A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [(5aR-trans)-5,5a,6,7,8, 9,9a,10-octahydro-6-propylpyrido[2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (NЈ-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(Ϯ)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(Ϫ)-(4aR)-4,4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(ϩ)-2-bromo-12Ј-hydroxy-2Ј-(1-methylethyl)-5Ј-(2-methylpropyl) ergotaman-3Ј,6Ј-18-trione methanesulfonate], and apomorphine [(R)-(Ϫ)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The antagonists, and PG01037 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl) were used to determine effects on doseresponse curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [(a,S)-a-(hydroxymethyl)benzeneacetic acid (1a,2b,4b,5a,7b)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine HCl), and the D3-preferring antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by PD-128,907, physostigmine [(3aS)-cis-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate hemisulfate], and N- [3-(trifluoromethyl)phenyl]piperazine HCl. The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist-mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptormediated activities. Dopamine D3 receptors have received considerable interest since originally cloned (Sokoloff et al., 1990). The D3 receptor shares significant sequence homology with the dopamine D2 receptor but displays a much more restricted, limbic pattern of distribution compared with that of the D2 , trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)

In this article, we use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine (PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 mg/kg, i.p.)-induced increases in ambulations, distance traveled, and reduced time spent at rest. LY404039 reversed PCP (7.5 mg/kg i.p.)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 (10 mg/kg i.p.) on PCP and AMP-evoked behavioral activation were absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice, indicating that the activation of mGlu2 and not mGlu3 receptors is responsible for the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039. In contrast, the atypical antipsychotic drugs clozapine and risperidone inhibited PCP-evoked behaviors in both wild-type and mGlu2/3 receptor-deficient mice. These data demonstrate that the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039 in psychostimulant models of psychosis are mechanistically distinct from those of atypical antipsychotic drugs and are dependent on functional mGlu2 and not mGlu3 receptors.Schizophrenia is a lifelong and devastating psychiatric disorder characterized by positive, negative, and cognitive symptoms (Andreasen and Carpenter, 1993;Ross et al., 2006). Although several neurotransmitter systems (dopamine, serotonin, and glutamate) have been implicated in the pathophysiology of schizophrenia, dopamine D 2 receptors are the primary target of all antipsychotic drugs. Although these medications reduce the severity of positive symptoms, they have only a modest effect on the negative or cognitive impairments present in the disorder. Due to these shortcomings, there is a clear need for alternative strategies for the treatment of schizophrenia. Recent clinical data suggest that a group II metabotropic glutamate (mGlu) receptor agonist LY2140023 (prodrug of LY404039) has antipsychotic properties and may represent an alternative, nondopaminergic treatment for schizophrenia (Patil et al., 2007).

We report on the pharmacological effects of the 20 fold D3 vs. D2 dopamine receptor preferring compound U99194A. It is shown that U99194A increases rat locomotor activity at doses that do not increase release or utilisation of dopamine in the striatum or the nucleus accumbens significantly. The data do not support any direct agonist action of U99194A at dopamine receptors. It is suggested that U99194A can antagonise a population of postsynaptic dopamine receptors involved in the suppression of some aspects of psychomotor activity. These postsynaptic receptors presumably belong to the D3 receptor subtype.

No abstract

The effects of lesions to the mesolimbic dopamine system on maternal and sexual behaviors in the female rat was assessed. Rat dams that were given ventral tegmental area microinfusions of 6-hydroxydopamine (6-OHDA) during lactation showed a persistent deficit in pup retrieval but were not impaired with respect to nursing, nest building, or maternal aggression. In addition, 6-OHDA-lesioned females failed to respond to amphetamine by showing locomotor hyperactivity. Administration of the dopamine blocker raclopride to neurologically intact dams also inhibited pup retrieval but had no effect on nursing. Females given 6-OHDA during pregnancy appeared completely unresponsive to pups, whereas no maternal deficits were seen in females that received 6-OHDA 8 weeks before parturition. Proceptive (hopping and darting) and receptive (lordosis) components of sexual behavior, assessed after ovariectomy and exogenous steroid hormone treatment, were not affected by mesolimbic 6-OHDA lesions.

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Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

The binding site for DETQ [2-(2,6-dichlorophenyl)-1-((1,3)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1)-yl)ethan-1-one], a positive allosteric modulator (PAM) of the dopamine D1 receptor, was identified and compared with the binding site for CID 2886111 [-(6--butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide], a reference D1 PAM. From D1/D5 chimeras, the site responsible for potentiation by DETQ of the increase in cAMP in response to dopamine was narrowed down to the N-terminal intracellular quadrant of the receptor; arginine-130 in intracellular loop 2 (IC2) was then identified as a critical amino acid based on a human/rat species difference. Confirming the importance of IC2, a 2-adrenergic receptor construct in which the IC2 region was replaced with its D1 counterpart gained the ability to respond to DETQ. A homology model was built from the agonist-state2-receptor structure, and DETQ was found to dock to a cleft created by IC2 and adjacent portions of transmembrane helices 3 and 4 (TM3 and TM4). When residues modeled as pointing into the cleft were mutated to alanine, large reductions in the potency of DETQ were found for Val119 and Trp123 (flanking the conserved DRY sequence in TM3), Arg130 (located in IC2), and Leu143 (TM4). The D1/D5 difference was found to reside in Ala139; changing this residue to methionine as in the D5 receptor reduced the potency of DETQ by approximately 1000-fold. None of these mutations affected the activity of CID 2886111, indicating that it binds to a different allosteric site. When combined, DETQ and CID 2886111 elicited a supra-additive response in the absence of dopamine, implying that both PAMs can bind to the D1 receptor simultaneously.