The receptor mechanisms underlying the disruptive effects of haloperidol and clozapine on rat maternal behavior: A double dissociation between dopamine D2 and 5-HT2A/2C receptors

Many antipsychotic drugs disrupt active components of maternal behavior such as pup approach, pup retrieval and nest building at clinically relevant doses in postpartum female rats. However, the neurochemical mechanisms underlying such a disruptive effect remain to be determined. This study examined the neurochemical mechanisms that mediate the disruptive effects of haloperidol (a typical antipsychotic) and clozapine (an atypical antipsychotic) on rat maternal behavior. Postpartum rats were administered with haloperidol (0.2 mg/kg, sc) or clozapine (10.0 mg/kg, sc) together with either vehicle (saline or water), quinpirole (a selective dopamine D₂/D₃ agonist, 0.5 or 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their maternal behaviors were tested at different time points before and after drug administration. Haloperidol and clozapine treatment disrupted pup approach, pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, dose-dependently reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, dose-dependently reversed the clozapine-induced disruptions. Quinpirole pretreatment even exacerbated the clozapine-induced disruption of pup retrieval and nest building. These findings suggest a double dissociation mechanism underlying the disruption of haloperidol and clozapine on rat maternal behavior. Specifically, haloperidol disrupts maternal behavior primarily by blocking dopamine D₂ receptors, whereas clozapine exerts its disruptive effect primarily by blocking the 5-HT_2A/2C receptors. Our findings also suggest that 5-HT receptors are involved in the mediation of rat maternal behavior.     

The effects of CCK-4 on dopamine D1 agonist-induced grooming are blocked by a CCKA receptor antagonist: Evidence for a novel CCK receptor subtype?

The neuropeptide cholecystokinin (CCK) has been shown to interact with dopamine in various ways, including attenuation of dopamine D₁ receptor-mediated vacuous chewing and grooming. While we have demonstrated a clear role for the CCK_A receptor in the attenuation of dopamine D₁ agonist-induced vacuous chewing, studies of grooming yielded anomolous results. We examined the effects of selective CCK receptor antagonists on the attenuation of SKF 38393-induced grooming by the CCK_B agonist CCK-4. Administration of SKF 38393 (5 mg/kg s.c.) to male Sprague-Dawley rats resulted in a significant increase in grooming which was reduced to control levels by CCK-4 (20 mg/kg i.p.). Pretreatment with either the CCK_A receptor antagonist devazepide or the CCK_B receptor antagonist L-365,260 significantly attenuated this effect over a range of doses (20, 100, 500 μg/kg i.p.). The suppression of dopamine D₁ agonist-induced grooming by CCK-4 does not appear to reflect a non-specific effect of anxiogenesis, as it was unaffected by the anxiolytic diazepam. The CCK receptor antagonists alone were without behavioural effect. Taken together with previous studies in models of anxiety and analgesia, our findings lend further support to the hypothesis that CCK-4 may act at a novel receptor subtype.     

The activity of pramipexole in the mouse forced swim test is mediated by D<Subscript>2</Subscript> rather than D<Subscript>3</Subscript> receptors

Rationale Recent studies have reported antidepressant-like activities of the dopamine D₂/D₃ agonist pramipexole in the chronic mild stress model and in the forced swim test, suggesting that D₃ receptor agonists may represent a new class of antidepressant drugs. However, the relative contribution of D₂ or D₃ receptors to the activity of pramipexole in these models is unclear.Objectives The aim of the current studies was to explore the role of dopamine D₂ and D₃ receptors in the activity of pramipexole in the mouse forced swim test.Methods The effect of pramipexole (0.1–3.2 mg/kg) in the mouse forced swim test was examined both in conjunction with D₂ and D₃ receptor antagonists (haloperidol (0.1–1 mg/kg) and LU-201640 (A-437203, 5.6–17.8 mg/kg), as well as in D₃ receptor knockout mice obtained on two different background strains (C57BL/6J and B6129SF2/J). Locomotor activity was also assessed following pramipexole administration.Results Pramipexole produced dose-dependent reductions in immobility in the forced swim test at doses that did not produce generalized increases in locomotor activity. LU-201640, the D₃ selective antagonist, failed to block the antidepressant-like effects of pramipexole. In contrast, the efficacy of pramipexole in the forced swim test was completely blocked by the D₂ antagonist, haloperidol. No baseline differences were observed between knockout and wild-type mice from either background strain in locomotor activity or in the forced swim test. Furthermore, in both background strains, pramipexole showed similar efficacy in the forced swim test for both wild-type and knockout mice.Conclusions Taken together, these studies suggest that the D₂ receptor rather than the D₃ receptor is important for the antidepressant-like activity observed for pramipexole in the mouse forced swim test.Portions of this work were presented at the 36th Winter Conference on Brain Research, Snowbird, UT, January 26–31, 2003.     

