D1 Agonist SKF Research Articles

D3 dopamine receptors interact with dopamine D1 but not D4 receptors in the GABAergic terminals of the SNr of the rat

The firing rate of substantia nigra reticulata (SNr) neurons is modulated by GABA release from striatonigral and pallidonigral projections. This release is, in turn, modulated by dopamine acting on dopamine D1 receptors at striatonigral terminals and D4 receptors at pallidonigral terminals. In addition, striatal neurons that express D1 receptors also express D3 receptors. In this study we analyzed the possible significance of D3 and D1 receptor colocalization in striatonigral projections. We found that these receptors coprecipitate in SNr synaptosomes suggesting their close association in this structure. D1 agonist SKF 38393 administered alone increased mIPSC frequency in SNr slices and cAMP production in SNr synaptosomes, however, the selective D3 agonist PD 128,907 increased mIPSC frequency and cAMP production only when D1 receptors were concurrently stimulated. The D1 antagonist SCH 23390 blocked completely the effects of the concurrent administration of these agonists while the selective D3 antagonist GR 103691 blocked only the potentiating effects of PD 128,907. These findings further indicate that D1 and D3 receptors are localized in the same structure. The D4 agonist PD 168,077 decreased mIPSCs frequency without changing amplitude, an effect that was blocked by the selective D4 antagonist L 745,870. The effects of D4 receptor stimulation disappeared after lesioning the globus pallidus. D3 agonist PD 128,907 did not reduce mIPSC frequency even in neurons that responded to D4 agonist. In sum, activation of D3 receptors in SNr potentiates the stimulation of transmitter release and cAMP production caused by D1 receptor activation of striatonigral projections while it is without effects in terminals, probably of pallidal origin, that are inhibited by activation of D4 receptors.

Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons

The physiological responses of dendrites to dopaminergic inputs are poorly understood and controversial. We applied dopamine on one dendritic branch while simultaneously monitoring action potentials (APs) from multiple dendrites using either calcium-sensitive dye, voltage-sensitive dye or both. Dopaminergic suppression of dendritic calcium transients was rapid (<0.5 s) and restricted to the site of dopamine application. Voltage waveforms of backpropagating APs were minimally altered in the same dendrites where dopamine was confirmed to cause large suppression of calcium signals, as determined by dual voltage and calcium imaging. The dopamine effects on dendritic calcium transients were fully mimicked by D1 agonists, partially reduced by D1 antagonist and completely insensitive to protein kinase blockade; consistent with a membrane delimited mechanism. This dopamine effect was unaltered in the presence of L-, R- and T-type calcium channel blockers. The somatic excitability (i.e. AP firing) was not affected by strong dopaminergic stimulation of dendrites. Dopamine and GABA were then sequentially applied on the same dendrite. In contrast to dopamine, the pulses of GABA prohibited AP backpropagation distally from the application site, even in neurons with natural Cl− concentration (patch pipette removed). Thus, the neocortex employs at least two distinct mechanisms (dopamine and GABA) for rapid modulation of dendritic calcium influx. The spatio-temporal pattern of dendritic calcium suppression described in this paper is expected to occur during phasic dopaminergic signalling, when midbrain dopaminergic neurons generate a transient (0.5 s) burst of APs in response to a salient event.

Dopaminergic modulation of low-Mg2+-induced epileptiform activity in the intact hippocampus of the newborn mouse in vitro

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, whereas >3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.

Neonatal (+)-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11-20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-d-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects.

D1–NMDA receptor interactions in the rat nucleus accumbens change during adolescence

Many aspects of the dopamine (DA) system mature during adolescence. For example, the DA modulation of glutamate responses in the rat prefrontal cortex (PFC) acquires adult characteristics during late adolescence. In the striatum, D₁ receptors modulate NMDA responses, but whether this behaviorally important interaction matures during adolescence is not known. Here, we tested whether the D₁ agonist SKF38393 affects NMDA actions on nucleus accumbens medium spiny neuron (MSN) excitability in slices from juvenile and young adult rats. NMDA dose-dependently increased excitability in both age groups, and the D₁ agonist produced a marginal increase of MSN excitability. In juvenile slices, the most common interaction was a downregulation of NMDA effects on excitability by the D₁ agonist, whereas in most adult MSN, the D₁ agonist increased NMDA effects on MSN excitability. These results suggest that D₁-NMDA receptor interactions in the nucleus accumbens change during adolescence, a change that may result in different processing of reward functions during this critical developmental stage.

