scholarly journals Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors

2012 ◽  
Vol 16 (2) ◽  
pp. 445-458 ◽  
Author(s):  
Jack Bergman ◽  
Rebecca A. Roof ◽  
Cheryse A. Furman ◽  
Jennie L. Conroy ◽  
Nancy K. Mello ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Abuse Liability ◽  
Cocaine Addiction ◽  
Dose Effect ◽  
Self Administration ◽  
Binding Studies ◽  
High Affinity ◽  
Reinforcing Effects

Abstract Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (∼98 and ∼29 nm respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose–effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction.

3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys

2000 ◽  
Vol 147 (4) ◽  
pp. 426-435 ◽  
Author(s):  
W. L. Woolverton ◽  
J. K. Rowlett ◽  
K. M. Wilcox ◽  
I. A. Paul ◽  
R. H. Kline ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Radioligand Binding ◽  
Self Administration ◽  
Binding Studies ◽  
Radioligand Binding Studies

scholarly journals Molecular target sizes of inositol 1,4,5-trisphosphate receptors in liver and cerebellum

1990 ◽  
Vol 265 (2) ◽  
pp. 393-398 ◽  
Author(s):  
D L Nunn ◽  
B V L Potter ◽  
C W Taylor
Keyword(s):  
Binding Sites ◽  
Radioligand Binding ◽  
Inositol Phosphate ◽  
Rank Order ◽  
Binding Protein ◽  
Molecular Target ◽  
Binding Studies ◽  
Single Class ◽  
Surface Receptors ◽  
High Affinity

Ins(1,4,5)P3 is the intracellular messenger that mediates the effects of many cell-surface receptors on intracellular Ca2+ stores. Although radioligand-binding studies have identified high-affinity Ins(1,4,5)P3-binding sites in many tissues, these have not yet been convincingly shown to be the receptors that mediate Ca2+ mobilization, nor is it clear whether there are differences in these binding sites between tissues. Here we report that Ins(1,4,5)P3 binds to a single class of high-affinity sites in both permeabilized hepatocytes (KD = 7.8 +/- 1.1 nM) and cerebellar membranes (KD = 6.5 +/- 2.4 nM), and provide evidence that these are unlikely to reflect binding to either of the enzymes known to metabolize Ins(1,4,5)P3. Furthermore, the rank order of potency of synthetic inositol phosphate analogues in displacing specifically bound Ins(1,4,5)P3 is the same as their rank order of potency in stimulating mobilization of intracellular Ca2+ stores, suggesting that the Ins(1,4,5)P3-binding site may be the physiological receptor. Radiation inactivation of the Ins(1,4,5)P3-binding sites of liver and cerebellum reveals that they have similar molecular target sizes: 257 +/- 36 kDa in liver and 258 +/- 20 kDa in cerebellum. We conclude that an Ins(1,4,5)P3-binding protein with a molecular target size of about 260 kDa is probably the receptor that mediates Ca2+ mobilization in hepatocytes, and our limited data provide no evidence to distinguish this from the cerebellar Ins(1,4,5)P3-binding protein.

Gene dose effect reveals no Gs-coupled A2A adenosine receptor reserve in murine T-lymphocytes: studies of cells from A2A-receptor-gene-deficient mice

2001 ◽  
Vol 354 (1) ◽  
pp. 123-130 ◽  
Author(s):  
John M. ARMSTRONG ◽  
Jiang Fan CHEN ◽  
Michael A. SCHWARZSCHILD ◽  
Sergey APASOV ◽  
Patrick T. SMITH ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Adenosine Receptors ◽  
Radioligand Binding ◽  
Dose Effect ◽  
Binding Studies ◽  
Extracellular Adenosine ◽  
Gene Dose ◽  
Receptor Reserve ◽  
A2ar Agonist

