Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys

Dopaminergic agonists can decrease cocaine self-administration at doses that do not decrease food-maintained responding, a pre-clinical effect indicative of a potential treatment for human cocaine abuse. To assess whether similar effects could be obtained with medications currently used to treat substance abuse, phentermine and fenfluramine were given alone and in combination to rhesus monkeys responding under schedules of food and cocaine delivery. Phentermine decreased cocaine-maintained responding with no effect on food-maintained responding. Fenfluramine also selectively decreased cocaine-maintained responding, but only at the highest dose. Combining a lower dose of fenfluramine with phentermine selectively decreased cocaine-maintained responding, but not more than with phentermine alone. These results suggest that phentermine, as well as its combination with fenfluramine, may be useful in the treatment of cocaine abuse.     

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3–3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10–130 and the unit dose was varied from 5.6–56.0 μg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909's effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine.

The effects of the high-affinity dopamine reuptake inhibitor, GBR 12909, were studied on responding maintained under multiple fixed ratio (FR) schedules of food and cocaine delivery in rhesus monkeys (Macaca mulatta). GBR 12909 decreased rates of responding maintained by both events in a dose-related manner, however, large decreases in cocaine-maintained responding could be obtained with doses of GBR 12909 that had little effect on food-maintained responding. This behavioral selective effect of GBR 12909 on cocaine-maintained responding was inversely related to the unit dose of cocaine. When responding was maintained by low doses of cocaine, GBR 12909 (1 mg/kg) decreased cocaine-maintained responding almost completely. When responding was maintained by the highest dose, the same dose of GBR 12909 had little effect on responding. To the extent that higher doses of cocaine may be expected to be more reinforcing, the current results suggest that the effect of GBR 12909 on cocaine-maintained responding was determined by the reinforcing efficacy of the unit dose of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: II. Comparisons with other drugs and repeated administrations.

A previous study (J. R. Glowa, F. H. E. Wojnicki, D. Matecka, et al, 1995) showed that acute doses of GBR 12909 selectively decreased cocaine-maintained responding without affecting food-maintained responding. This report extended these observations to some related drugs and to the effects of repeated administration. When responding was maintained under a multiple fixed ratio (FR) 30 food, FR 30 cocaine schedule, acute doses of GBRR 12935, CFT, and d-amphetamine decrease cocaine-maintained responding more than food-maintained responding. However, in contrast to GBR 12909, none of these drugs completely decreased cocaine-maintained responding without affecting food-maintained-responding. Repeated administration of GBR 12909 sustained and of GBR 12935 improved, these selective deceases in cocaine-maintained responding. The selective effect of these dopamine reuptake inhibitors on cocaine-maintained responding is consistent with their known pharmacological selectivity for the dopamine reuptake side and can be well-maintained with repeated administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cloning of a thermostable ascorbate oxidase gene from Acremonium sp. HI-25 and modification of the azide sensitivity of the enzyme by site-directed mutagenesis

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.     

Antagonism of cocaine's reinforcing and discriminative stimulus effects by !a-flupenthixol.

Examined the effects of the D?/D? dopamine receptor antagonist α-flupenthixol in animal models designed to assess abuse-related behavioral effects of cocaine. Rhesus monkeys self-administered cocaine (17 or 33 μg/kg/injection, iv) during 1-hr daily sessions; periods of food-maintained behavior preceded and followed cocaine access. α-Flupenthixol (0.003–0.03 mg/kg, iv) increased self-administration rates, indicating an antagonism of cocaine's reinforcing effects but decreased rates of food-maintained responding. α-Flupenthixol (0.03 mg/kg) blocked the discriminative stimulus effects of cocaine (0.3 mg/kg) in squirrel monkeys but did not do so in rats trained to discriminate 10 mg/kg cocaine from saline. On the basis of available animal data and preliminary clinical trials, α-flupenthixol may warrant further study as a cocaine abuse pharmacotherapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2–32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32–56 mg/kg/day, IV) on food- and cocaine-maintained (0.001–0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors

A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (I) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.8, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SERT site.     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Pharmacological characterization of the novel discriminative stimulus effects of a low dose of cocaine

