Dopamine D1-like receptors in prelimbic, but not infralimbic, medial prefrontal cortex contribute to chronic stress-induced increases in cue-induced relapse to palatable food seeking during forced abstinence.

Chronic stress exposure causes increased vulnerability to future relapse-like behavior in male, but not female, rats with a history of palatable food self-administration. These effects are mediated by dopamine D1-like receptors, but the anatomical location of chronic stress' dopaminergic mechanism is not known. Thus, male rats were trained to respond for palatable food pellets in daily sessions. During subsequent forced abstinence from food self-administration, stress was manipulated (0 or 3 h restraint/day for 7 days). Rats also received bilateral microinjections of the D1-like receptor antagonist SCH-23390 (0.25 µg/0.5 µl/side) or vehicle (0.5 µl/side) delivered to either prelimbic or infralimbic medial prefrontal cortex prior to daily treatments. Relapse tests in the presence of food-associated cues were conducted 7 days after the last treatment. Stress caused an increase and a decrease in responding during relapse tests in rats that received prelimbic vehicle and SCH-23390 infusions, respectively, relative to unstressed rats. In rats receiving IL infusions, however, stress caused an increase in responding regardless of whether the infusion was vehicle or SCH-23390. These results establish a specific role for prelimbic D1-like receptors in chronic stress-potentiated relapse.

The involvement of mesolimbic dopamine system in cotinine self-administration in rats.

Cotinine is the major metabolite of nicotine and has recently been shown to be self-administered intravenously by rats. However, mechanisms underlying cotinine self-administration remained unknown. Mesolimbic dopamine system projecting from the ventral tegmental area (VTA) to nucleus accumbens (NAC) is closely implicated in drug reinforcement, including nicotine. The objective of the current study was to determine potential involvement of mesolimbic dopamine system in cotinine self-administration. An intracranial self-administration experiment demonstrates that cotinine at 0.88 and 1.76 ng/100 nl/infusion was self-infused into the VTA by rats. Rats produced more infusions of cotinine than vehicle and responded more on active than inactive lever during acquisition, reduced responding when cotinine was replaced by vehicle, and resumed responding during re-exposure to cotinine. Microinjection of cotinine at 1.76 ng/100 nl/infusion into the VTA increased extracellular dopamine levels within the NAC. Subcutaneous injection of cotinine at 1 mg/kg also increased extracellular dopamine levels within the NAC. Administration of the D1-like receptor antagonist SCH 23390 attenuated intravenous cotinine self-administration. On the other hand, bupropion, a catecholamine uptake inhibitor, did not significantly alter intravenous cotinine self-administration. These results suggest that activation of mesolimbic dopamine system may represent one cellular mechanism underlying cotinine self-administration. This shared mechanism between cotinine and nicotine suggests that cotinine may play a role in nicotine reinforcement.

Dopaminergic neurons project to the nucleus accumbens regulates anxiety-like behaviors through dopamine D1 signaling.

Dopamine (DA) transmission is important in the regulation of mood and anxiety behaviors. However, how specific dopaminergic signaling pathways respond to anxiogenic stimuli as well as regulate behaviors remains unknown. To understand how DA regulates the animal behaviors under anxiety we performed retrograde labeling and c-Fos staining of midbrain DA neurons. Our c-Fos labeling results showed that DA neurons projected to nucleus accumbens (NAc) are activated in animals treated with the elevated plus-maze (EPM). Real-time measurement of DA release using fast scanning cyclic voltammetry (FSCV) in NAc of freely behaving mice showed that increased DA release and more DA transients in the close arms than the open arms in the EPM. Meanwhile, we also observed a reduction of DA level from the close arms to the open arms. Local infusion of DA D1 receptor antagonist, SCH23390 in the core of NAc, leads to an anxiolytic-like effect in the open-field and EPM. These anxiolytic effects were not observed in animals received D2 receptor antagonist sulpiride infusion in the core of NAc. Taken together, our results reveal a novel function of the mesolimbic DA pathway through the D1 receptor in the regulation of anxiety-like behaviors.

The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced l-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia.

Dopamine (DA)-replacement therapy utilizing l-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of l-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing l-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of l-DOPA-induced AIMs without induction of parkinsonism.

AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations.

Developmental exposure to an organophosphate flame retardant alters later behavioral responses to dopamine antagonism in zebrafish larvae.