Agonist binding to extracellular A2A adenosine receptors (A2ARs) inhibits the activation of virtually all tested functions of T-cells and can induce apoptosis in thymocytes. The evaluation of levels of expression of these immunosuppressive receptors is expected to clarify whether the absence of spare A2ARs (no ‘receptor reserve’) might be one of the mechanisms of attenuation of the effects of extracellular adenosine on T-cells. A2A transcript is found in T-cells and functional receptors can be demonstrated, but the density of receptor on T-cells is too low to be detected by radioligand binding. Studies of direct radioligand binding to murine brain with the selective A2AR agonist [3H]CGS21680 (2-{4-[(2-carboxyethyl)-phenyl]ethylamino}-5′-N-ethylcarboxamidoadenosine) established that striata levels of A2AR are virtually absent from A2A knock-out mice. Mice that are heterozygous (A2AR+/-) for the A2AR express significantly decreased levels of A2AR. To test for the presence of spare receptors in T-cells we took advantage of this gene dose effect and examined whether the decrease in the number of receptors in thymocytes from A2AR+/- mice was proportionately reflected in a decrease in the functional cAMP response of T-cells to adenosine. cAMP accumulation and apoptosis induced by adenosine and by A2AR agonist are of a lower magnitude in T-cells from A2AR+/- heterozygous mice than in T-cells from A2AR+/+ littermate control mice. These results indicate that there is no A2AR reserve in murine T-cells. Strongly decreased adenosine-triggered cAMP increases were detected in thymocytes from A2AR-/- mice, suggesting that A2B adenosine receptors cannot fully compensate for the loss of A2ARs in murine T-cells. We conclude that the number of A2ARs is the limiting factor in determining the maximal cAMP response of T-lymphocytes to extracellular adenosine, thereby minimizing the immunosuppressive effects of extracellular adenosine.

Truxillic Acid Derivatives, Neuromuscular Blocking Agents with Very High Affinity for the Allosteric Binding Site of Muscarinic Acetylcholine Receptors

1999 ◽  
Vol 64 (12) ◽  
pp. 1980-1992 ◽  
Author(s):  
Marek Urbanský ◽  
Jan Proška ◽  
Jan Říčný ◽  
Pavel Drašar
Keyword(s):  
Binding Site ◽  
Radioligand Binding ◽  
Muscarinic Acetylcholine Receptor ◽  
Neuromuscular Blocking ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtype ◽  
Binding Studies ◽  
Muscarinic Acetylcholine ◽  
High Affinity ◽  
Truxillic Acid

Bis-quaternary salts of 3-piperidinopropyl esters of α-truxillic acid were synthesized in order to study their allosteric action on muscarinic acetylcholine receptor. Using radioligand binding studies, it has been demonstrated that most of prepared compounds bind with high affinity to the allosteric binding site of M2 muscarinic receptor subtype (Kd values in the range 1-10 nM). Bulky substitution of the quaternary ammonium center led to effective positive modulators of [3H]N-methylscopolamine binding to M2 receptors. Due to its high allosteric potency, the structure of phenacyl derivative seems to be the most promising candidate for future design of photoaffinity probes or radiolabelled ligands for mapping the allosteric binding site.

Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist

2006 ◽  
Vol 552 (1-3) ◽  
pp. 36-45 ◽  
Author(s):  
Julia N. Heinrich ◽  
Julie Brennan ◽  
Margaret H. Lai ◽  
Kelly Sullivan ◽  
Geoff Hornby ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
Partial Agonist ◽  
D2 Receptor ◽  
High Affinity ◽  
Dopamine D2 ◽  
Selective Dopamine

scholarly journals Enhanced responsiveness of endothelium in the growing/motile state to tumor necrosis factor/cachectin.

1989 ◽  
Vol 170 (3) ◽  
pp. 913-931 ◽  
Author(s):  
H Gerlach ◽  
H Lieberman ◽  
R Bach ◽  
G Godman ◽  
J Brett ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Binding Sites ◽  
Cell Shape ◽  
Radioligand Binding ◽  
Cell Binding ◽  
Binding Studies ◽  
Endothelial Cell Surface ◽  
High Affinity ◽  
Radioligand Binding Studies

Some in vivo observations have suggested that growing or perturbed endothelium, such as that which occurs during angiogenesis, is more sensitive to the action of cytokines (TNF/cachectin, TNF, or IL-1) than normal quiescent endothelial cells. This led us to examine the responsiveness of endothelium to TNF as a function of the growth/motile state of the cell. TNF-induced modulation of endothelial cell surface coagulant function was half-maximal at a concentration of approximately 0.1 nM in subconfluent cultures, whereas 1-2 nM was required for the same effect in postconfluent cultures. Perturbation of endothelial cell shape/cytoskeleton was similarly more sensitive to TNF in subconfluent cultures. Consistent with these results, radioligand binding studies demonstrated high affinity TNF binding sites, Kd approximately 0.1 nM on subconfluent cultures, whereas only lower affinity sites (Kd approximately 1.8 nM) were detected on postconfluent cultures. The mechanisms underlying this change in the affinity of endothelium for TNF were studied in four settings. Crosslinking experiments with 125I-TNF and endothelium showed additional bands corresponding to Mr approximately 66,000 and approximately 84,000 with subconfluent cultures that were not observed with postconfluent cultures. Experiments with X-irradiated endothelium, whose growth but not motility was blocked, indicated that proliferation was not required for induction of high affinity TNF sites. Postconfluent endothelium, triggered to enter the proliferative cycle by microbutuble poisons, expressed high affinity TNF binding sites together with changes in cell shape/cytoskeleton well before their entry into S phase. Using wounded postconfluent monolayers, cells that migrated into the wound and those close to the wound edge displayed enhanced TNF binding and modulation of coagulant properties. These results suggest a model for targetting TNF action within the vasculature; regulation of high affinity endothelial cell binding sites can direct TNF to activated cells in particular parts of the vascular tree.