Twelve rats were trained to press one lever after cocaine injection (3 mg/kg i.p.) and another lever after saline injection. Once rats were reliably discriminating cocaine from saline, other drugs were examined for their efficacies in substituting for cocaine. The dopamine uptake inhibitors WIN 35,428 [2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane-1,5-naphthalene - disulfonate] and GBR 12909 (1-[2-bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine dihydrochloride) fully substituted for cocaine (cocaine responding > 80%), whereas the peripherally active cocaine methiodide and the 5-hydroxytryptamine uptake inhibitor fluoxetine did not substitute at all. Pentobarbital also failed to produce any cocaine-appropriate responding. Two selective norepinephrine uptake inhibitors were tested: tomoxetine fully substituted for the 3-mg/kg dose of cocaine and nisoxetine approached full substitution (79.7% cocaine responding). The direct-acting dopamine D-1 agonists SKF 38393 [(+-)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepin e HCl], SKF 77434 [(+-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine HCl] and SKF 75670 [3-methyl-7,8-dihydroxyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zep ine HBr] fully substituted for cocaine, whereas the peripherally active dopamine D-1 agonist fenoldopam did not. Of four dopamine D-2 agonists tested, only quinpirole fully substituted; the others (N-0434 [(+-)-2-(N-propyl-N-phenylethylamino)-5-hydroxytetralin], (-)-NPA [R(-)-propylnorapomorphine HCl] and SDZ 208-912 (N-[(8-)-2,6-dimethylergoline-8-yl]-2,2-dimethyl-propanamide)) produced very limited partial substitution (cocaine responding < 32%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys

The behavioral effects of the nonpeptidic delta opioid agonist SNC80 and a series of related piperazinyl benzamides derived from the parent compound BW373U86 were evaluated in rhesus monkeys. SNC80 (0.1-10 mg/kg) decreased response rates maintained by food-reinforcement in a dose- and time-dependent manner, with maximal effects occurring within 10 min of intramuscular injection. The potency of SNC80 and five other piperazinyl benzamides in this assay of schedule-controlled responding correlated with their affinity at cloned human delta opioid receptors but not with their affinity for cloned human mu receptors. Moreover, the effects of SNC80 were selectively antagonized by the delta-selective antagonist naltrindole (1.0 mg/kg), but not by the mu selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist norbinaltorphimine (3.2 mg/kg). These findings indicate that SNC80 functions as a systemically active, delta-selective agonist with a rapid onset of action in rhesus monkeys. The antinociceptive effects of SNC80 were examined in a warm-water tail-withdrawal assay of thermal nociception. SNC80 (0.1-10 mg/kg) produced weak but replicable antinociceptive effects that were antagonized by naltrindole (1.0 mg/kg). SNC80 antinociception was also dose-dependently antagonized by BW373U86 (0.56-1.0 mg/kg), which was inactive in this procedure. These findings suggest that SNC80 may have higher efficacy than BW373U86 at delta opioid receptors. Moreover, SNC80 at doses up to 32 mg/kg did not produce convulsions, which suggests that SNC80 may also be safer than BW373U86. The effects of SNC80 were also examined in monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) or self-administer cocaine (0.032 mg/kg/injection,i.v.). In drug discrimination studies, SNC80 (0.1-10 mg/kg) produced a dose-dependent and naltrindole-reversible increase in cocaine-appropriate responding, and complete substitution for cocaine was observed in five of seven monkeys tested. However, SNC80 (1.0-100 micrograms/kg/injection) did not maintain responding in monkeys trained to self-administer cocaine. Thus, despite its ability to produce cocaine-like discriminative stimulus effects, SNC80 may have relatively low abuse potential.     

Effects of chlordiazepoxide, buspirone and cocaine on behavior suppressed by timeout presentation

Male Wistar rats were exposed to a two-component multiple schedule: a random-interval 30 s schedule of pellet presentation and a conjoint random-interval 30 s schedule of pellet presentation, random-interval 2 s schedule of timeout 10 s presentation. Once responding had stabilized subjects were injected intraperitoneally with vehicle, chlordiazepoxide (1-30 mg/kg), buspirone (0.1-4.2 mg/kg) or cocaine (1-30 mg/kg), 15 min before the start of the experimental session. Before drug administration, punished response rates were less than 30% of unpunished response rates for four of the six subjects, and 60% and 75% for the other two. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased punished responding (range 25-300%), and slightly increased unpunished response rates (by 25% in all but one subject, whose rates increased by 75%). The higher doses of chlordiazepoxide (10-30 mg/kg) dose-dependently decreased response rates in both components. The lower doses of buspirone (0.1 and 0.3 mg/kg) either did not affect, or decreased response rates in both components of the schedule; the higher doses produced dose-dependent decreases. Low doses of cocaine (1, 3 and 5.6 mg/kg) did not affect response rates in either component of the multiple schedule, whereas higher doses produced a dose-dependent decrease in response rates, except for one subject whose punished response rates increased substantially. The behavioral effects of chlordiazepoxide and buspirone observed in the present experiment were similar to those observed in experiments in which response rates were suppressed by shock presentation.     

Polydrug self-administration in rats: cocaine-heroin is more rewarding than cocaine-alone

The i.v. self-administration by rats of a polydrug combination of cocaine and heroin was explored. The rewarding efficacies of a range of cocaine doses (0.25-8 mg/kg/injection) alone or in combination with heroin (12.5 or 25 microg/kg/injection) were compared using a progressive ratio (PR) schedule of reinforcement. Breaking points (BP) for one group of rats were determined at each dose of cocaine alone and for two other groups at each of the same cocaine doses plus one of the heroin doses, respectively. The cocaine-heroin combination was associated with higher BPs than cocaine alone at all doses of cocaine. These data demonstrate that cocaine-heroin combinations (speedballs) are more rewarding than the identical doses of cocaine alone. Some possible mechanisms by which heroin increases cocaine reward are discussed.     