Dopamine D1 receptor involvement in latent inhibition and overshadowing

Latent inhibition (LI) manifests as poorer conditioning to a stimulus that has previously been experienced without consequence. There is good evidence of dopaminergic modulation of LI, as the effect is reliably disrupted by the indirect dopamine (DA) agonist amphetamine. The disruptive effects of amphetamine on LI are reversed by both typical and atypical antipsychotics, which on their own are able to facilitate LI. However, the contribution of different DA receptors to these effects is poorly understood. Amphetamine effects on another stimulus selection procedure, overshadowing, have been suggested to be D1-mediated. Thus, in the current experiments, we systematically investigated the role of D1 receptors in LI. First, we tested the ability of the full D1 agonist SKF 81297 to abolish LI and compared the effects of this drug on LI and overshadowing. Subsequently, we examined whether the D1 antagonist SCH 23390 can lead to the emergence of LI under conditions that do not produce the effect in normal animals (weak pre-exposure). Finally, we tested the ability of SCH 23390 to block amphetamine-induced disruption of LI. We found little evidence that direct stimulation of D1 receptors abolishes LI (although there was some attenuation of LI at 0.4 mg/kg SKF 81297). Similarly, SCH 23390 failed to enhance LI. However, SCH 23390 did block amphetamine-induced disruption of LI. These data indicate that, while LI may be unaffected by selective manipulation of activity at D1 receptors, the effects of amphetamine on LI are to some extent dependent on actions at D1 receptors.

Neonatal exposure to the D1 agonist SKF38393 inhibits pair bonding in the adult prairie vole

The monogamous prairie vole displays developmental sensitivity to early pharmacological manipulation in a number of species-typical social behaviors. The long-term consequences of altering the neonatal dopamine system are not well characterized. This study examined whether early manipulation of the dopamine system, a known mediator of adult prairie vole social behavior, during neonatal development would affect adult aggressive and attachment behaviors. Eight-day-old pups were given a single treatment with either 1 mg/kg of SKF38393 (D1 agonist), quinpirole (D2 agonist), SCH23390 (D1 antagonist), eticlopride (D2 antagonist), or saline vehicle. As adults, animals received tests for intrasexual aggression and partner preference. Activation of D1-like receptors in pups impaired partner preference formation, but had no effect on aggression. Other neonatal treatments had no effect on their behavior as adults. To determine whether D1 activation in pups induced changes in dopamine receptor expression, we performed autoradiography on striatal tissue from a second cohort of saline-treated and SKF38393-treated animals. Although sex differences were observed, we found no treatment differences in D1 or D2 receptor binding in any striatal subregion. This study shows that exposure to a single early pharmacological alteration of dopamine receptor activity may have long-term effects on the social behavior of prairie voles.

Dopamine Modulates the Voltage Response of Human Rod Photoreceptors by Inhibiting thehCurrent

The h current (I(h)) is a hyperpolarization-activated current that plays important roles in the physiological functions of different types of cells. In the retina of lower vertebrates, I(h) contributes to the rod responses to light stimuli by bringing the membrane potential back to the dark level in the presence of continuous light. The purpose of this study was to determine how dopamine modulates I(h) in human rods and regulates voltage responses. A patch-clamp recording technique was used on surgically excised human retinas to investigate the effects of dopamine on the I(h) of isolated rods. Dopamine was applied in the superfusate. Dopamine reversibly decreased the amplitude of the I(h) induced by hyperpolarizing voltage steps from a holding potential of -60 mV. At a voltage step of -100 mV, 20 μM dopamine decreased the amplitude of I(h). The D2 dopamine agonist quinpirole inhibited I(h), but the D1 agonist SKF-38393 had no effect. Dopamine-induced reduction of I(h) amplitude was blocked by the D2 dopamine antagonist sulpiride. Under current-clamp conditions, an injection of hyperpolarizing current steps to rods produced voltage responses that exhibited a gradual decay. Adding dopamine to the superfusate inhibited the decay in the voltage responses. Quinpirole also inhibited the voltage decay, whereas SKF-38393 was ineffective. Dopamine reduced I(h) through a D2 receptor and inhibited the gradual decay in the voltage response through a D2 receptor, indicating that dopamine slows the recovery phase of responses to light stimuli by inhibiting I(h) in human rods.