Human exposure to organophosphate flame retardants (OPFRs) is widespread, including pregnant women and young children with whom developmental neurotoxic risk is a concern. Given similarities of OPFRs to organophosphate (OP) pesticides, research into the possible neurotoxic impacts of developmental OPFR exposure has been growing. Building upon research implicating exposure to OP pesticides in dopaminergic (DA) dysfunction, we exposed developing zebrafish to the OPFR tris(1,3-dichloroisopropyl) phosphate (TDCIPP), during the first 5 days following fertilization. On day 6, larvae were challenged with acute administration of dopamine D1 and D2 receptor antagonists and then tested in a light-dark locomotor assay. We found that both developmental TDCIPP exposure and acute dopamine D1 and D2 antagonism decreased locomotor activity separately. The OPFR and DA effects were not additive; rather, TDCIPP blunted further D1 and D2 antagonist-induced decreases in activity. Our results suggest that TDCIPP exposure may be disrupting dopamine signaling. These findings support further research on the effects of OPFR exposure on the normal neurodevelopment of DA systems, whether these results might persist into adulthood, and whether they interact with OPFR effects on other neurotransmitter systems in producing the developmental neurobehavioral toxicity.

Pharmacological evidence that dopamine inhibits the cardioaccelerator sympathetic outflow via D2-like receptors in pithed rats.

It has been suggested that N,N-di-n-propyl-dopamine (dopamine analogue) decreased heart rate in rats through stimulation of dopamine receptors. Nevertheless, the role of prejunctional dopamine D1/2-like receptors or even α2-adrenoceptors to mediate cardiac sympatho-inhibition induced by dopamine remains unclear. Hence, this study identified the pharmacological profile of the cardiac sympatho-inhibition to dopamine in pithed rats. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. I.v. continuous infusions of dopamine (endogenous ligand) or quinpirole (D2-like agonist) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. In contrast, SKF-38393 (100 µg/kg∙min, D1-like agonist) failed to modify both of these responses. The sympatho-inhibition to dopamine (1.8 µg/kg∙min) or quinpirole (100 µg/kg∙min): i) remained unaltered after saline or the antagonists SCH-23390 (D1-like, 300 µg/kg) and rauwolscine (α2-adrenoceptors, 300 µg/kg); and ii) was significantly antagonized by raclopride (D2-like, 300 µg/kg). These antagonists, at the above doses, failed to modify the sympathetically-induced tachycardic responses. The above results suggest that the inhibition of the cardiac sympathetic outflow to dopamine and quinpirole is primarily mediated by prejunctional D2-like receptors but not D1-like receptors or α2-adrenoceptors.

Inhibition of 5α-reductase attenuates behavioral effects of D1-, but not D2-like receptor agonists in C57BL/6 mice.

Converging lines of evidence point to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of steroid 5α-reductase (5αR), the key rate-limiting enzyme in neurosteroidogenesis, attenuates the behavioral effects of non-selective DA receptor agonists in rats, including stereotyped responses and sensorimotor gating deficits, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. Since previous findings suggested that the role of DA D(1)- and D(2)-like receptor families in behavioral regulation may exhibit broad interspecies and interstrain variations, we assessed the impact of 5αR blockade on the behavioral effects of DAergic agonists in C57BL/6 mice. The prototypical 5αR inhibitor finasteride (FIN; 25-50 mg/kg, intraperitoneally, IP) dose-dependently countered the PPI deficits and the enhancement of rearing responses induced by the full D(1)-like receptor agonist SKF-82958 (0.3 mg/kg, IP); however, FIN did not significantly affect the hyperlocomotive and startle-attenuating effects of SKF-82958. Whereas the D(2)-like receptor agonist quinpirole (QUIN; 0.5 mg/kg, IP) did not induce significant changes in PPI, the combination of this agent and FIN surprisingly produced marked gating and startle deficits. In contrast with previous data on rats, FIN did not affect the reductions of startle reflex and PPI produced by the non-selective DAergic agonist apomorphine (APO; 0.5 mg/kg, IP). These findings collectively indicate that, in C57BL/6 mice, 5αR differentially modulates the effects of D(1)- and D(2)-like receptor agonists in behavioral regulation.