Characterization of dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptor function in socially housed cynomolgus monkeys self-administering cocaine

Rationale Social rank has been shown to influence dopamine (DA) D₂ receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D₁ receptors.Objective Examine the effects of a high-efficacy D₁ agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D₁ agonist on cocaine self-administration, as well as the effects of cocaine exposure on D₂ receptor function across social ranks, as determined by positron emission tomography (PET).Methods Effects of the high-efficacy D₁ agonist SKF 81297 and cocaine (0.3–3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D₁ agonist SKF 38393 (0.1–17 mg/kg) to decrease cocaine self-administration (0.003–0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D₂ receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET.Results SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D₂ receptor levels did not differ across social ranks.Conclusions These results suggest that D₁ receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D₂ receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D₂ receptor levels such that D₂ receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.     

??-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors

Drugs that induce psychosis, such as 𝒟-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D₂ (D₂). All antipsychotic drugs are D₂ antagonists, but D₂ antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D₂ is necessary for their behavioral effects. Using D₂-null mice (Drd₂−/−), we first investigated whether D₂ is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd₂−/−. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd₂−/−. AMP disruption of LI was attenuated in mice lacking dopamine receptor D₁ (Drd₁−/−), suggesting that D₁ may play a role in AMP disruption of LI. Further supporting this possibility, we found that D₁ antagonist {"type":"entrez-protein","attrs":{"text":"SKF83566","term_id":"1157390490","term_text":"SKF83566"}}SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd₂−/−. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D₂ receptors. Data suggest that D₂ is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D₁ merits investigation in the mediation of AMP disruption of these processes.     

D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs

The affinities of 13 atypical and 12 typical antipsychotic drugs for the cloned rat D₄ dopamine receptor and the D₄/D₂ ratios were examined. Of the atypical antipsychotic drugs tested, only clozapine, risperidone, olanzapine, zotepine and tiospirone had affinities less than 20 nM. In fact, many atypical antipsychotic drugs had relatively low affinities for the cloned rat D₄ receptor, with Ki values greater than 100 nM (Seroquel, fluperlapine, tenilapine, FG5803 and melperone). Additionally, several typical antipsychotic drugs had high affinities for the cloned rat D₄ receptor, with K_is less than 20 nM (loxapine, chlorpromazine, fluphenazine, mesoridazine, thioridazine and trifluoroperazine). The ratios of D₂/D₄ affinities did not differentiate between these two types of antipsychotic drugs. Thus, D₄ dopamine receptor affinity, used as a single measure, does not distinguish between the group of typical and atypical antipsychotic drugs analyzed.     

PNA-Based Multivalent Scaffolds Activate the Dopamine D2 Receptor

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Withdrawal from repeated morphine sensitises mice to the striatal dopamine release enhancing effect of acute morphine

The effects of morphine withdrawal and challenge on the a-methyl-p-tyrosine (MT)-induced depletion of dopamine (DA) as well as on DA metabolism and ³H-SCH 23390 and ³H-spiperone binding were studied in the striata of male mice. Morphine was given s.c. 3 times daily for 5 days followed by 1 to 3 days' withdrawal.The MT induced DA depletion was retarded in mice withdrawn for 1 day from repeated morphine. At this time point the striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) fell, too. In mice withdrawn for 3 days from morphine neither DA depletion nor DOPAC or HVA concentrations differed from those of control mice. In control mice acute morphine challenge accelerated the DA depletion at the dose 10 mg/kg but not at the dose 30 mg/kg. Both doses elevated striatal DOPAC and HVA. In mice withdrawn from repeated morphine for 1 day acute morphine partially counteracted the withdrawal-induced retardation of DA depletion and elevated striatal DOPAC and HVA clearly less than in control mice. However, in mice withdrawn for 3 days 10 mg/kg of morphine clearly enhanced DA depletion and its effect on striatal HVA was significantly augmented. In these mice as in controls the 30 mg/kg dose did not alter striatal DA depletion and elevated HVA less than in controls. Acute morphine did not alter striatal 3-methoxytyramine (3-MT) concentration in control mice but at the dose 10 mg/kg increased it in mice withdrawn for 3 days. Morphine withdrawal did not significantly affect striatal 3H-SCH 23390 binding, but slightly decreased ³H-spiperone binding in mice withdrawn for 3 days indicating a down-regulation of D₂ receptors.Our results by using three different indices of DA release (DA depletion after aMT, HVA and 3-MT) show that long enough withdrawal from repeated morphine treatment augments the morphine-induced release of striatal DA in mice. We propose that the striatal DA release in mice is regulated by two opposite opioid sensitive mechanisms with different dose-dependencies and different tolerance development. Correspondence to: L. Ahtee at the above address     

