Dopamine D2High receptors stimulated by phencyclidines,lysergic acid diethylamide,salvinorin A,and modafinil

Although it is commonly stated that phencyclidine is an antagonist at ionotropic glutamate receptors, there has been little measure of its potency on other receptors in brain tissue. Although we previously reported that phencyclidine stimulated cloned‐dopamine D2Long and D2Short receptors, others reported that phencyclidine did not stimulate D2 receptors in homogenates of rat brain striatum. This study, therefore, examined whether phencyclidine and other hallucinogens and psychostimulants could stimulate the incorporation of [³⁵S]GTP‐γ‐S into D2 receptors in homogenates of rat brain striatum, using the same conditions as previously used to study the cloned D2 receptors. Using 10 μM dopamine to define 100% stimulation, phencyclidine elicited a maximum incorporation of 46% in rat striata, with a half‐maximum concentration of 70 nM for phencyclidine, when compared with 80 nM for dopamine, 89 nM for salvinorin A (48 nM for D2Long), 105 nM for lysergic acid diethylamide (LSD), 120 nM for R‐modafinil, 710 nM for dizocilpine, 1030 nM for ketamine, and >10,000 nM for S‐modafinil. These compounds also inhibited the binding of the D2‐selective ligand [³H]domperidone. The incorporation was inhibited by the presence of 200 μM guanylylimidodiphosphate and also by D2 blockade, using 10 μM S‐sulpiride, but not by D1 blockade with 10 μM SCH23390. Hypertonic buffer containing 150 mM NaCl inhibited the stimulation by phencyclidine, which may explain negative results by others. It is concluded that phencyclidine and other psychostimulants and hallucinogens can stimulate dopamine D2 receptors at concentrations related to their behavioral actions. Synapse 63:698–704, 2009. © 2009 Wiley‐Liss, Inc.     

Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2High receptor

The glutamate agonist LY404,039 has been used to treat schizophrenia. Because all currently used antipsychotics act on dopamine receptors, it was decided to examine whether this glutamate agonist also had an affinity for dopamine D2 receptors in vitro. The present data show that LY404,039 inhibited the binding of [³H]domperidone and [³H](+)PHNO by 15.5 ± 1.5% to the high‐affinity state, D2^High, of cloned dopamine D2_Long receptors and rat striatal tissue with dissociation constants of between 8.2 and 12.6 nM. This high‐affinity component of LY404,039 on the binding of [³H]domperidone was inhibited by the presence of guanine nucleotide, indicating an agonist action of the drug at D2^High. LY404,039 also stimulated the incorporation of [³⁵S]GTP‐γ‐S into D2_Long receptors (EC50% = 80 ± 15 nM) over the same range of concentrations as occurred for the inhibition of [³H]domperidone by LY404,039 at D2^High (IC50%^High = 50 ± 10 nM). A possible clinical antipsychotic action of LY404,039 may depend on the combined stimulation of glutamate receptors and a partial dopamine agonist action that would interfere with neurotransmission at D2^High receptors. Synapse 63:935–939, 2009. © 2009 Wiley‐Liss, Inc.     

Glutamate agonists for treating schizophrenia have affinity for dopamine D2High and D3 receptors

Although the glutamate agonist LY 404,039 has been used to treat schizophrenia, its closest congener LY 379,268 has an affinity for both glutamate and dopamine (DA) D2^High receptors. Considering that all antipsychotics act on dopamine receptors, and considering that another laboratory reported that LY 379,268 did not have any affinity for the D2^High receptor, it was necessary to examine whether such glutamate agonists have an affinity for D2 and D3 dopamine receptors in vitro. The present data show that 50–200 nM LY 379,268 inhibited the binding of [³H]domperidone and [³H](+)PHNO to cloned dopamine D2 receptors consistently and reproducibly by 16% with dissociation constants of 2.1 and 2.5 nM at D2^High, respectively. In addition, LY 379,268 inhibited the binding of [³H]domperidone and [³H](+)PHNO to cloned dopamine D3 receptors with dissociation constants of 130 and 10 nM, respectively. LY 379,268 also inhibited the binding of [³H]domperidone to rat striata with a dissociation constant of 22 nM, predicting a clinical antipsychotic dose of 80–100 mg/day. LY 379,268 appears to act as an agonist at D2^High and as an antagonist at D3, because guanine nucleotide eliminated the competition at D2^High but had no effect on the competition at D3. The findings indicate that this type of glutamate agonist, LY 379,268, has a significant affinity for D2^High and D3 receptors. Synapse 63:705–709, 2009. © 2009 Wiley‐Liss, Inc.     