Biphasic firing response of nucleus accumbens neurons elicited by THPB-18 and its correlation with DA receptor subtypes.

AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antagonist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was recorded in the nucleus accumbens (NAc) neurons of naive and unilateral-6-hydroxydopamine (6-OHDA)-lesioned Sprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by the change of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced a decrease-increase biphasic firing pattern in the NAc neurons during cumulative doses. High dose of THPB-18 was capable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on NAc firing activity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which was reversed by the D1 selective antagonist SCH23390. The tested NAc neurons were effectively inhibited by iontophoretically applied THPB-18 in 90 % of 6-OHDA-lesioned rats, while THPB-18 caused variable effects on the firing of NAc neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked by iontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to L-stepholidine, THPB-18 also possesses the D1 agonistic-D2 antagonistic dual action on the VTA-NAc DA system.

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats.

RATIONALE: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. OBJECTIVE: This rodent model was used to characterize the putative antiparkinsonian effects of the full D1 dopamine receptor agonist, SKF 82958. METHODS: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. RESULTS: SKF 82958 (0.5-2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D1 dopamine receptor antagonist SCH 23390 (0.025-0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D2 antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5-2.0 micrograms/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5-2.0 micrograms/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 micrograms/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. CONCLUSIONS: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D1 receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D1 agonists.

MK-801 reverses Fos expression induced by the full dopamine D1 receptor agonist SKF-82958 in the rat striatum.

Administration of the selective and full dopamine D1 receptor agonist SKF-82958 ((+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-b enzazepine) (1 and 3 mg/kg i.p.) led to a dose-dependent induction of Fos protein in the rat striatum. The 3 mg/kg SKF-82958-induced expression of striatal Fos protein was blocked by the dopamine D1 receptor antagonist SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine) (0.3 mg/kg i.p.). The noncompetitive NMDA receptor antagonist MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5 ,10-imine) (1 mg/kg i.p.) also completely prevented striatal Fos induction by an injection of 3 mg/kg SKF-82958. These results suggest that dopamine D1 receptor activation by the full agonist SKF-82958 is sufficient to trigger Fos expression in the striatum, but that concomitant stimulation of NMDA receptors is required for the striatal Fos induction in response to dopamine D1 receptor activation.

Characteristics of tetrahydroprotoberberines on dopamine D1 and D2 receptors in calf striatum.

AIM: To study the characteristics of tetrahydroprotoberberines (THPB) on dopamine D1 and D2 receptors and elucidate their structure-activity relationship. METHODS: Radioligand assay in vitro with a two-site model program analysis. RESULTS: Four THPB with two hydorxyl groups on C2 and C9 or C2 and C10 exhibited RH and RL two binding sites to D1 receptors and guanosine triphosphate regulated the RH binding site of SPD and THPB-132A in competition assay, while eleven THPB including nonhydroxy-THPB, monohydroxy-THPB, and THPB with two hydroxyl groups attaching to C3 and C10 showed one binding site to D1 receptors under the same conditions. However, the tested eleven THPB all manifested one binding site to D2 receptors in competition assay, and the 2-hydroxy-THPB had the most potent affinity for D2 receptors. CONCLUSION: Dihydroxy-THPB with two hydroxyl groups attaching to C2 and C9 or C2 and C10 possess the intrinsic activity of agonist to D1 receptors, while the other THPB do not. The tested eleven THPB all are the antagonists of D2 receptors.

The full D1 dopamine receptor agonist SKF-82958 induces neuropeptide mRNA in the normosensitive striatum of rats: regulation of D1/D2 interactions by muscarinic receptors.

