Selective D2 receptor actions on the functional circuitry of working memory

Prefrontal neurons engaged by working memory tasks express a sequence of phasic and tonic activations linked to a train of sensory, mnemonic, and response-related events. Here, we report that the dopamine D2 receptor selectively modulates the neural activities associated with memory-guided saccades in oculomotor delayed-response tasks yet has little or no effect on the persistent mnemonic-related activity, which is instead modulated by D1 receptors. This associates the D2 receptor with a specific component of working memory circuitry and fractionates the modulatory effects of D1 and D2 receptors on the neural machinery of a cognitive process.     

D1 dopamine receptor activation required for postsynaptic expression of D2 agonist effects

D1 and D2 dopamine receptors exert synergistic effects on the firing rates of basal ganglia neurons and on the expression of stereotyped behavior in rats. Moreover, the ability of D2 agonists to induce changes in basal ganglia single unit activity and spontaneous motor activity is dependent upon the presence of endogenous dopamine to stimulate D1 receptors; in rats treated with alpha-methyl-rho-tyrosine to reduce endogenous dopamine levels, the neurophysiological and behavioral effects of the D2 agonist quinpirole are significantly attenuated, while the effects of nonselective agonists like apomorphine, which stimulate both D1 and D2 receptors, or combinations of a D2 agonist and a D1 agonist are not attenuated. Thus, the previously held view that D2 receptors alone are responsible for evoking the changes in behavior and basal ganglia output induced by nonselective dopamine agonists and endogenous dopamine is not supported by these results, which indicate that these phenomena require concurrent stimulation of both dopamine receptor subtypes.     

D1 dopamine receptors in prefrontal cortex: involvement in working memory

The prefrontal cortex is involved in the cognitive process of working memory. Local injections of SCH23390 and SCH39166, selective antagonists of the D1 dopamine receptor, into the prefrontal cortex of rhesus monkeys induced errors and increased latency in performance on an oculomotor task that required memory-guided saccades. The deficit was dose-dependent and sensitive to the duration of the delay period. These D1 antagonists had no effect on performance in a control task requiring visually guided saccades, indicating that sensory and motor functions were unaltered. Thus, D1 dopamine receptors play a selective role in the mnemonic, predictive functions of the primate prefrontal cortex.     

Effects of working-memory training on striatal dopamine release

Updating of working memory has been associated with striato-frontal brain regions and phasic dopaminergic neurotransmission. We assessed raclopride binding to striatal dopamine (DA) D2 receptors during a letter-updating task and a control condition before and after 5 weeks of updating training. Results showed that updating affected DA activity before training and that training further increased striatal DA release during updating. These findings highlight the pivotal role of transient neural processes associated with D2 receptor activity in working memory.     

D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons

The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.     

Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function

The physiological role of striatal cholinergic interneurons was investigated with immunotoxin-mediated cell targeting (IMCT). Unilateral cholinergic cell ablation caused an acute abnormal turning behavior. These mice showed gradual recovery but displayed abnormal turning by both excess stimulation and inhibition of dopamine actions. In the acute phase, basal ganglia function was shifted to a hyperactive state by stimulation and suppression of striatonigral and striatopallidal neurons, respectively. D1 and D2 dopamine receptors were then down-regulated, relieving dopamine-predominant synaptic perturbation but leaving a defect in controlling dopamine responses. The acetylcholine-dopamine interaction is concertedly and adaptively regulated for basal ganglia synaptic integration.     

Dual signaling regulated by calcyon, a D1 dopamine receptor interacting protein

The synergistic response of cells to the stimulation of multiple receptors has been ascribed to receptor cross talk; however, the specific molecules that mediate the resultant signal amplification have not been defined. Here a 24-kilodalton single transmembrane protein, designated calcyon, we functionally characterize that interacts with the D1 dopamine receptor. Calcyon localizes to dendritic spines of D1 receptor-expressing pyramidal cells in prefrontal cortex. These studies delineate a mechanism of Gq- and Gs-coupled heterotrimeric GTP-binding protein-coupled receptor cross talk by which D1 receptors can shift effector coupling to stimulate robust intracellular calcium (Ca2+i) release as a result of interaction with calcyon. The role of calcyon in potentiating Ca2+-dependent signaling should provide insight into the D1 receptor-modulated cognitive functions of prefrontal cortex.     

Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates

This study provides evidence that the alpha 2-adrenergic receptor agonist clonidine ameliorates the cognitive deficits exhibited by aged nonhuman primates through drug actions at alpha 2 receptors. Furthermore, pharmacological profiles in animals with lesions restricted to the dorsolateral prefrontal cortex indicate that this area may be the site of action for some of clonidine's beneficial effects. These results demonstrate that alpha-adrenergic systems contribute to cognitive function and suggest a new strategy for treating memory disorders in aged humans.     

Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.     

Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward

The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.     

Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele

The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity. Thus, we tested whether striatal activation in response to food intake is related to current and future increases in body mass and whether these relations are moderated by the presence of the A1 allele of the TaqIA restriction fragment length polymorphism, which is associated with dopamine D2 receptor (DRD2) gene binding in the striatum and compromised striatal dopamine signaling. Cross-sectional and prospective data from two functional magnetic resonance imaging studies support these hypotheses, which implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.     

Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET

D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.     

印楝素对果蝇厌恶性味觉记忆的诱导及多巴胺能神经元的影响

【目的】明确印楝素是否能诱导果蝇产生厌恶性味觉记忆,并探讨多巴胺信号在这种记忆形成中的调控作用。【方法】利用印楝素诱导果蝇产生短期厌恶性味觉记忆,并通过昆虫口器伸展反应测试诱导结果;采用压力注射给药方式及果蝇全脑膜片钳记录,研究印楝素对果蝇脑内不同亚群多巴胺能神经元兴奋性及受体电流的影响。【结果】印楝素A及印楝素干粉均能显著抑制果蝇口器伸展的概率,口器伸展反应(PER)分别为60.34%和17.24%,(P0.007),并且干粉的效果更加明显;印楝素对不同亚群的多巴胺能神经元的兴奋性有不同的作用,PPL1、PAM和PPM2亚群兴奋性呈现增加趋势,其中PPL1亚群兴奋性改变最为显著;印楝素对多巴胺D1受体具有激动效应,这种激动效应可被D1受体特异性拮抗剂抑制。【结论】印楝素可以诱导果蝇产生厌恶性味觉记忆,这种记忆受果蝇脑内多巴胺能信号的调控。     

Tremor and involuntary movements in monkeys: effect of L-dopa and of a dopamine receptor stimulating agent

Either L-dopa, in combination with 1-alpha-methyldopa hydrazine (MK-486), or 1-(2'-pyrimidyl)-4-piperonylpiperazine, an agent that stimulates dopamine receptors, relieves surgically induced tremor in monkeys and concomitantly evokes involuntary movements. These results indicate that tremor and involuntary movements are associated with a common mechanism and that the activity of the dopamine receptors is involved in the regulation of these dysfunctions.     

Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior

Midbrain dopamine neurons regulate many important behavioral processes, and their dysfunctions are associated with several human neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. Here, we report that these neurons in mice selectively express guanylyl cyclase-C (GC-C), a membrane receptor previously thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine 3',5'-monophosphate-dependent protein kinase (PKG). Mice in which GC-C has been knocked out exhibit hyperactivity and attention deficits. Moreover, their behavioral phenotypes are reversed by ADHD therapeutics and a PKG activator. These results indicate important behavioral and physiological functions for the GC-C/PKG signaling pathway within the brain and suggest new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons.     

Dichotomous dopaminergic control of striatal synaptic plasticity

At synapses between cortical pyramidal neurons and principal striatal medium spiny neurons (MSNs), postsynaptic D1 and D2 dopamine (DA) receptors are postulated to be necessary for the induction of long-term potentiation and depression, respectively-forms of plasticity thought to underlie associative learning. Because these receptors are restricted to two distinct MSN populations, this postulate demands that synaptic plasticity be unidirectional in each cell type. Using brain slices from DA receptor transgenic mice, we show that this is not the case. Rather, DA plays complementary roles in these two types of MSN to ensure that synaptic plasticity is bidirectional and Hebbian. In models of Parkinson's disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms.     

Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity

Somatostatin and dopamine are two major neurotransmitter systems that share a number of structural and functional characteristics. Somatostatin receptors and dopamine receptors are colocalized in neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated control of motor activity. However, the molecular basis for such interaction between the two systems is unclear. Here, we show that dopamine receptor D2R and somatostatin receptor SSTR5 interact physically through hetero-oligomerization to create a novel receptor with enhanced functional activity. Our results provide evidence that receptors from different G protein (heterotrimeric guanine nucleotide binding protein)-coupled receptor families interact through oligomerization. Such direct intramembrane association defines a new level of molecular crosstalk between related G protein-coupled receptor subfamilies.     

Cholinergic enhancement and increased selectivity of perceptual processing during working memory

Using functional magnetic resonance imaging, we investigated the mechanism by which cholinergic enhancement improves working memory. We studied the effect of the cholinesterase inhibitor physostigmine on subcomponents of this complex function. Cholinergic enhancement increased the selectivity of neural responses in extrastriate cortices during visual working memory, particularly during encoding. It also increased the participation of ventral extrastriate cortex during memory maintenance and decreased the participation of anterior prefrontal cortex. These results indicate that cholinergic enhancement improves memory performance by augmenting the selectivity of perceptual processing during encoding, thereby simplifying processing demands during memory maintenance and reducing the need for prefrontal participation.     

Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist

Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.