Dopamine partial agonist actions of the glutamate receptor agonists LY 354,740 and LY 379,268

Because glutamate compounds alter the release of dopamine and prolactin, the present study examined whether group II metabotropic receptor agonists, LY 354,740 and LY 379,268, had any direct in vitro action on dopamine D2 receptors on rat striatal tissue, cloned D2Long receptors, and prolactin release from anterior pituitary cells. In competition versus the D2-specific ligand [(3)H]domperidone, LY 354,740 had a dissociation constant of 24 nM at D2(High) (the functional high-affinity state of dopamine D2 receptors), while the value for LY 379,268 was 21 nM. LY 354,740 also stimulated by 50% the incorporation of [(35)S]-GTP-gamma-S at a concentration of 120 nM, but its maximal stimulation was only 22% of the maximum elicited by dopamine. LY 379,268 stimulated by 50% the incorporation of [(35)S]-GTP-gamma-S at 280 nM, but its maximal stimulation was also only 22% of the maximum elicited by dopamine. However, both LY 354,740 and LY 379,268 potently inhibited the dopamine-induced incorporation of [(35)S]-GTP-gamma-S with inhibitory Ki values of 43 nM and 30 nM, respectively. The release of prolactin from rat isolated anterior pituitary cells in culture was 50% inhibited by 20 nM LY 379,268 and by 100 nM LY 354,740. These Ki values are similar to those known for the mGluR II receptor, suggesting that these compounds may have both glutamate and dopamine actions in vivo. The dopamine agonist and antagonist actions of these compounds indicate that these drugs have properties of a dopamine partial agonist, and may, therefore, have antipsychotic action.     

The dopaminergic stabilizer ASP2314/ACR16 selectively interacts with D2High receptors

Dopaminergic stabilizers are recognized as compounds that can either enhance or antagonize dopamine (DA)‐dependent behaviors depending on the prevailing dopaminergic tone. The dopaminergic stabilizer ASP2314 is being tested clinically and has been reported to have antipsychotic effects in a clinical trial as an add on medication. To elucidate the mechanisms of action of this dopaminergic stabilizer, its potency on the functional dopamine D2^High receptors was examined. In competition with D2 receptors selectively labeled by [³H]domperidone, ASP2314 had a dissociation constant, Ki^High, of 1.62 μM for D2^High in human cloned D2Long receptors and 0.83 μM for rat homogenized striata. Using the D2 agonist ligand [³H](+)‐4‐propyl‐3,4,4a,5,6,10b‐hexahydro‐2H‐naphtho[1,2‐b][1,4]oxazin‐9‐ol ((+)PHNO), ASP2314 had a high‐affinity K_i of 32 nM for D2^High for rat homogenized striata. ASP2314 stimulated the incorporation of [³⁵S]GTP‐γ‐S into rat striata by 50% at 43 nM, and into the cloned D2Long membranes by 50% at 3.2 μM (compared to 100% stimulation by 10 μM dopamine). With similar concentrations of ASP2314 inhibiting the binding of ligands at D2^High and stimulating [³⁵S]GTP‐γ‐S incorporation, the data indicate that the dopaminergic stabilizing action of ASP2314 may be related to the selectivity for the D2^high state of the D2 receptor. Synapse 63:930–934, 2009. © 2009 Wiley‐Liss, Inc.     

