Role of D1 and D2 dopamine receptors in the behavioral effects of cocaine.
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Animals↗
Biomedical subjects
K F Melia
Publications and source records attributed to K F Melia.
Pharmacological characterization of the discriminative-stimulus effects of GBR 12909.
Squirrel monkeys were trained to discriminate the selective dopamine uptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)-methoxy] ethyl]-4-(3-phenylpropyl)piperazine) from saline in a two-lever drug-discrimination procedure. After i.v. injections of GBR 12909, 10 consecutive responses on one lever produced food, whereas after i.v. saline, 10 consecutive responses on the other lever produced food. By using a cumulative-dosing procedure, several inhibitors of monoamine uptake as well as dopamine receptor agonists and antagonists were evaluated for their ability to substitute for, or attenuate, the discriminative-stimulus effects of GBR 12909. Dopamine uptake inhibitors, including GBR 12909, cocaine, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane, mazindol, bupropion and methylphenidate, as well as the dopamine releasing drug (+)-amphetamine substituted fully (greater than 80% drug-lever responding) for the training dose of GBR 12909. In contrast, the selective norepinephrine uptake inhibitors, desipramine and talsupram, and the selective serotonin uptake inhibitor, citalopram, occasioned averages of only 13 to 19% drug-lever responding. The dopamine D1 agonist SKF 81297 (6-chloro-7,8-ddhydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine), the D2 agonists, (+)-4-propyl-9-hydroxynaphthoxazine and quinpirole, and the nonselective dopamine agonist, (-)-apomorphine, all occasioned a majority of responses (mean = 56-82%) on the drug-appropriate lever. The D1 partial agonists, R-SKF 38393 (R-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro- [1H]-3-benzazepine) and SKF 75670 (7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-[1H]-3-benzazepine), however, occasioned an average of no more than 21% drug-appropriate responding.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Discriminative stimulus effects of cocaine in squirrel monkeys: involvement of dopamine receptor subtypes.
The involvement of dopamine (DA) receptor subtypes in the discriminative stimulus effects of cocaine was investigated in squirrel monkeys trained to discriminate cocaine from vehicle using a two-lever choice procedure. Lever pressing was maintained under a 10-response fixed-ratio schedule of food presentation. In substitution tests, (-)-cocaine and its high-affinity analogs 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) and 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (CCT) engendered dose-related increases in the proportion of cocaine-appropriate responses. Full (97-100%) substitution for the training dose of cocaine was observed with all three drugs, the rank order of potency being: CCT greater than CFT greater than cocaine. DA agonists differing in selectivity for D1 and D2 receptor subtypes [6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297), 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958), (+)-4-propyl-9-hydroxynapthoxazine [(+)-PHNO], quinpirole, quinelorane, (-)-4,6,6a,7,8,-12b-hexahydro-7-methyl-indolo[4,3-ab]phen ant hridine (CY 208-243) and (-)-apomorphine] also engendered dose-related increases in cocaine-appropriate responses. However, maximally effective doses of these drugs occasioned an average of only 54 to 77% responses on the cocaine-associated lever and markedly reduced response rates. Combinations of the D1 agonist SKF 81297 and the D2 agonist (+)-PHNO did not engender a consistently higher proportion of cocaine-appropriate responses than did either drug alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ethanol effects on delayed spatial matching as modeled by a negative exponential forgetting function.
Performance on delayed matching-to-position as a function of ethanol was investigated in rats and dose effects assessed by fitting an exponential decay model of forgetting to signal detection sensitivity scores. Three ethanol doses (0.25, 0.50, and 0.75 g/kg) and one isovolume saline control were examined. For further comparison, one dose of chlordiazepoxide (CDP; 5 mg/kg) and its saline control were also given. Forgetting functions were reasonably well described by the decay model under all treatment conditions. In addition, the functions's decay constant (-b) proved to be differentially sensitive to both drug and dose effects. Reduced decay estimates were obtained following the two lowest ethanol doses, the reduction being statistically significant for the 0.25 g/kg dose. In contrast, the function estimate of initial sensitivity, the intercept parameter (SI0), was not significantly affected by ethanol. Consistent with the low-dose ethanol effects, CDP significantly decreased the value of the decay parameter while leaving the intercept parameter unaffected. But unlike ethanol, the variance accounted for by the model for the individual data was less following CDP administration. Drug effects were interpreted using the exponential decay model of forgetting, and the results suggest independent discriminative control over SI0 and b. The significant effect of the low-dose sedative-hypnotics upon b, with no attendant effects upon SI0, is suggested to result from enhanced, spontaneous, delay interval mediation.
Animals↗
Signal detection analysis of ethanol effects on a complex conditional discrimination.
The effects of ethanol on a conditional object identification task were investigated using an operant analog of Signal Detection Analysis. Water and three doses of ethanol (0.40, 0.75 and 1.5 g/kg) were orally administered on three separate occasions to three adult squirrel monkeys. Significant discrimination impairment as a function of increasing ethanol dose was observed. At the 1.5 g/kg dose, impairment extended to nonspecific effects, with subjects ceasing to respond early into the session. Subsequent signal detection analyses revealed that the reduction in performance resulted from losses in discriminability. Response bias was found to change unpredictably and independently of ethanol administration. Reaction time measures also showed no changes except a moderate, nonsignificant, facilitation in speed at the lowest (0.40 g/kg) dose. Taken together, these data suggest that ethanol acts to impair complex, or cognitive, performance by disrupting current sources of stimulus control within the range of doses tested.
Animals↗
Post-learning ethanol effects on a water-finding task in rats.
Ethanol's post-training facilitation of memory was examined using a latent learning paradigm known as the "water-finding task." Rats were assigned to one of two ethanol groups (E0.75 g/kg or E1.5 g/kg) or to a control group (saline) and individually placed in a novel open field containing a drinking tube. Following this exposure, subjects were immediately administered intraperitoneal (IP) injections of either the saline or ethanol and 48 hours later, re-introduced to the field. Initial latencies to contact the tube each time were recorded. A linear regression analysis of trial 2 latencies regressed onto trial 1 latencies indicated a statistically significant effect of ethanol on the relation between initial and subsequent latencies. Though the control rats' trial 2 latencies were completely random with respect to their previous speeds (rSAL = -0.07), the ethanol rats' trial 2 latencies were positively correlated with initial speeds (rE0.75 = 0.35, rE1.5 = 0.67). These results suggest that under conditions of post-training ethanol, trial 2 behavior is more similar to, or controlled by, trial 1 behavior and are consistent with the argument that, under certain training and testing contexts, ethanol can come to exert control over a response's recurrence.
Analysis of Variance↗