Alpha 2-adrenoceptor- and D2-dopamine receptor-mediated analgesic response of B-HT 920.

The involvement of D2-dopamine receptors in the antinociceptive action of B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-(4H) thiazolo-(4,5d)-azepine) has been investigated in mice. B-HT 920 (0.1-2.0 mg kg-1) and apomorphine (0.1-2.0 mg kg-1) produced a dose-dependent increase in tail flick latency. Analgesia induced by apomorphine was blocked by the D2-antagonist, haloperidol (1 mg kg-1) but not by the opioid antagonist, naloxone (1 mg kg-1). The antinociceptive action of B-HT 920 was potentiated by the D1-agonist SKF 38393 (5 mg kg-1), an action antagonized by haloperidol. The selective alpha 2-adrenoceptor blocking drug yohimbine (1 mg kg-1) and naloxone (1 mg kg-1) blocked the antinociceptive action of B-HT 920 (1 mg kg-1). Haloperidol, however, failed to modify the B-HT 920-induced increase in tail flick latency. B-HT 920 and apomorphine reversed reserpine (2 mg kg-1) 4 h-induced hyperalgesia. The reversing action of apomorphine was blocked by haloperidol but not by yohimbine. Thus, a role of alpha 2-adrenoceptors and D2-dopamine receptors is postulated in the antinociceptive action of B-HT 920.

Importance of D1 and D2 receptors in the dorsal caudate-putamen for the locomotor activity and stereotyped behaviors of preweanling rats

Dopaminergic compounds often affect the unlearned behaviors of preweanling and adult rats differently, although the brain regions underlying these age-dependent behavioral effects have not been specified. A candidate brain region is the dorsal caudate-putamen (CPu); thus, a goal of the present study was to determine whether D1 and D2 receptors in the dorsal CPu are capable of modulating the unlearned behaviors of preweanling rats. In Experiments 1 and 2, selective and nonselective dopamine agonists were bilaterally microinjected into the dorsal CPu on postnatal day (PD) 18 and both locomotor activity and stereotypy were measured. In Experiment 3, the functional coupling of D1 and D2 receptors was assessed by microinjecting the D1 agonist SKF-82958 and the D2/D3 agonist quinpirole either alone or in combination. In Experiments 4 and 5, quinpirole and the D1 receptor antagonist SCH-23390, or SKF-82958 and the D2 receptor antagonist raclopride, were co-administered into the dorsal CPu to further assess whether a functional D1 or D2 receptor system is necessary for the expression of quinpirole- or SKF-82958-induced behaviors. Results showed that selective stimulation of D1 or D2 receptors in the dorsal CPu increased both the locomotor activity and stereotypy of preweanling rats. Receptor coupling was evident on PD 18 because co-administration of a subthreshold dose of SKF-82958 and quinpirole produced more locomotor activity than either agonist alone. Lastly, the dopamine antagonist experiments showed that both D1 and D2 receptor systems must be functional for SKF-82958- or quinpirole-induced locomotor activity to be fully manifested. When the present data are compared to results from non-ontogenetic studies, it appears that pharmacological manipulation of D1 and D2 receptors in the dorsal CPu affects the behavior of preweanling and adult rats in a generally similar manner, although some important age-dependent differences are apparent. For example, D1 and/or D2 agonists preferentially induce locomotor activity, and not intense stereotypy, in younger animals.

Working memory span capacity improved by a D2 but not D1 receptor family agonist

Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice ( n = 12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia.