Neuropeptide and immediate early gene expression in striatonigral neurons of the normosensitive striatum is induced by mixed D1/D2 receptor agonists and indirect dopamine agonists, such as cocaine and amphetamine. Both D1 and D2 receptor antagonists block these events. In contrast, the partial D1 agonist, SKF-38393, does not evoke striatonigral gene expression in intact rats. These findings have contributed to the idea that both D1 and D2 receptors must be stimulated to evoke gene expression in striatonigral neurons. How these "D1/D2 interactions" are accomplished is unclear in light of the controversy over whether striatonigral neurons express both D1 and D2 receptors. This study addresses these issues by demonstrating that in intact rats 1) a full D1 receptor agonist, SKF-82958, induced behavioral activity and preprodynorphin (PPD) and substance P (SP) gene expression in medium spiny neurons in the dorsal, and especially, in the ventral striatum, 2) either a D1 antagonist, SCH-23390, or a D2 antagonist, eticlopride, blocked these effects, 3) the muscarinic antagonist, scopolamine, augmented PPD and SP mRNA expression induced by SKF-82958 and prevented the ability of eticlopride to block SKF-82958-induced PPD and SP mRNAs and 4) the SKF-82958-induced increase in preproenkephalin mRNA in striatopallidal neurons was blocked by SCH-23390 or scopolamine but not by eticlopride. These data indicate that endogenous acetylcholine attenuates D1 receptor-stimulated PPD/SP gene expression in medium spiny neurons, mediates D1 receptor-stimulated preproenkephalin gene expression in striatopallidal neurons and contributes to D2 receptor involvement in D1-stimulated PPD/SP gene expression.

Long-term treatment with low doses of the D1 antagonist NNC 756 and the D2 antagonist raclopride in monkeys previously exposed to dopamine antagonists.

Eight Cebus apella monkeys previously exposed to D1 and D2 antagonists were treated subcutaneously for 8 weeks with the D1 antagonist NNC 756 (0.01 mg/kg), followed by a wash-out period of 4 weeks and treatment with the D2 antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia-inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D1 agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D2/D3 agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D1 antagonists may induce less dystonia and oral dyskinesia as compared with D2 antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D1 and D2 receptor systems.

NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists.

In the present study, we investigated the ability of NMDA receptor antagonists to inhibit catalepsy induced by haloperidol, or SCH23390 and clebopride, selective dopamine D1 and D2 receptor antagonists respectively. Catalepsy was measured by recording the time the animal remained with its forepaws placed over a rod 6 cm above the bench. Pretreatment with either the non-competitive NMDA receptor antagonist, MK-801 (0.25-0.5 mg/kg i.p.) or the competitive antagonist, LY274614 (10-20 mg/kg i.p.) reduced the cataleptic response produced by haloperidol (10 mg/kg), SCH23390 (2.5-10 mg/kp i.p.) or clebopride (5-20 mg/kg i.p.). This demonstrates that NMDA receptor antagonists will reduce both dopamine D1 and D2 receptor antagonist-induced catalepsy. Muscle relaxant doses of chlordiazepoxide (10 mg/kg i.p.) failed to reduce the catalepsy induced by haloperidol, suggesting that the anticataleptic effect of the NMDA receptor antagonists was not due to a non-specific action. These results support the hypothesis that NMDA receptor antagonists may have beneficial effects in disorders involving reduced dopaminergic function, such as Parkinson's disease.

Effects of vasoactive intestinal peptide on ganglion cells in the rabbit retina.

The effects of vasoactive intestinal peptide (VIP) on the extracellularly recorded activity of ganglion cells were studied in superfused rabbit retinas. VIP, applied to the bathing solution, significantly increased the maintained activity of both OFF-center and ON-center brisk ganglion cells. The transient, excitatory responses of these cells to flashes of light (spots or annuli centered over the receptive field) were either unaffected or moderately reduced. VIP did not affect the responses of most ON/OFF directionally selective ganglion cells to a moving light stimulus. Furthermore, maintained activity of most of these cells remained absent. Effects of VIP on the light responses of ganglion cells were pronounced in retinas that were bathed with the dopamine D1 antagonist (+)-SCH 23390. For OFF-center brisk ganglion cells, VIP brought out both the center and surround excitatory responses that were selectively reduced by (+)-SCH 23390. Similarly, VIP brought out the leading edge responses that were reduced by (+)-SCH 23390 in ON/OFF directionally selective ganglion cells to a moving light stimulus. VIP did not however reverse the effects of (+)-SCH 23390 on ON-center brisk ganglion cells. It is argued that VIP counteracts the effects of (+)-SCH 23390 on OFF-center brisk ganglion cells and ON/OFF directionally selective ganglion cells by stimulating adenylate cyclase activity in dopamine-receptive cells of the retina.

Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy induced by SCH 23390 in the rat.