Metabolism of the vitamin D3 analogue EB1089 alters receptor complex formation and reduces promoter selectivity

1. 1α,25-dihydroxyvitamin₃ (VD) is a nuclear hormone that has important cell regulatory functions but also a strong calcemic effect. EB1089 is a potent antiproliferative VD analogue, which has a modified side chain resulting in increased metabolic stability and a selective functional profile. Since EB1089 is considered for potential systemic application, it will be investigated to what extent its recently identified metabolites (hydroxylated at positions C26 and C26a) contribute to biological profile of the VD analogue.
2. Limited protease digestion analysis demonstrated that EB1089 is able to stabilize the high affinity ligand binding conformation of the VDR, starting at concentrations of 0.1 nM and affecting up to 80% of all receptor molecules. The metabolites EB1445 and EB1470 showed to be 100 fold less potent than EB1089, whereas the remaining three metabolites (EB1435, EB1436 and EB1446) showed a clearly reduced ability to stabilize the high affinity ligand binding conformation. Interestingly, at pharmacological concentrations all EB1089 metabolites stabilized a second, apparently lower affinity conformation to a much higher extent than EB1089.
3. In reporter gene assays all metabolites showed lower potency than EB1089. Moreover, the preference of EB1089 for activation of VDR binding to sites formed by inverted palindromic arrangements spaced by nine nucleotide (IP9-type VD response elements) appeared to be reduced (with EB1445 and EB1470) or completely lost (with EB1435, EB1436 and EB1446). The ranking of EB1089 and its metabolites that was obtained by limited protease digestion and reporter gene assays was confirmed by an analysis of their antiproliferative effect in breast cancer cells.
4. The potency and selectivity of the EB1089 metabolites in mediating gene regulatory effects was found to be drastically reduced in comparison to the parent compound suggesting that the contribution of the metabolites to the biological effect of EB1089 is minor. However, the compounds showed to be interesting tools for understanding the selective biological profile of EB1089.

     

D2 dopamine receptors and modulation of spontaneous acetylcholine (ACh) release from rat striatal synaptosomes

1. The effect of two D_3/2 dopamine receptor agonists, LY-171555 (quinpirole) and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on spontaneous [³H]-acetylcholine ([³H]-ACh) release were investigated in rat striatal synaptosomes.
2. Quinpirole and 7-OH-DPAT inhibited in a concentration-dependent manner the basal efflux of [³H]-ACh with similar E_max (maximal inhibitory effect) values (29.95±2.91% and 33.19±1.21%, respectively). Significant differences were obtained between the pEC₅₀ (−log of molar concentration) of quinpirole (7.87±0.12) and 7-OH-DPAT (7.21±0.17; P<0.01).
3. Different concentrations (0.3–10 nM) of haloperidol (D_2/3 dopamine receptor antagonist) shifted to the right the concentration-response curves elicited by quinpirole and 7-OH-DPAT, without modifications in the E_max.
4. Slopes of a Schild plot obtained with haloperidol in the presence of quinpirole and 7-OH-DPAT were not signficantly different from unity (0.85±0.05 and 1.17±0.11, respectively) and consequently haloperidol interacted with a homogeneous receptor population. The pK_B values of haloperidol obtained from Schild regression were 9.96±0.15 (in presence of quinpirole) and 9.90±0.09 (in presence of 7-OH-DPAT).
5. Specific binding of [³H]-YM-09151-2 to membranes of striatal synaptosomes and cells expressing D₂ and D₃ dopamine receptors was inhibited by haloperidol. Analysis of competition curves revealed the existence of a single population of receptors. There were no differences between the estimated pK_i (−log of molar concentration) values for synaptosomes (8.96±0.02) and cells expressing D₂ receptors (8.81±0.05), but the pK_i value from cells expressing D₃ dopamine receptors differed significantly (8.48±0.06; P<0.01).
6. In conclusion, the data obtained in the present study indicate that quinpirole and 7-OH-DPAT, two D_3/2 dopamine receptor agonists, inhibit the spontaneous [³H]-ACh efflux and this effect is competitively antagonized by haloperidol and probably mediated through dopamine D₂ receptors.