Goldfish brain somatostatin-28 differentially affects dopamine- and pituitary adenylate cyclase-activating polypeptide-induced GH release and Ca2+ and cAMP signals

Dopamine (DA) and pituitary adenylate cyclase-activating polypeptide (PACAP) stimulate goldfish growth hormone (GH) release via cAMP- and Ca2+-dependent pathways while DA also utilizes NO. In this study, identified goldfish somatotropes responded to sequential applications of PACAP and the DA D1 agonist SKF38393 with increased intracellular Ca2+ levels ([Ca2+]i), indicating that PACAP and DA D1 receptors were present on the same cell. A native goldfish brain somatostatin (gbSS-28) reduced SKF38393-stimulated cAMP production and PACAP- and NO donor-elicited GH and [Ca2+]i increases, but not PACAP-induced cAMP production nor the GH and [Ca2+]i responses to forskolin, 8-bromo-cAMP and SKF38393. gbSS-28 might inhibit PACAP-induced GH release by interfering with PACAP's ability to increase [Ca2+]i in a non-cAMP-dependent manner. However, DA D1 receptor activation bypassed gbSS-28 inhibitory effects on cAMP production and NO actions via unknown mechanisms to maintain a normal [Ca2+]i response leading to unhampered GH release.

Dyskinetic potential of dopamine agonists is associated with different striatonigral/striatopallidal zif-268 expression

In the dopamine-depleted striatum, an altered post-synaptic signalling of efferent neurons might underline the onset of variable dyskinetic responses to dopaminergic agonists. We have previously shown that a subchronic treatment with the D1 agonist SKF-38393 and the D2 agonist ropinirole induces a dyskinetic response of high and low intensities respectively, in 6-hydroxydopamine-lesioned rats. Here, zif-268 mRNA expression was evaluated in striatonigral and striatopallidal neurons to assess a neurochemical marker of these different dyskinetic responses upon drug administration. Acute and subchronic SKF-38393 (3mg/kg) increased zif-268 expression per neuron in the striatonigral pathway, albeit the number of neurons displaying high early-gene levels was reduced by the subchronic treatment. Zif-268 mRNA in striatopallidal neurons was not affected by SKF-38393 treatments. In contrast, ropinirole (5mg/kg) did not alter zif-268 mRNA in striatonigral neurons acutely, whereas ropinirole decreased zif-268 mRNA subchronically. Both acute and subchronic ropinirole decreased zif-268 levels in the striatopallidal pathway. The differential expression of zif-268 in striatonigral and striatopallidal neurons might provide a biochemical correlate of the dyskinetic outcome displayed by SKF-38393 and ropinirole treatments, suggesting that evaluation of neuronal responses upon drug administration provides a tool for the preclinical characterization of dyskinetic potential beyond behavioural tests.

Dopamine Induces Optical Changes in the Cichlid Fish Lens

The crystalline lens in the cichlid fish Aequidens pulcher undergoes a transformation of its optical properties every dawn and dusk as the eye adapts to changes in light conditions. During dusk the transformation result in an increase of the refractive power in the lens cortex, the outermost 40 percent. The change is thought to match the optical properties of the lens to the requirements of the retina. Using a short term in vitro lens culturing system together with optical measurements we here present data that confirm that the optical properties of the lens can change within hours and that dopamine influences the optical properties of the lens. Dopamine yields dose-dependent decrease of the refractive power in the lens cortex. The D1-agonist SKF-38393 induces a similar decrease of the refractive power in the cortex, while the D2-agonist quinpirole has no effect. The effect of dopamine can be blocked by using the D1-antagonist SCH 23390. Our results suggest that dopamine alone could be responsible for the light/dark adaptive optical changes in the lens, but the involvement of other signaling substances cannot be ruled out.

D1 priming enhances both D1- and D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization upon repeated treatment with dopamine agonists, a phenomenon called ‘priming’. We examined the effectiveness of priming with D1 or D2 agonists on rotational behavior and striatal Fos expression following challenge with D1 or D2 agonists. Twenty-one days post-lesion, rats received three priming injections, spaced 3–6 days apart, with water, D1 agonist SKF38393 (10 mg/kg) or D2 agonist quinpirole (1 mg/kg). One week later, 6-OHDA rats were challenged with water, SKF38393 (1 or 10 mg/kg) or quinpirole (0.25 mg/kg). 6-OHDA rats challenged with SKF38393 (1 mg/kg) showed no contralateral rotational behavior, but robust striatal Fos expression in D1-primed animals. Challenge with SKF38393 (10 mg/kg) led to pronounced contralateral rotational behavior and striatal Fos expression in all priming groups — with the largest behavioral response in D1- and D2-primed rats. Quinpirole challenge (0.25 mg/kg) led to robust contralateral rotational behavior and striatal Fos expression in D1-primed animals, but only mild rotational behavior and baseline levels of striatal Fos expression in D2-primed animals. These data suggest that D1- or D2-priming enhances rotational behavior following challenge with D1 or D2 agonist, but only D1-priming enhances D1- and D2-mediated striatal Fos expression in 6-OHDA rats.