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D1 (-48%) and D2 (-51%) DA receptors available for binding to [3H]SCH 23390 and [3H]raclopride, respectively. A challenge dose of the D2 agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D1 agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D1 and D2 DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting that EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D1 or D2 DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D2 antagonist raclopride (20 mg/kg, i.p.) or of the D1 antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D2 DA receptors is similar to that found in rats in which both D1 and D2 DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D1 DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glutamate and dopamine components in schizophrenia

The treatment of schizophrenia for the last half century has been with dopamine (DA) D₂ receptor blockers, implicating a hyperdopamine basis for psychosis. However, a 2007 report found that the glutamate agonist LY404039 was effective in schizophrenia, suggesting a hypoglutamate state for the illness. Although phencyclidine psychosis also supports a hypoglutamate cause, assessing the basic and clinical findings shows that phencyclidine has DA D₂ agonist actions as well. Accurate Dreiding models of phencyclidine and the LY glutamate agonists precisely fit the known tetrahedral model of the D₂ receptor that accommodates all DA agonists. A further view is that metabotropic glutamate agonists also exert D₂ agonism, and their antipsychotic doses (about 100 mg/d) are predicted by their dissociation constants (about 20 nM) for D₂. Hence, the clinical antipsychotic action of a glutamate agonist may depend on its ability to interfere with DA neurotransmission by its DA partial agonism.     

Absence of direct effects on the dopamine D2 receptor by mGluR2/3‐selective receptor agonists LY 354,740 and LY 379,268

We previously reported the absence of high‐affinity binding of the group II metabotropic glutamate receptor agonists LY 354,740 and LY 379,268 to the D2L dopamine receptor. A rebuttal to our findings has since been reported (see Introduction section); this study represents our response. Analysis by LCMS of LY 354,740 and LY 379,268 used in this study revealed the correct molecular mass for these compounds. Both LY 354,740 and LY 379,268 exhibited potent agonist activity for mGluR₂ in the ³⁵S‐GTPγS assay. Functionally, neither compound displayed antagonist activity in the GTPγS assay with recombinant D₂. At concentrations up to 10 μM, both compounds failed to displace [³H]‐raclopride, [³H]‐PHNO, or [³H]‐domperidone in filter‐binding assays under isotonic (120 mM NaCl or N‐methyl glucamine) or low‐ionic strength (no NaCl or N‐methyl glucamine) conditions. Some displacement of [³H]‐domperidone (20–40%) was observed at 30 μM of LY 354,740 under low‐ionic strength and under isotonic conditions in the absence of NaCl. No displacement of [³H]‐domperidone was detected in a two site model at lower (<100 nM) concentrations of either compound. Moreover, no D₂ activity was observed for LY 354,740 or LY 379,268 in the CellKey? (cellular dielectric spectroscopy) assay. In this communication, we discuss the possible reasons for differences in our study and the previously published work and implications of these studies for mechanisms of antipsychotic action. Synapse 65:64–68, 2011. © 2010 Wiley‐Liss, Inc.     

The group I metabotropic glutamate receptor antagonist S-4-CPG modulates the locomotor response produced by the activation of D1-like, but not D2-like, dopamine receptors in the rat nucleus accumbens

Functional interactions between dopamine (DA) and glutamate neurotransmissions in both the dorsal and the ventral striatum have been described for long time. However, there is much controversy as to whether glutamate transmission stimulates or attenuates DA release and locomotor activity. We investigated the functional interactions on locomotor activity between group I metabotropic glutamatergic receptors (mGlu receptors) and both D1-like and D2-like DA receptors in the rat nucleus accumbens. Intra-accumbens administration of the selective group I mGlu receptor antagonist S-4-CPG (0.2 or 2 microg per side), which had no effect when injected alone, prevented the increase in locomotor activity produced by the selective D1-like receptor agonist SKF 38393 (1 microg per side). Co-administration with S-4-CPG of the group I mGlu receptor agonist DHPG, but not of the group II mGlu receptor agonist APDC or the group III mGlu receptor agonist AP4, reversed the antagonistic effect of S-4-CPG on the SKF 38393-induced increase in locomotor activity. This indicates that the antagonistic effect of S-4-CPG could result from an action at the group I mGlu receptors. In contrast, administration of S-4-CPG showed no effect on the locomotor responses produced by either the selective D2-like receptor agonist LY 171555 (1 microg per side) or a mixed solution of SKF 38393 + LY 171555 (1 microg per side each). Altogether, these results confirm that glutamate transmission may control locomotor function through mGlu receptors in a DA-dependent manner, and further indicate that group I mGlu receptors would interact with D1-like receptors, but not D2-like receptors, to modulate DA transmission and locomotor activity.     

Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive,with elevated D2High receptors and marked supersensitivity to the dopamine agonist (+)PHNO

The finding that the mGlu2/3 metabotropic glutamate receptor agonist, LY404039, improves clinical symptoms in schizophrenia warrants a search for a possible interaction between mGlu2/3 receptors and dopamine D2 receptors. Here, this topic is examined in striatal tissue of mice lacking either mGlu2 or mGlu3 receptor. Such mice are known to be behaviorally supersensitive to dopamine receptor agonists. Therefore, to determine the basis of this dopamine supersensitivity, the proportion of dopamine D2^High receptors was measured in the striata of mGlu2 and mGlu3 receptor knockout mice. The proportion of D2^High receptors was found to be elevated by 220% in the striata of both knockouts. To measure the functional dopamine supersensitivity, the D2 agonist (+)PHNO was used to stimulate the incorporation of GTP‐γ‐S in the striatal homogenates in the presence of drugs that blocked the dopamine D1, D3, and D5 receptors. Compared with control striata, the mGlu2 receptor knockout tissues were 67‐fold more sensitive to (+)PHNO, while the mGlu3 receptor knockout tissues were 17‐fold more sensitive. These data suggest that group II mGlu receptors—mGlu2 receptors in particular—may normally regulate D2 receptors by reducing the proportion of high‐affinity D2 receptors in membranes. Such regulation may contribute to the antipsychotic action of mGlu2/3 receptor agonists. Synapse 63:247–251, 2009. © 2008 Wiley‐Liss, Inc.     

In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg(-1) i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3"). [11C]Raclopride V3" was reduced by 24 +/- 10%, 32 +/- 6%, and 44 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. [11C]NPA V3" was reduced by 32 +/- 2%, 45 +/- 3%, and 53 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.     

Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation

Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine.     

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

Memantine agonist action at dopamine D2High receptors

Memantine is reported to improve symptoms in moderate cases of Alzheimer's disease and Parkinson's disease, but is also known to trigger psychosis in some Parkinson patients. Because these clinical features suggested a possible dopamine component of memantine action, we measured the potency of memantine on the functional high-affinity state of dopamine D2 receptors, or D2(High). Using [(3)H]domperidone to label D2 receptors, the memantine dissociation constant at D2(High) was 917 +/- 23 nM for rat striatal D2 receptors and 137 +/- 19 nM for human cloned D2Long receptors. The memantine dissociation constant for striatal N-methyl-D-aspartate (NMDA) receptors labeled by [(3)H]MK 801 was 2200 +/- 400 nM. Memantine stimulated the incorporation of [(35)S]GTP-gamma-S into D2-expressing Chinese Hamster Ovary cells with a dissociation constant of 1200 +/- 400 nM. Memantine, between 200 and 2000 nM, directly acted on D2(High) to inhibit the release of prolactin from isolated anterior pituitary cells in culture. Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors.     

Group III metabotropic glutamate receptors and D1-like and D2-like dopamine receptors interact in the rat nucleus accumbens to influence locomotor activity

Evidence for functional interactions between metabotropic glutamate (mGlu) receptors and dopamine (DA) neurotransmission is now clearly established. In the present study, we investigated interactions between group III mGlu receptors and D1- and D2-like receptors in the nucleus accumbens (NAcc). Administration, into the NAcc, of the selective group III mGlu receptor agonist, AP4, resulted in an increase in locomotor activity, which was blocked by pretreatment with the group III mGlu receptor antagonist, MPPG. In addition, pretreatment with AP4 further blocked the increase in motor activity induced by the D1-like receptor agonist, SKF 38393, but potentiated the locomotor responses induced by either the D2-like receptor agonist, quinpirole, or coinfusion of SKF 38393 and quinpirole. MPPG reversed the effects of AP4 on the motor responses induced by D1-like and/or D2-like receptor activation. These results confirm that glutamate transmission may control DA-dependent locomotor function through mGlu receptors and further indicate that group III mGlu receptors oppose the behavioural response produced by D1-like receptor activation and favour those produced by D2-like receptor activation.     

Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo

[11C]PHNO is a recently introduced agonist to image DA D2-like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2-like antagonists (such as [11C]raclopride) or other D2-like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3') in baboons was much higher in GP (3.88 +/- 1.15) than in the dorsal striatum (DST, 2.07 +/- 0.43), whereas the reverse was true for [11C]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [11C]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3' and [11C]raclopride V3' in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2-like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [11C]raclopride V3' by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3' by 57% +/- 11%, 30% +/- 11%, and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA.     

