plasticity to adapt to a changing environment. The dopaminergic system is under morphological and physiological changes during this phase. In the present study, we investigated if changes in the dopaminergic tone alter mice behavior in a receptor and sex-specific manner, specifically at the beginning of the puberty period. We administered L-Dopa, SKF-38393 (D1 dopamine receptor agonist), and Quinpirole (D2 dopamine receptor agonist) and tested male and female mice's motor, anxiety- and depressive-like behavior. While females displayed an impaired exploratory drive, males presented an intense depressive-like response. Our results provide insights into the function of dopaminergic development in adolescent behavior and highlight the importance of studies in this time window with male and female subjects.