Infusions of anti-sense oligonucleotides for DARPP-32 to the ventral tegmental area reduce effects of progesterone- and a dopamine type 1-like receptor agonist to facilitate lordosis

Manipulating dopamine and/or adenosine 3′,5′ monophosphate regulated phosphoprotein of 32kDa (DARPP-32) can influence sexual behavior of rodents. The ventral tegmental area (VTA) is an important brain site for progestogens to facilitate sexual behavior of rodents. We hypothesized that, in the VTA, dopamine type 1-like receptor (D1)-mediated increases in progesterone (P4)-facilitated lordosis involve DARPP-32. To investigate this, ovariectomized hamsters and rats, primed with estradiol (E2; 10μg), received infusions to the VTA of saline vehicle or sense or anti-sense oligonucleotides targeted against DARPP-32 (4nM). Subjects were then administered P4 via subcutaneous injection (hamsters: 200μg; rats: 0 or 100μg). Hamsters and rats were pre-tested for lordosis 3.5h post-P4 injections, and then infused with the D1 agonist SKF38393 (100ng) or vehicle to the VTA, and re-tested for sexual behavior 30min later. Anti-sense oligonucleotides targeted against DARPP-32, but not infusions of sense oligonucleotides, to the VTA blocked the ability of systemic P4 to enhance receptive behavior of hamsters and rats. Similarly, SKF38393-mediated increases in P4-facilitated sexual behaviors were blocked by DARPP-32 anti-sense oligonucleotides to the VTA. The same pattern of effects was not observed in rats that were primed with E2-alone. Together, these findings suggest that, in the midbrain VTA, P4's actions to facilitate sexual behavior of female rodents, involving D1 receptors, may require DARPP-32.

Striatal Alterations of Secretogranin-1, Somatostatin, Prodynorphin, and Cholecystokinin Peptides in an Experimental Mouse Model of Parkinson Disease

The principal causative pathology of Parkinson disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum in the brain. The information regarding the expression of neuropeptides in parkinsonism is very limited. Here we have elucidated striatal neuropeptide mechanisms in experimental parkinsonism using the unilateral 6-hydroxydopamine model to degenerate dopamine neurons. A thoroughly controlled sample preparation technique together with a peptidomics approach and targeted neuropeptide sequence collections enabled sensitive detection, identification, and relative quantitation of a great number of endogenous neuropeptides. Previously not recognized alterations in neuropeptide levels were identified in the unilateral lesioned mice with or without subchronic 3,4-dihydroxy-L-phenylalanine administration, the conventional treatment of Parkinson disease. Several of these peptides originated from the same precursor such as secretogranin-1, somatostatin, prodynorphin, and cholecystokinin. Disease-related biotransformation of precursors into individual peptides was observed in the experimental model of Parkinson disease. Several previously unreported potentially biologically active peptides were also identified from the striatal samples. This study provides further evidence that neuropeptides take part in mediating the central nervous system failure associated with Parkinson disease.