Cesarean plus anoxia at birth induces hyperresponsiveness to locomotor activity by dopamine D2 agonist

Transient global anoxia after Cesarean birth in rats may produce alterations in the subcortical DA function and related behaviors. The reports only tested the behavioral changes induced by a general DA agonist, such as amphetamine or apomorphine, in adult rats. Here we investigated the role of perinatal anoxia on the locomotion induced by a specific dopamine (DA) agonist and its relation to the DA D1-like and D2-like receptors, measured by autoradiography at two different ages, prepubertal (35 days old, P35) and postpubertal (60 days old, P60). Cesarean birth with or without (C-only) an additional period of 10 min of the anoxia was done in Sprague-Dawley rats, and the effects of the DA D1-like and D2-like agonist and their receptors were studied at P35 and P60. In addition, a third group of animals born vaginally served as the control. The quantitative autoradiography study of the DA D1-like and D2-like receptors revealed an enhancement of the DA D1-like receptor levels in the nucleus accumbens (NAcc) and dorsolateral part of the caudate-putamen in the prepubertal C-only animals. The postpubertal C-only rats showed a decrease in the levels of DA D2-like receptors in the NAcc. However, quinpirole, a DA D2 agonist (0.125 and 0.25 mg/kg, s.c.), induced a dose-dependent increase of the locomotor activity in the animals born by Cesarean with anoxia at birth at both ages. Our results suggest that Cesarean with or without anoxia at birth may mediate differently the neurodevelopmental aspects of the dopaminergic system before and after puberty.     

D1 dopamine receptor--the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and its functional implications

The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptors can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.     

Topographic nonoverlapping distribution of D1 and D2 dopamine receptors in the amygdaloid nuclear complex of the rat brain.

The distribution of D1 and D2 dopamine (DA) receptors in the nuclei and subnuclear zones of the rat amygdaloid complex was mapped using quantitative light microscopic autoradiography. [125I]iodosulpiride and [125I]SCH 23982 (in the presence of 50 nM ketanserin) were used to label D2 and D1 DA receptors, respectively. The DA receptor subtypes exhibited a topographic, nonoverlapping distribution which generally conformed to the cytoarchitectonic boundaries of the component nuclei and subnuclear zones of the amygdaloid complex. The highest density of [125I]iodosulpiride binding sites was observed in the main intercalated cell group and the central amygdaloid nucleus where a medial to lateral gradient of binding sites was localized to its subnuclear zones. [125I]SCH 23982 binding sites were localized in the main intercalated cell group and the basolateral amygdaloid nucleus with a uniform low density in the central nucleus. The functional topography of mesoamygdaloid DA neurons may therefore be mediated, in part, at the level of DA receptor subtypes. The pattern of distribution of [125I]iodosulpiride binding sites in subdivisions of the central amygdaloid nucleus and bed nucleus of the stria terminalis suggests that the functions of the "extended amygdala," a major system of the functional organization of the basal forebrain, may be regulated by DA afferents at multiple key sites of D2 receptor action.     

Modulation of acetylcholine release by D1, D2 dopamine receptors in rat striatum under freely moving conditions

Using in vivo brain dialysis under freely moving conditions, we have studied the effects of dopamine (DA) agonists and antagonists on acetylcholine (ACh) and DA release in rat striatum. The striatal infusion of the D1 DA receptor specific agonist, SKF38393, increased striatal ACh release in a dose-dependent manner (10(-6) to 10(-4) M), and 3 x 10(-5) M SKF38393 elicited a 60% augmentation in the level of ACh release. The level of ACh was increased with perfusion of 10(-4) M SCH23390, a D1 specific antagonist, but decreased with 10(-3) M SCH23390. The D2 specific agonist, LY171555, and the antagonist, sulpiride, slightly altered the level of ACh in the striatum. On the other hand the level of DA dramatically increased in a dose-dependent manner with SKF38393 or SCH23390 and decreased with LY171555. LY171555 inhibited the effect of 10(-4) M SKF38393 on ACh release, and enhanced the effect of SKF38393 on DA release. These results suggest that the D1 DA receptor mainly mediates ACh release and the D2 DA receptor modifies the effects of the D1 receptor.