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J W Boja

Publications and source records attributed to J W Boja.

At least 55 records · Page 3Linked to original sources
PubMed1992

Behavioral effects of novel cocaine analogs: a comparison with in vivo receptor binding potency.

Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, have been examined for their stimulatory effects on locomotor activity and for their ability to displace [3H]WIN 35,428 binding in vivo in mice. These compounds, like WIN 35,428, lack an ester link between the phenyl group and the tropane ring and have para-substitutions on the phenyl ring. They were much more potent than (-)-cocaine in producing increases in locomotor activity. In addition, they were more potent than (-)-cocaine in inhibiting [3H]WIN 35,428 binding in vivo in mouse striatum. Thus, these compounds demonstrate similar high potency in behavioral tests and in receptor binding assays, both in vivo and in vitro. Results support the hypothesis of a relationship between binding at the dopamine transporter and the behavioral effects of cocaine-like drugs. Further, assuming that maximal occupancy occurs with total displacement of [3H]WIN 35,428 binding in vivo, the data suggest that maximal locomotor effects occur with near total occupancy of transporter binding sites.

Animals↗
PubMed1991

Possible serotonergic and dopaminergic mediation of the N-ethyl-3,4-methylenedioxyamphetamine discriminative stimulus.

Eight male rats previously trained to discriminate 2.0 mg/kg N-ethyl-3,4-methylenedioxyamphetamine (MDE) from its vehicle in a two-lever, food motivated task were utilized to characterize the stimulus properties of MDE. The 5-HT receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP), quipazine and 6-methoxy-1,2,3,4 tetrahydro-beta-carboline were able to generalize to the stimulus produced by MDE. However, the 5-HT receptor agonists m-chlorophenylpiperazine (mCPP), buspirone and norfenfluramine, the dopamine receptor agonist amphetamine, as well as the acetylcholine receptor agonist arecoline did not completely generalize. In addition, the simultaneous administration of norfenfluramine and amphetamine generalized to MDE. Pretreatment with the serotonin receptor antagonists cinanserin and metergoline or the dopamine receptor antagonist haloperidol failed to completely inhibit the discriminative stimulus produced by MDE. Multiple p-chlorophenylalanine (PCPA) pretreatments significantly reduced MDE discrimination, whereas vehicle discrimination was unaffected. Five days following cessation of PCPA pretreatment, MDE discrimination returned to criterion levels and remained at that level. These results suggest that the stimulus produced by MDE involve a complex interaction of various neurotransmitters, with both serotonergic and dopaminergic components.

3,4-Methylenedioxyamphetamine↗
PubMed1991

Dopamine transporter: deglycosylation with exo- and endoglycosidases.

The dopamine transporter from rat caudate-putamen was photolabeled with [125I]DEEP as previously described. Treatment of photolabeled membranes with neuraminidase and N-glycanase reduced the molecular weight of the [125I]DEEP photolabeled dopamine transporter complex, whereas treatment with alpha-mannosidase had no effect. The solubilized [125I]DEEP photolabeled dopamine transporter complex readily bound to wheat-germ agglutinin but not to concanavalin-A sepharose columns. These results suggest that the carbohydrate moiety of the dopamine transporter is N-linked and contains significant quantities of sialic acid but not high mannose residues. A DEEP binding protein was readily detectable in other brain regions including the nucleus accumbens and olfactory tubercle, but not in the prefrontal cortex, olfactory bulb or hypothalamus under similar conditions. The DEEP binding protein in the other brain regions was similar to that in the striatum.

Animals↗
PubMed1991

The dopamine hypothesis of the reinforcing properties of cocaine.

A variety of evidence suggests a 'dopamine hypothesis' for the reinforcing properties of cocaine. This hypothesis proposes that cocaine binds at the dopamine transporter and mainly inhibits neurotransmitter re-uptake; the resulting potentiation of dopaminergic neurotransmission in mesolimbocortical pathways ultimately causes reinforcement. This model suggests potential medications for treatment of cocaine abuse and dependence. Some, but not all, pharmacological data in humans support the hypothesis and additional experimentation is needed.

Amphetamine↗
PubMed1991

Synthesis and ligand binding of cocaine isomers at the cocaine receptor.

The cocaine binding site at the dopamine transporter has been found to be stereoselective. Thus, the seven possible stereoisomers of (-)-cocaine have been synthesized and found to inhibit [3H]-2 beta-carbomethoxy-3 beta-(4-fluoro-phenyl)tropane [( 3H]WIN 35,428) with potencies ranging from 1/60 to 1/600 of that of (-)-cocaine. The synthesis and characterization of all new compounds is presented.

Animals↗
PubMed1991

Synthesis, ligand binding, QSAR, and CoMFA study of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters.

A series of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters (2) were synthesized and found to possess high affinity for the cocaine binding site in rat striatum. The p-chloro (2c) and p-iodo (2n) compounds, which were the most potent analogues prepared, were found to be 85 and 78 times more potent than (-)-cocaine. The p-bromo (2m) and p-methyl (2d) were also 56 and 60 times more potent than cocaine. QSAR and CoMFA studies were conducted to correlate binding affinity of the cocaine analogues with their structural features. Whereas the QSAR study gave relatively low correlations, the CoMFA study gave a correlation with high predictive value.

Animals↗
PubMed1991

Isothiocyanate derivatives of cocaine: irreversible inhibition of ligand binding at the dopamine transporter.

Isothiocyanate derivatives of (-)-cocaine were prepared and tested for inhibitory potency at the cocaine receptor in rat striatal membranes. Coincubation with m-isothiocyanatobenzoylecgonine methyl ester (m-ISOCOC), p-isothiocyanatobenzoylecgonine methyl ester (p-ISOCOC), and 3 beta-(4-isothiocyanatophenyl)tropane-2-carboxylic acid methyl ester (ISOWIN) resulted in inhibition of [3H]WIN 35,428 binding, but the compounds were about 10-fold weaker than (-)-cocaine. However, p-ISOCOC was approximately 3-fold more potent than metaphit, an isothiocyanate derivative of phencyclidine. p-ISOCOC was equipotent at the serotonin transporter but was much less potent at the norepinephrine transporter and was inactive at the D2 dopamine receptor at 1000 microM concentration. The IC50 value for m-ISOCOC and p-ISOCOC varied with tissue concentration, suggesting irreversible inhibition of binding. Preincubation with m-ISOCOC and p-ISOCOC resulted in inhibition of [3H]WIN 35,428 binding that could not be removed by washing of the membranes; in contrast, preincubation with (-)-cocaine caused inhibition that was readily removed by washing. Preincubation with 1 microM concentrations of p-ISOCOC resulted in a large reduction in Bmax of the high affinity binding site for [3H]WIN 35,428. Preincubation with 100 microM p-ISOCOC eliminated the high affinity site and apparently reduced the affinity at the low affinity site. Coincubation of 10 microM p-ISOCOC with 100 microM cocaine prevented the total loss of [3H]WIN 35,428 binding. The uptake of [3H]dopamine was inhibited by p-ISOCOC with an IC50 comparable to that of cocaine. Additionally, preincubation of rat striatal synaptosomes with 10 microM p-ISOCOC reduced the Vmax of [3H]dopamine uptake after washing. These data suggest that m-ISOCOC and p-ISOCOC are useful irreversible acylators of (-)-cocaine binding sites at the dopamine transporter.

Animals↗
PubMed1991

In vivo labeling of cocaine binding sites on dopamine transporters with [3H]WIN 35,428.

After in vivo administration, [3H]WIN 35,428 accumulated in mouse brain regions containing dopaminergic nerve terminals. The highest accumulation was in the striatum and it peaked between 30 and 60 min. The accumulation was saturable with increasing doses of WIN 35,428, and was blocked by compounds that bind to the dopamine transporter. Paroxetine, a drug that blocks serotonin transporters, had no effect. Moreover, the in vivo potency of cocaine analogs correlated with their in vitro potency. Thus, [3H]WIN 35,428 is a suitable ligand for labeling cocaine receptors associated with dopamine transporters in vivo.

Animals↗
PubMed1990

New, potent cocaine analogs: ligand binding and transport studies in rat striatum.

Two potent cocaine analogs have been developed that have the highest known affinities for the cocaine binding site in rat striatum. Both 3 beta-(4-chlorophenyl)- (RTI-COC-31) and 3 beta-(4-methylphenyl)-tropane-2-carboxylic acid methyl ester (RTI-COC-32) compete for [3H]WIN 35,428 and [3H]mazindol binding with a IC50 that is 100 times more potent than that of (-) cocaine. Additionally, these compounds inhibit [3H]dopamine uptake with a similar, high potency. These results may lead to the development of high affinity probes for the cocaine binding site.

Animals↗
PubMed1990

Increased drug sensitivity in the drug discrimination procedure afforded by drug versus drug training.

Rats were trained to discriminate norfenfluramine (NF) 1.4 mg/kg from its vehicle or amphetamine (AMPH) 0.8 mg/kg or pentobarbital (PB) 6.0 mg/kg in order to determine the role that drug combination training plays in the rate of learning and sensitivity to lower drug doses. The results suggest that drug versus drug training can increase the rate of drug discrimination learning for some drugs that are learned slowly when trained in a drug versus vehicle training procedure, whereas drug versus drug training does not increase the rate of learning for other drugs that are learned rapidly. Drug versus drug training does, however, appear to increase the level of stimulus control of the training drug for all drugs examined in this study.

Amphetamine↗
PubMed1990

Phencyclidine binding to striatal cocaine receptors.

PCP and related compounds inhibit 3H-mazindol binding to the cocaine receptor on dopamine transporters. The relative potencies of these compounds are such that some of the behavioral effects of PCP could be related to its action at the cocaine receptor; however, the affinity of PCP at the cocaine site (Ki = 1.59 microM) is less than its affinity at its own receptor (Ki about 0.12 microM). More data will be needed to conclusively implicate the cocaine receptor in the action of PCP.

Animals↗
PubMed1990

[3H]WIN 35,065-2: a ligand for cocaine receptors in striatum.

[3H]WIN 35,065-2 binding to striatal membranes was characterized, primarily by centrifugation assay. Like [3H]cocaine, [3H]WIN 35,065-2 binds to both high- and low-affinity sites. [3H]WIN 35,065-2, however, exhibits consistently higher affinities than [3H]cocaine. Saturation experiments indicate a low-affinity binding site with an apparent KD of approximately 160 nM and a Bmax of 135 fmol/mg of tissue. A high-affinity site has also been identified with an apparent KD of 5.6 nM and a Bmax of 5.2 fmol/mg of tissue. The specific-to-nonspecific binding ratios with [3H]WIN 35,065-2 were higher than with [3H]cocaine in both centrifugation and filtration assays. Pharmacological characterization suggests that [3H]WIN 35,065-2 binds to the dopamine transporter. Mazindol, GBR 12909, nomifensine, and (-)-cocaine are potent inhibitors of [3H]WIN 35,065-2 binding. In contrast, the norepinephrine transporter ligand desipramine is a weak inhibitor, and the serotonin transporter ligand citalopram does not inhibit binding. The effect of sodium on binding was examined under conditions in which (a) the low-affinity site was primarily (87%) occupied and (b) approximately 50% of both sites were occupied. The results indicate that both sites are sodium dependent. Injection of 6-hydroxydopamine into the striatum results in a significant loss of both high- and low-affinity sites, a finding suggesting that both sites are on dopaminergic nerve terminals. Taken together, these data are consistent with the presence of multiple cocaine binding sites associated with the dopamine transporter.

Animals↗
PubMed1989

[3H]cocaine binding and inhibition of [3H]dopamine uptake is similar in both the rat striatum and nucleus accumbens.

Cocaine binds with high affinity to the dopamine transporter in both the striatum and the nucleus accumbens. We examined Na(+)-dependent [3H]cocaine binding, mazindol inhibition of [3H]cocaine binding and cocaine inhibition of [3H]dopamine uptake in both rat brain areas. The striatum and nucleus accumbens demonstrated Na(+)-dependent [3H]cocaine binding with similar densities. Mazindol inhibited [3H]cocaine binding with a similar IC50 in both the striatum and nucleus accumbens. Likewise, cocaine inhibited [3H]dopamine uptake in both brain regions with equivalent efficacy. From these data we conclude that the dopamine transporter is similar in both the striatum and nucleus accumbens.

Animals↗
PubMed1989

Stability of the stimulus properties of drugs over time.

Three separate groups of rats were trained to discriminate the stimulus effects of either 600 mg/kg ethanol (n = 5), 0.8 mg/kg d-amphetamine (n = 8) or 1.0 mg/kg 1-(3-trifluoromethylphenyl)piperazine (TFMPP; n = 10). Once criterion performance was attained, each group was tested with various doses of the drug used in their training, thus allowing for calculations of dose-response curves and ED50 values. A second dose-response relationship was established at a later time, averaging over a year later, and this result was compared to the initial curve. In none of the three groups was there substantial change in the sensitivity of the rats to different doses of the drug used in training as indicated by similar ED50 values. These results suggest that the drug discrimination procedure is stable over a period of continuous training and testing.

Animals↗
PubMed1989

The antinociceptive effects of 3,4-methylenedioxymethamphetamine (MDMA) in the rat.

The antinociceptive effects of MDMA and morphine were examined in rats using the tail-flick and hot-plate analgesiometric tests. MDMA, in the dose range of 1.5-6.0 mg/kg IP, produced a dose-dependent elevation in hot-plate latency, but did not elevate tail-flick latency. In contrast, morphine (2-8 mg/kg, IP) produced analgesia on both the tail-flick and hot-plate tests in a dose-dependent manner. Neither the opiate antagonist naltrexone nor the adrenoceptor antagonist phentolamine effectively attenuated MDMA-induced analgesia. Conversely, the serotonin antagonist methysergide significantly reversed the analgesic effects of MDMA on the hot-plate test. These findings suggest that the antinociceptive effects of MDMA are serotonergically mediated. Furthermore, the results verify earlier findings describing the test-specific effects of serotonin-induced pain modulation.

3,4-Methylenedioxyamphetamine↗