神经细胞中多巴胺D1和D5受体不同亚细胞分布和胞内转运的特性

To explore the possible differential trafficking properties of the dopamine D1-like receptor subtypes, D1 receptor and D5 receptor. To visualize distributions of dopamine D1-like receptor subtypes at subcellular level, the yellow and cyan variants of green fluorescent protein (GFP) were used to tag D1 and D5 receptors. After transfection with the tagged dopamine receptors, the neuroblastoma cells NG108-15 were treated with D1 agonist SKF38393 or acetylcholine (ACh). Then we observed the subcellular distributions of the tagged receptors under the confocal microscopy and tried to determine trafficking properties by comparing their distribution patterns before and after the drug treatment. In resting conditions, D1 receptors located in the plasma membrane of NG108-15 cells, while D5 receptors located in both plasma membrane and cytosol. With the pre-treatment of SKF38393, the subcellular distribution of D1 receptors was changed. The yellow particle-like fluorescence of tagged D1 receptors appeared in the cytosol, indicating that D1 receptors were internalized into cytosol from the cell surface. Same situation also occurred in ACh pre-treatment. In contrast, the subcellular distribution of D5 receptors was not changed after SKF38393 or ACh treatment, indicating that D5R was not translocated to cell surface. Interestingly, when D1 and D5 receptors were co-expressed in the same cell, both kept their distinct subcellular distribution patterns and the trafficking properties. Our present study reveals that in NG108-15 nerve cells, dopamine D1 and D5 receptors exhibit differential subcellular distribution patterns, and only D1 receptor has a marked trafficking response to the drug stimulation. We further discuss the potential role of the differential trafficking properties of D1-like receptors in complex modulation of DA signaling.

Monoamines block kainate‐ and carbachol‐induced γ‐oscillations but augment stimulus‐induced γ‐oscillations in rat hippocampus in vitro

Monoamines are implicated in a cognitive processes in a variety of brain regions, including the hippocampal formation, where storage and retrieval of information are facilitated by synchronous network activities. We have investigated the effects of norepinephrine, serotonin, and dopamine on carbachol-, kainate-, and stimulus-induced hippocampal gamma-oscillations employing combined extra- and intracellular recordings. Monoamines dose-dependently and reversibly suppressed kainate- and carbachol-induced gamma-oscillations while increasing the frequency. The effect of serotonin was mimicked by fenfluramine, which releases serotonin from presynaptic terminals. Forskolin also suppressed kainate- and carbachol-induced gamma-oscillations. This effect was mimicked by 8-Br-cAMP and isoproterenol, an agonist of noradrenergic beta-receptor suggesting that the monoamines-mediated suppression of these oscillations could involve intracellular cyclic adenosine 3',5'-cyclic monophosphate (AMP). By contrast, stimulus-induced gamma-oscillations were dose-dependently augmented in power and duration after monoamines application. Intracellular recordings from pyramidal cells revealed that monoamines prolonged the stimulus-induced depolarization and membrane potential oscillations. Stimulus-induced gamma-oscillations were also suppressed by isoproterenol, the D1 agonist SKF-38393 forskolin, and 8-Br-cAMP. This suggests that the augmentation of stimulus-induced gamma-oscillations by monoamines involves--at least in part-different classes of cells than in case of carbachol- and kainate-induced gamma-oscillations.

Dopamine's role in social modulation of infant isolation‐induced vocalization: II. Maternally modulated infant separation responses are regulated by D1‐ and D2‐family dopamine receptors

Mammalian infant behavior directed toward caregivers is critical to survival and may play a role in establishing social bonds. Most mammalian infants vocalize when isolated. Rat pups vocalize at a higher rate when isolated following an interaction with an adult female than after an interaction with littermates, a phenomenon termed maternal potentiation. We previously reported that the D2 receptor family agonist quinpirole disrupts maternal potentiation at a dose that does not alter vocalization rate following contact with littermates. Here we further examine the role of dopamine in maternal potentiation by testing effects of both D1 and D2 receptor family ligands, alone and in combination, on maternal potentiation. We tested the drugs' effects on isolation vocalization subsequent to littermate contact and then another isolation preceded by a brief "reunion" period of exposure either to the anesthetized dam or a handling-only "pickup" condition. D2 receptor stimulation blocked the increase in vocalizations following reunion with the dam. The D2 agonist effect in the dam-reunion condition was much larger than its small effect in the pickup condition, providing further evidence that D2 receptors exert a selective modulation of maternal potentiation. On the other hand, systemic administration of the D1 agonist SKF81297 reduced isolation vocalizations nonspecifically, across all the experimental conditions. Finally, the D1 and D2 receptor dual antagonist, alpha-flupenthixol, increased isolation vocalizations and disrupted potentiation, but at doses that also inhibited locomotion. We conclude that D2 receptor family activation has a more selective effect of disrupting maternal potentiation than D1 receptor family activation.