In the present experiments, it was shown that the catalepsy induced by the dopamine D1 antagonist SCH 23390 (0.2 mg kg-1 sc), was completely antagonised by the administration of 8-OH-DPAT (0.1 mg kg-1 sc) for the duration of the effect of SCH 23390 (approx. 120 min). Neither the catalepsy induced by raclopride (16 mg kg-1 sc) nor that induced by SCH 23390 (0.2 mg kg-1 sc) could be antagonised by treatment with the 5-HT2 receptor antagonist ritanserin (0.13-2.0 mg kg-1 sc). Administration of SCH 23390 (0.0125-0.2 mg kg-1 sc) produced a significant suppression of avoidance behavior at all doses, and also produced a significant decrease in the number of intertrial crosses. At the higher doses, 0.05 and 0.2 mg kg-1 sc, there were also escape failures. In contrast to the finding in our previous report that raclopride and 8-OH-DPAT in a synergistic manner produce a suppression of conditioned avoidance behavior, no such interaction was found between 8-OH-DPAT (0.1 mg kg-1 sc) and SCH 23390 (6 micrograms kg-1 sc) in the present study.

GBR 12909 reverses the SCH 23390 inhibition of rewarding effects of brain stimulation.

Curve-shift was used to test the effect of SCH 23390, a dopamine D1 receptor antagonist, and GBR-12909, a selective dopamine uptake blocker, on self-stimulation behavior. GBR 12909 (8 mg/kg) produced a significant decrease in self-stimulation threshold when administered alone, and reversed the increase in threshold produced by SCH 23390 (0.08 mg/kg). The reversal of the SCH 23390 effect by GBR 12909 suggests that the inhibition of self-stimulation produced by SCH 23390 is due to blockade of dopamine receptors.

Interaction of permanently charged chlorpromazine and dopamine analogs with the striatal D-1 dopaminergic receptor.

Although a structural feature common to all dopaminergic agonists and antagonists is a side-chain basic amino group, it is unclear whether this moiety binds to the D-1 dopamine (DA) receptor in the charged or uncharged form. To obtain information on this point, we synthesized permanently charged dimethylsulfonium and quaternary ammonium analogs of chlorpromazine and DA and determined whether these compounds can bind to the D-1 receptor by measuring their abilities to inhibit the binding of SCH 23390, a D-1 receptor antagonist. Chlorpromazine and the dimethylsulfonium and trimethylammonium analogs of chlorpromazine were found to inhibit the binding of [3H]SCH 22390, which was maximally inhibited to the same extent by all three compounds. In addition, inhibition curves for the compounds fit a one-site binding model, indicating binding to a single class of sites. However, while the permanently charged chlorpromazine analogs were able to inhibit [3H]SCH-23390 binding, they were considerably less potent than chlorpromazine. DA and dimethyl DA were also able to inhibit [3H]SCH 23390 binding. However, the permanently charged dimethylsulfonium and trimethylammonium analogs of DA were ineffective in inhibiting [3H]SCH 23390 binding. In addition, the permanently uncharged methylsulfide analog did not inhibit binding. These studies show that permanently charged analogs of chlorpromazine can bind to the striatal D-1 receptor, which is consistent with an anionic recognition site on the D-1 receptor that interacts with antagonists in the cationic form. In addition, it appears that a nitrogen atom is not required for binding to the D-1 receptor, since the sulfonium analog of chlorpromazine bound to the receptor to the same extent as chlorpromazine. However, since the permanently charged or uncharged analogs of DA did not bind to the D-1 receptor, it is still unclear as to whether the charged form of a dopaminergic agonist can bind. The lower potency or ineffectiveness of the permanently charged analogs compared to the parent amines (chlorpromazine, DA, dimethyl DA) in binding to the D-1 receptor may reflect the inability of the permanently charged analogs to undergo hydrogen binding with the anionic site of the receptor.

Inhibition of lipopolysaccharide-induced alpha/beta-interferon synthesis by dopamine and the dopamine-1 agonist fenoldopam.

In vitro incubation of Listeria monocytogenes-immune spleen cells in the presence of dopamine or fenoldopam, a dopamine-1 (D1) agonist, inhibited alpha/beta-interferon (IFN) synthesis induced by the mitogen lipopolysaccharide (LPS), in a manner that appeared to be concentration dependent. In addition, the inhibitory effect of dopamine and fenoldopam on the synthesis of IFN was prevented by incubating immune spleen cells in the presence of haloperidol, a D1 antagonist.