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.     

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats

The effects of acute and chronic administration of cocaine on the antinociception and tolerance to the antinociceptive actions of mu-(morphine), kappa-(U-50,488H), and delta-([D-Pen2,D-Pen5]enkephalin; DPDPE), opioid receptor agonists were determined in male Swiss-Webster mice. Intraperitoneal injection of 40 mg/kg of cocaine by itself produced weak antinociceptive response as measured by the tail-fick test but the lower doses were ineffective. Administration of morphine (10 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (10 microg/mouse, ICV) produced antinociception in mice. Cocaine (20 mg/kg) potentiated the antinociceptive action of morphine and DPDPE but had no effect on U-50,488H-induced antinociception. Administration of morphine (20 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (20 microg/mouse, ICV) twice a day for 4 days resulted in the development of tolerance to their antinociceptive actions. Tolerance to the antinociceptive actions of morphine and U-50,488H was inhibited by concurrent treatment with 20 or 40 mg/kg doses of cocaine; however, tolerance to the antinociceptive action of DPDPE was not modified by cocaine. It is concluded that cocaine selectively potentiates the antinociceptive action of mu- and delta- but not of the kappa-opioid receptor agonist. On the other hand, cocaine inhibits the development of tolerance to the antinociceptive actions of mu- and kappa- but not of delta-opioid receptor agonists in mice.     

Effects of d-amphetamine, pentobarbital, chlorpromazine and promazine on electric shock postponement responding by the pigeon

The effects of d-amphetamine, pentobarbital, chlorpromazine and promazine on responding under schedules of electric shock postponement were studied in pigeons. Responding was maintained by three different response-shock intervals (10, 20 and 60 seconds). Low doses (0.3-3 mg/kg) of d-amphetamine increased response rates without decreasing shock rates under all three response-shock intervals. The highest dose (10 mg/kg) of d-amphetamine increased the shock rates under all response-shock intervals and decreased the high response rate under the 10-second response-shock interval but did not decrease the lower rates of responding under the 20- and 60-second response-shock intervals. Pentobarbital decreased the high rate of responding maintained under the 10-second response-shock interval at lower dose (10 mg/kg) than the lower rates of under the 20- and 60-second response-shock intervals. The high dose (17.5 mg/kg) of pentobarbital decreased responding and the low doses (1-3 mg/kg) had no effect under all three response-shock intervals. Chlorpromazine (3-100 mg/kg) did not affect the average rate of responding under all response-shock intervals and only slightly increased shock rates under the 20- and 60-second response-shock intervals. Promazine (3-30 mg/kg) increased the rates of responding and decreased shock rates under all three response-shock intervals. Analysis of the temporal patterns of responding within the response-shock interval showed that d-amphetamine tended to induce the animals to respond earlier than they normally would in the response-shock interval while otherwise maintaining the temporal pattern of responding, pentobarbital decreased the probability of responses late in the response-shock interval, and chlorpromazine and promazine increased the probability of responses in the middle of the response-shock interval, producing a lessening of the temporal patterning of responding within the response-shock interval.     

"Taste reactivity responses elicited by cocaine-, phencyclidine-, and methamphetamine-paired sucrose solutions": Correction to Parker.

Reports an error in "Taste reactivity responses elicited by cocaine-, phencyclidine-, and methamphetamine-paired sucrose solutions" by Linda A. Parker (Behavioral Neuroscience, 1993[Feb], Vol 107[1], 118-129). Table 1, on page 119, contains two errors. In the first section, the dose/route for the agent nicotine should read as follows: 1.2-2.0 mg/kg sc. In the second section, the dose/route for the agent morphine should read as follows: 2-80 mg/kg ip. Also, on page 121, paragraph 3, line 14, the parenthetical information after 40 mg/kg cocaine should read (40C; 2 × 20 mg/kg/3 cc). (The following abstract of the original article appeared in record 1993-24959-001.) The nature of flavor–drug associations produced by a range of doses of the reinforcing agents cocaine (5, 10, 15, 20, or 40 mg/kg, sc), phencyclidine (0.5, 2, 10, or 20 mg/kg, sc), and methamphetamine (2, 5, or 10 mg/kg, ip) were assessed by the taste reactivity (TR) test and the conditioned taste avoidance (CTA) test. Even at the highest doses tested, none of the agents produced aversive TR responding. At doses that produced equivalent-strength CTA, lithium did establish aversive TR responding. Results provide evidence that drugs that serve as reinforcers in other paradigms produce conditioned flavor avoidance that is not motivated by a conditioned dislike for the flavor. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Euphorigenic doses of cocaine reduce [123I]beta-CIT SPECT measures of dopamine transporter availability in human cocaine addicts

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/- 0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.