scholarly journals Regulation of Pigmentation in Human Epidermal Melanocytes by Functional High-Affinity β-Melanocyte-Stimulating Hormone/Melanocortin-4 Receptor Signaling

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1250-1258 ◽  
Author(s):  
J. D. Spencer ◽  
K. U. Schallreuter
Keyword(s):  
Radioligand Binding ◽  
Epidermal Differentiation ◽  
Epidermal Keratinocytes ◽  
Binding Studies ◽  
Human Epidermal Keratinocytes ◽  
Melanocyte Stimulating Hormone ◽  
High Affinity ◽  
Melanocortin 4 Receptor ◽  
Human Melanocyte

To date, the principal receptor considered to regulate human pigmentation is the melanocortin-1 receptor (MC1-R) via induction of the cAMP/protein kinase A pathway by the melanocortins α-MSH and ACTH. In this context, it is noteworthy that β-MSH can also induce melanogenesis, although it has a low affinity for the MC1-R, whereas the preferred receptor for this melanocortin is the MC4-R. Because β-MSH is present in the epidermal compartment, it was of interest to ascertain whether functioning MC4-Rs are present in human epidermal keratinocytes and melanocytes. Our results provide evidence that the MC4-R is expressed in situ and in vitro throughout the human epidermis at the mRNA and protein level using RT-PCR, Western blotting, and double immunofluorescence staining. Moreover, radioligand binding studies yielded high-affinity receptors for β-MSH on epidermal melanocytes (3600 receptors per cell), undifferentiated keratinocytes (7200 receptors per cell), and differentiated keratinocytes (72,700 receptors per cell), indicating that MC4-R expression correlates with epidermal differentiation. Importantly, increased melanogenesis after stimulation of the β-MSH/cAMP/microphthalmia-associated transcription factor/tyrosinase cascade proved the functionality of this signal in melanocytes, which was attenuated in the presence of the specific MC4-R antagonist HS014. In summary, our results imply an important role for the β-MSH/MC4-R cascade in human melanocyte biology, although the function and purpose of this signal in keratinocytes needs further elucidation. Although a high affinity MC4-R signal in human epidermal melanocytes (3,600 receptors/cell) stimulates melanogenesis via the β-MSH /cAMP/MITF/tyrosinase cascade, the purpose of this signal in keratinocytes remains unclear.

scholarly journals Locomotor and Reinforcing Effects of Pentedrone, Pentylone and Methylone in Rats

2017 ◽  
Author(s):  
Mehrak Javadi-Paydar ◽  
Jacques D. Nguyen ◽  
Sophia A. Vandewater ◽  
Tobin J. Dickerson ◽  
Michael A. Taffe
Keyword(s):  
Wistar Rats ◽  
Second Generation ◽  
Female Rats ◽  
Dose Effect ◽  
Male Rats ◽  
Structural Motif ◽  
Self Administration ◽  
Male And Female ◽  
Female Wistar Rats ◽  
Reinforcing Effects

AbstractThe broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the α-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for α-PVP and α-pyrrolidinohexiophenone (α-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 °C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 °C) was observed for four hours after 10 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than α-PVP or α-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone.

scholarly journals Daidzein modulates cocaine-reinforcing effects and cue-induced cocaine reinstatement in CD-1 male mice

2021 ◽  
Author(s):  
Miquel Martin ◽  
Miriam Gutiérrez-Martos ◽  
Roberto Cabrera ◽  
Klaus Langohr ◽  
Rafael Maldonado ◽  
...  
Keyword(s):  
Chemical Structure ◽  
Chronic Treatment ◽  
Cocaine Addiction ◽  
Male Mice ◽  
Self Administration ◽  
Operant Responding ◽  
Reinforcing Effects ◽  
Synthetic Derivatives ◽  
Cocaine Reinstatement

ABSTRACT Rationale Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. Objectives Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. Results Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. Conclusions Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.

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