     

The role of dopamine D<Subscript>3</Subscript> compared with D<Subscript>2</Subscript> receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel,selective antagonists in rats

Background The role of dopamine D₃/D₂ receptors in the control of locomotion is poorly understood.Objectives To examine the influence of selective antagonists at D₃ or D₂ receptors on locomotion in rats, alone and in interaction with the preferential D₃ versus D₂ receptor agonist, PD128,907.Methods Affinities of ligands at rat D₂ and cloned, human hD₃, hD_2S, hD_2L and hD₄ sites were determined by standard procedures. Locomotion was monitored automatically in rats pre-habituated for 30 min to an open-field environment. Extracellular levels of dopamine (DA) were determined by dialysis in the nucleus accumbens and striatum. Drugs were given acutely via the systemic route.Results PD128,907, which preferentially recognised D₃ versus D₂ sites, biphasically reduced and enhanced locomotion at low (0.01–0.63 mg/kg) and high (2.5–10 mg/kg) doses, respectively. L741,626 and S23199, which behaved as preferential D₂ versus D₃ receptor antagonists, enhanced the reduction in locomotion evoked by the low dose of PD128,907, blocked the increase provoked by the high dose and suppressed spontaneous locomotion alone. Analogous findings were obtained with haloperidol and raclopride which showed equilibrated affinity at D₂ and D₃ receptors. UH232 and AJ76, which showed a mild preference for D₃ versus D₂ sites, did not modify the effect of a low dose of PD128,907, slightly enhanced the hyperlocomotion elicited by the high dose and exerted little influence on locomotion alone. S14297 and U99194, which acted as preferential D₃ versus D₂ receptor antagonists, abolished the reduction in locomotion elicited by a low dose of PD128,907, potentiated the induction of locomotion by a high dose, and failed to influence locomotion alone. The actions of S14297 were stereoselective inasmuch as they were mimicked by the racemic form, S11566, but not by the inactive enantiomer, S17777. In contrast to S14297, S11566 and U99194, however, S33084, SB269,652, GR218,231 and N-[-4-[-(1-naphtyl)piperazine-1-yl]butyl] anthracene-2-carboxamide (NGB-1), highly selective D₃ versus D₂ receptor antagonists, were inactive under all conditions. PD128,907 (0.01–10.0 mg/kg) suppressed dialysate levels of DA in the nucleus accumbens and striatum, actions blocked by L741,626 and haloperidol, yet unaffected by S14297 and S33084.Conclusions The facilitatory influence of a high dose of PD128,907 upon locomotion is mediated by postsynaptic D₂ receptors and, possibly, countered by their D₃ counterparts. Correspondingly, selective blockade of D₂ but not of D₃ receptors alone suppresses motor function. The reduction in locomotion provoked by a low dose of PD128,907 may be mediated by D₂ autoreceptors, but a role of postsynaptic D₃ receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D₃ receptor antagonists upon locomotion remain to be elucidated.     

In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors

Aripiprazole is the first dopamine D₂/D₃ receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D₂ and serotonin 5-HT_1A receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D_2S, D_2L, D₃ Ser-9 and D₃ Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D₂/D₃ receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D_2S and D_2L receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D₃ Ser-9 and D₃ Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D₂/D₃ receptors for clinical efficacy and safety.     

