Effects of the novel D1 dopamine receptor agonist ABT-431 on cocaine self-administration and reinstatement.

Selective D1 dopamine agonists represent a potential pharmacotherapy for the treatment of cocaine addiction. Here we report that systemic injections of the novel D1 agonist ABT-431 lack the ability to induce cocaine-seeking behavior, and completely attenuate the ability of cocaine to induce this behavior in rats tested in a reinstatement paradigm. Similar doses suppress the initiation of cocaine self-administration, and produce an extinction-like response pattern in animals that subsequently initiate self-administration, without altering responding maintained by food pellets. There was no tolerance to this effect over 4 days of testing. The results suggest that ABT-431 attenuates the motivation to seek cocaine, and masks the reinforcing effects of cocaine during self-administration. The profile of ABT-431 is similar to the behavioral effects of other structurally distinct D1 agonists, and is consistent with the desired profile of a "methadone-like" compounds for cocaine addiction.

Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior.

cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc) has been implicated in cocaine addiction because (1) cocaine reinforcement is mediated by dopamine receptors that modulate cAMP formation, and (2) repeated exposure to cocaine upregulates the cAMP system in NAc neurons. This study tested PKA involvement in cocaine self-administration and relapse of cocaine-seeking behavior by infusing cAMP analogs that activate or inhibit PKA into the NAc of rats. Bilateral intra-NAc infusions of the PKA inhibitor Rp-cAMPS reduced baseline cocaine self-administration, shifted the dose-response curve for cocaine self-administration to the left, and induced relapse of cocaine-seeking behavior after extinction from cocaine self-administration, consistent with an enhancement of cocaine effects in each paradigm. In contrast, pretreatment with intra-NAc infusions of a PKA activator, Sp-cAMPS or dibutyryl cAMP, increased baseline cocaine self-administration during the second hour of testing and shifted the dose-response curve to the right, consistent with an antagonist-like action. After extinction from cocaine self-administration, similar infusions of Sp-cAMPS induced generalized responding at both drug-paired and inactive levers. As an index of PKA activity in vivo, NAc infusions of Rp-cAMPS reduced basal levels of dopamine-regulated phosphoprotein-32 phosphorylation and blocked amphetamine-induced increases in cAMP response element-binding protein (CREB) phosphorylation. Conversely, NAc infusions of Sp-cAMPS increased phosphorylation of CREB. Together, these results suggest that sustained upregulation of the cAMP system in the NAc after repeated cocaine exposure could underlie tolerance to cocaine reinforcement, whereas acute inhibition of this system may contribute to drug craving and relapse in addicted subjects.

Electrolytes and reproductive hormone concentrations in maternal plasma and fetal fluids of dairy cows with hydrops.

Electrolytes, metabolites, cortisol and reproductive hormones were measured in maternal plasma taken at least twice daily from three cases of bovine hydrops before, during and after parturition induced by dexamethasone or prostaglandin. Caesarean operations were required for two of the cases. Maternal plasma electrolytes remained within the normal range, but average potassium and creatinine concentrations were higher (9.2 and 0.68 mmol/litre, respectively) than normal (4.7 and 0.42 mmol/litre) in samples of amniotic fluid obtained at calving. Sodium (100 mmol/litre) and chloride (67 mmol/litre) in allantoic fluid were also higher than normal (53 and 20 mmol/litre, respectively). Conversely, creatinine concentrations were lower than normal in allantoic fluid (2.2 vs 13.8 mmol/litre). Oestradiol concentrations were lower than normal in maternal plasma (ranges: less than 20 to 140 pg/ml vs 30 to 440 pg/ml); maximum prostaglandin F metabolite (PGFM) concentrations were slightly elevated (ranges 1.1 to 2.0 ng/ml vs 0.4 to 0.9 ng/ml). Progesterone and cortisol concentrations remained within the normal range; the latter hormone increased markedly in parallel with raised PGFM concentrations. In two cases, the concentrations of reproductive hormones tended to be lower in the amniotic fluid than in the allantoic fluid. For example, progesterone concentrations were 42.8 and 14.9 ng/ml in the amniotic fluids vs 64.2 and 29.8 ng/ml in the allantoic fluids of the two cows; PGFM concentrations were 27.7 and 4.3 ng/ml vs 34.6 and 5.0 ng/ml, and oestradiol concentrations were 1.5 and 3.5 ng/ml vs 1.1 and 6.4 ng/ml in the two fluids, respectively.