Selective Blockade of Dopamine D3 Receptors Enhances while D2 Receptor Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex

Dopamine D₃ receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D₃ vs D₂ receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D₃ receptor antagonist, {type:entrez-protein,attrs:{text:S33084,term_id:420474,term_text:pir||S33084}}S33084 (0.04–0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D₃ receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D₂ receptor antagonist, L741,626 (0.16–5.0 mg/kg), or with the dopamine D₃ agonist, PD128,907 (0.63–40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of {type:entrez-protein,attrs:{text:S33084,term_id:420474,term_text:pir||S33084}}S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63–2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63–2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D₃ receptors enhances both SND and NOR, whereas D₃ receptor activation or antagonism of dopamine D₂ receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D₃ receptor antagonism.     

Postpartum and Depression Status are Associated With Lower [11C]raclopride BPND in Reproductive-Age Women

The early postpartum period is associated with increased risk for affective and psychotic disorders. Because maternal dopaminergic reward system function is altered with perinatal status, dopaminergic system dysregulation may be an important mechanism of postpartum psychiatric disorders. Subjects included were non-postpartum healthy (n=13), postpartum healthy (n=13), non-postpartum unipolar depressed (n=10), non-postpartum bipolar depressed (n=7), postpartum unipolar (n=13), and postpartum bipolar depressed (n=7) women. Subjects underwent 60 min of [¹¹C]raclopride–positron emission tomography imaging to determine the nondisplaceable striatal D_2/3 receptor binding potential (BP_ND). Postpartum status and unipolar depression were associated with lower striatal D_2/3 receptor BP_ND in the whole striatum (p=0.05 and p=0.02, respectively) that reached a maximum of 7–8% in anteroventral striatum for postpartum status (p=0.02). Unipolar depression showed a nonsignificant trend toward being associated with 5% lower BP_ND in dorsal striatum (p=0.06). D_2/3 receptor BP_ND did not differ significantly between unipolar depressed and healthy postpartum women or between bipolar and healthy subjects; however, D_2/3 receptor BP_ND was higher in dorsal striatal regions in bipolar relative to unipolar depressives (p=0.02). In conclusion, lower striatal D_2/3 receptor BP_ND in postpartum and unipolar depressed women, primarily in ventral striatum, and higher dorsal striatal D_2/3 receptor BP_ND in bipolar relative to unipolar depressives reveal a potential role for the dopamine (DA) system in the physiology of these states. Further studies delineating the mechanisms underlying these differences in D_2/3 receptor BP_ND, including study of DA system responsivity to rewarding stimuli, and increasing power to assess unipolar vs bipolar-related differences, are needed to better understand the affective role of the DA system in postpartum and depressed women.     

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D₂ autoreceptors and subsequent activation of G protein-gated inwardly rectifying K⁺ (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D₂ receptor/GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA_B receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca²⁺ with BAPTA augments D₂ inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP₃)-induced intracellular Ca²⁺ release and Ca²⁺/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D₂, but not GABA_B, receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP₃ generation leads to cross-desensitization of D₂/GIRK-mediated responses. We propose that enhancement of D₂ receptor-mediated autoinhibition via attenuation of a Ca²⁺-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.     

Role of basolateral amygdala dopamine in modulating prepulse inhibition and latent inhibition in the rat

Rationale The dopamine (DA) projection to the basolateral amygdala (BLA) modulates nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) DA transmission. Given the involvement of the BLA, and of NAc and mPFC DA, in select forms of information processing, we sought to determine the role of BLA DA in modulating prepulse inhibition (PPI) and latent inhibition (LI).Objective The effects of BLA D₁ (SCH 23390) and D₂/D₃ (raclopride) receptor blockade on PPI and LI were examined.Methods Separate groups of male Long–Evans rats received bilateral intra-BLA infusions of SCH 23390 (3.2 or 6.4 g/0.5 l per side), raclopride (2.5 or 5.0 g/0.5 l per side) or saline prior to testing. In two experiments, the effects of BLA DA receptor antagonism on PPI of the acoustic startle response (ASR) and LI of conditioned taste aversion were determined. A control group received bilateral intra-striatal infusions of SCH 23390 or raclopride prior to PPI testing.Results Intra-BLA SCH 23390 or raclopride had no effect on the ASR. Intra-BLA SCH 23390 enhanced and raclopride disrupted PPI, both in a dose-related manner. Intra-striatal SCH 23390 or raclopride had no effect on PPI or ASR magnitude. Finally, BLA DA receptor blockade had no effect on LI.Conclusions These results indicate that PPI is modulated by BLA DA and suggest that this modulation occurs independently of changes in NAc and/or mPFC DA transmission. They also suggest that BLA DA is not involved in modulating LI and add to evidence indicating that PPI and LI are mediated by different neural substrates.     

Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

The striatum contains a high density of histamine H(3) receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H(3) and dopamine D(1) receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H(3) and dopamine D(2) receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H(3) and D(1) and also between H(3) and dopamine D(2) receptors. The selective H(3) receptor agonist imetit inhibited, while the H(3) receptor antagonist thioperamide potentiated locomotor activation induced by either the D(1) receptor agonist SKF 38393 or the D(2) receptor agonist quinpirole. High scores of locomotor activity were obtained with H(3) receptor blockade plus D(1) and D(2) receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H(3)-D(2) receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H(3) receptors with several H(3) receptor agonists significantly decreased the affinity of D(2) receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H(3) (but not H(4)) receptors were found to form heteromers with D(2) receptors. This study demonstrates an important role of postsynaptic H(3) receptors in the modulation of dopaminergic transmission by means of a negative modulation of D(2) receptor function.     

Roles of conserved intracellular sequences regions for the proper expression of dopamine D2 and D3 receptors

The dopamine D(2) receptor and D(3) receptor (D(2)R, D(3)R) have high homology in both their amino acid composition and signaling pathways. Virtually all signaling pathways reported thus far overlap between the two receptors with the exception that the D(3)R signals are 2 approximately 5 times less efficient than D(2)R. Previous studies have suggested that conformational constraints of D(3)R might be responsible for the poor coupling with the G protein. To this hypothesis, point mutations were introduced into some of the conserved regions between D(2)R and D(3)R, and their effects on receptor expression were investigated. Among the four conserved intracellular receptor regions examined (TTT motif in the 1(st) intracellular loop, SS motif in the 2(nd) intracellular loop, YxxL and TxxS/xS motifs in the 3(rd) intracellular loop), a mutation of the Thr-Thr-Thr (TTT) motif in the first intracellular loop or the LxxY motif in the 3(rd) intracellular loop markedly decreased the level of D(3)R expression compared with D(2)R. The TTT motif was further mutated individually or in combination to test which residue plays a critical role on the expression of the receptor proteins. Different amino acids between D(2)R and D(3)R in the 1(st) intracellular loop were exchanged to determine if the adjacent amino acid residues are responsible for the differences between D(2)R and D(3)R. The first two threonine residues become more important when the individual threonine residue is mutated. However, all three intact threonine residues are essential for proper expression of the receptor proteins. The neighboring sequences around the triplet threonine residues in the 1(st) loop of D(3)R are not important for proper positioning of the receptor proteins on the plasma membrane. It was concluded that D(2)R has a more flexible overall conformation that can accept mutated residues in the intracellular region than D(3)R, which might be partly responsible for the quantitative differences in the signaling efficiency between D(2)R and D(3)R.     

Dopaminergic control of locomotion,mouthing, snout contact,and grooming: opposing roles of D1 and D2 receptors

The study compares the behavioral profiles induced in rats (N=118) by the D₂-dopaminergic receptor agonist quinpirole (0.03 and 0.5 mg/kg), and the D₁-agonist SKF38393 (1.25–40 mg/kg), and both agonists administered together. Locomotion and snout contact frequency were reduced by the low but increased by the high dose of quinpirole; SKF38393 also reduced these behaviors and attenuated the effect of the high quinpirole dose. Only the high dose of quinpirole increased the duration of snout contact bouts and the frequency of mouthing; SKF38393 had no effect but in combination with the high dose of quinpirole, it enhanced the performance of these behaviors greatly. The duration of mouthing bouts was not affected by either agonist but was greatly extended when SKF38393 was administered together with the high dose of quinpirole. Grooming was inhibited by both the low and the high dose of quinpirole, and stimulated by the injection of SKF38393 or its addition to the low dose of quinpirole. These findings suggest that snout contact is controlled by modulating the frequency of episodes whereas mouthing is controlled by modulating the duration of episodes. Moreover, although they do not disprove the prevailing notion of D₁–D₂ receptor synergism, the present data are consistent also with an oppositional model of D₁–D₂ receptor interaction in the regulation of locomotion, snout contact, mouthing, and grooming in intact animals.     

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist α-flupenthixol (α-flu) and in DA D₂ receptor knockout mice. Conversely, α-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D₂ receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals.