Functional expression of recombinant N-methyl-D-aspartate receptors in the yeast Saccharomyces cerevisiae--localization and pharmacological characterization

Several agents have been used to treat cocaine-related cardiovascular complications and toxicity occurring in sensitive individuals, yet the causes of hemodynamic responsiveness and differential sensitivity to cocaine are unknown. In this study, we sought to examine the role of different mediators in a model of variable cardiovascular responses to cocaine. As noted previously in conscious rats, cardiac output (CO) and systemic vascular resistance (SVR) responses to cocaine (5 mg/kg, i.v.) varied widely. Twenty of 34 rats exhibited cocaine-induced decreases in CO of > or =8% and large increases in SVR (designated vascular responders). The remaining rats with little change or an increase in CO and smaller increases in SVR were named mixed responders. Pretreatment with propranolol (1 mg/kg) or metoprolol (1 mg/kg) reduced heart rate. In mixed responders, propranolol or metoprolol reversed the cocaine-induced increase in CO and stroke volume and enhanced the increase in SVR, making these rats respond like vascular responders. Nicardipine (25 microg/kg) reduced the pressor response and selectively reversed the CO responses in vascular responders. N omega-nitro-L-arginine methyl ester (L-NAME; 2.7 mg/kg) increased arterial pressure by increasing SVR. Cocaine induced greater pressor and SVR responses apparently because of a shift in baseline values elicited by L-NAME alone. Therefore, differences in hemodynamic responses patterns may be the result of differences in beta-adrenergic activation or subsequent calcium channel activation or both. We predict that calcium channel antagonists may be useful to treat cocaine-induced cardiovascular complications, whereas beta-adrenergic antagonists are not likely to be beneficial.     

The effects of cadmium contamination on the discriminative stimulus properties of cocaine and related drugs.

Rats were exposed to a diet containing 100 ppm cadmium chloride or a control diet. At 52 days of exposure, rats were trained to discriminate between saline and 5 mg/kg cocaine injections. After acquisition training, successive substitution tests were conducted using cocaine, the indirect dopamine agonist d-amphetamine, the mixed D?-D? agonist apomorphine, SKF 38393 and SKF 82958 (both preferential D? agonists), quinpirole (a preferential D? agonist), GBR 12909 (a dopamine reuptake inhibitor), procaine (a local anesthetic), and morphine (an opiate). The results showed that cadmium-exposed rats were slower to acquire the saline–cocaine discrimination than controls. Moreover, cadmium contamination reduced substitution when apomorphine, SKF 82958, and GBR 12909 were presented during generalization testing. Also, cadmium exposure blocked tolerance to cocaine that was evident in control rats following 14 days of exposure to 60 mg/kg/day cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Self-administration of GBR 12909 on a fixed ratio and progressive ratio schedule in rats

Intravenous self-administration of GBR 12909, an indirect dopamine agonist, was examined on a Fixed Ratio (FR 1) and a Progressive Ratio (PR) schedule of reinforcement in rats. Subjects were first trained to self-administer cocaine (1.5 mg/kg/inj) during daily 5 h sessions, after which GBR 12909 (0.187-1.5 mg/kg/inj) was substituted. On the FR 1 schedule, the inter-infusion interval for GBR 12909 self-administration was directly related to dose and was approximately three times longer than that established for equivalent doses of cocaine. Breaking points on the PR schedule were comparable for GBR 12909 and cocaine self-administration. The data indicate that, compared to cocaine, GBR 12909 has a longer duration of action and a similar reinforcing efficacy.     

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)     

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 phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey

Drugs that decrease drug-maintained responding at doses that do not decrease other behaviors in animals may be suitable candidates for development as medications to treat drug abuse in humans. The present study examined whether this effect could be obtained with phentermine, a drug that has been reported to decrease cocaine intake in humans. Rhesus monkeys were trained under multiple fixed-ratio 30-response schedules of food and i.v. cocaine delivery. Phentermine was always given as a slow, i.v. infusion. Acute treatment with phentermine (0.3-10 mg/kg) decreased cocaine-maintained responding at doses that did not decrease, or decreased less, food-maintained responding for each of three unit doses of cocaine (10-100 microg/kg/injection). Subacute treatment with phentermine (3 or 5.6 mg/kg, daily) also decreased cocaine-maintained responding more than food-maintained responding. After subacute treatment was terminated, rates of cocaine-maintained responding generally recovered to levels comparable to those seen during untreated control sessions. Phentermine (0.3-3 mg/kg) did not generally increase responding associated with a very low (1 microg/kg/injection) unit dose of cocaine, suggesting that the decrease in cocaine-maintained responding at higher unit doses was not the result of a leftward shift in the cocaine unit dose-effect function. Phentermine (0.1-3 mg/kg) decreased responding maintained by 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine (GBR 12909) (30 microg/kg/injection) at doses similar to those that decreased food-maintained responding. These results show that phentermine is effective in decreasing cocaine self-administration and suggest that it may be an effective medication for cocaine abuse.     

Sensitization to the rewarding effects of the specific dopamine uptake inhibitor GBR12783

The conditioned place preference (CPP) induced by increasing doses (1.25-40 mg/kg) of cocaine or the specific dopamine uptake inhibitor GBR12783 was investigated in rats previously treated with cocaine (10 or 20 mg/kg), GBR12783 (10 mg/kg) or morphine (10 mg/kg) for 15 days. In solvent-pretreated rats, cocaine- and GBR12783-induced CPPs were biphasic, with the highest scores observed at 20 mg/kg. Prior exposure to GBR12783 sensitized the rats to the rewarding effects of low doses of either GBR12783 or cocaine. Pretreatment with cocaine 20 mg/kg, but not 10 mg/kg, sensitized the rats to its own rewarding effects. Furthermore, it was less efficient than GBR12783 in sensitizing the animals to the rewarding effects of both drugs. These data confirm the major role of dopamine uptake inhibition in the sensitization process. On the other hand, the magnitude of CPP induced by a high dose of both drugs (20 mg/kg) was decreased after pretreatment with either GBR12783 or cocaine, reaching the lower scores observed at 40 mg/kg. This decrease was unrelated to altered anxiety level but was associated with sensitization to stereotypies. Morphine pretreatment modified neither the CPP induced by high doses of cocaine or GBR12783 nor cocaine- or GBR12783-induced stereotypies. However, prior exposure to morphine sensitized the rats to the rewarding effects of cocaine (2.5 mg/kg) but not to those of GBR12783, suggesting that other mechanisms working in concert with dopamine may facilitate the rewarding effect of cocaine without affecting that of GBR12783.     

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)     

Ovine fetal-placental cocaine pharmacokinetics during continuous cocaine infusion

OBJECTIVE: To investigate fetal-placental cocaine clearance, and to determine the fetal catecholamine and cardiovascular responses to continuous intravenous cocaine infusion in fetal sheep. METHODS: Eleven pregnant ewes and their fetuses (127 +/- 2 days' gestation; term 150 days) were chronically instrumented. Fetuses received intravenous cocaine at 0.05, 0.1, or 0.2 mg/kg/minute. Fetal cardiovascular and hematologic measurements were made before and serially for 90 minutes after initiation of the cocaine infusion. RESULTS: Steady-state fetal plasma cocaine concentrations were observed by 15 minutes of infusion and averaged 136 +/- 11, 318 +/- 65, and 610 +/- 36 ng/mL, respectively, at each dose. Fetal-placental cocaine clearance rate was independent of dose (337 +/- 39 mL/kg/minute), indicating that it is a first-order pharmacokinetic process. Fetal plasma concentration of benzoylecgonine, a principle cocaine metabolite, increased throughout the study to approximately 25% above cocaine levels by 90 minutes. There were significant increases in fetal heart rate (from 169 +/- 11 to 242 +/- 36 beats per minute), mean blood pressure (from 53 +/- 4 to 63 +/- 5 mmHg), and systolic blood pressure (from 68 +/- 2 to 80 +/- 5 mmHg), with a corresponding increase in catecholamine levels seen in the fetuses infused with 0.2 mg/kg/minute. These changes were not seen in the fetuses given lower doses of cocaine. CONCLUSION: Fetal-placental clearance of cocaine is a rapid, first-order pharmacokinetic process. During prolonged cocaine exposure, plasma benzoylecgonine concentrations accumulate significantly. Significant catecholamine and cardiovascular changes are seen in fetal sheep with a continuous infusion of cocaine at 0.2 mg/kg/minute or greater.     

Generalization of D-, L- and DL-chlorpheniramine and zolantidine to the discriminative stimulus effects of cocaine and methamphetamine

We recently demonstrated that some H-antagonists have cocaine or methamphetamine-like discriminative stimulus effects. In the present study, the effects of optical isomers of chlorpheniramine (D-, L- and DL-forms) on the discriminative stimulus effects of cocaine and methamphetamine were examined in rats trained to discriminate between cocaine (10.0 mg/kg) or methamphetamine (1.0 mg/kg) and saline, to determine whether these effects of H1-antagonists are mediated by the blockade of H-receptors. In generalization tests with optical isomers of chlorpheniramine, the D-, L- and DL-forms all completely generalized to the discriminative stimulus effects of cocaine, but did not generalize to those of methamphetamine. Dose-generalization by the optical isomers of chlorpheniramine to the discriminative stimulus effects of cocaine did not correlate with the H-antagonistic potency of these drugs. These results suggest that all of the optical isomers of chlorpheniramine have cocaine-like discriminative stimulus effects, but that these effects are not mediated by H1-receptor blockade. On the other hand, the H2-antagonist, zolantidine, generalized to the discriminative stimulus effects of methamphetamine, but not to those of cocaine, suggesting that zolantidine may have methamphetamine-like discriminative stimulus effects. In the present study, GBR12909 (dopamine uptake inhibitor) completely generalized to the discriminative stimulus effects of cocaine, but not to those of methamphetamine, whereas apomorphine (dopamine receptor agonist) generalized more potently to the discriminative stimulus effects of methamphetamine than to those of cocaine. These findings imply that although the dopaminergic system plays an important role in the discriminative stimulus effects of both cocaine and methamphetamine, there may be differences between their effects.     

Repeated injection of GBR 12909, but not cocaine or WIN 35,065-2, into the ventral tegmental area induces behavioral sensitization

A role for the mesolimbic dopamine system in the development of behavioral sensitization to psychostimulants, such as cocaine and amphetamine, is well established. Previous reports have suggested that the ventral tegmental area (VTA) is involved in the initiation of, while the nucleus accumbens is in involved in the expression of behavioral sensitization. This hypothesis is supported in part, by studies which demonstrated that behavioral sensitization could be induced by repeated intra-VTA, but not intra-accumbal, administration of amphetamine. The present studies were designed to determine whether repeated intra-VTA cocaine would similarly induce behavioral sensitization. Rats receiving four daily injections of cocaine (1.5, 5 or 15 nmol/side) into the VTA did not show a sensitized behavioral response when challenged with cocaine (15 mg/kg, ip) 1 week later. In contrast to this, repeated injection of the specific dopamine reuptake inhibitor, GBR 12909 (15 nmol/side) produced behavioral sensitization to a challenge injection of cocaine. Repeated injections of the cocaine analog WIN 35,065-2 did not induce behavioral sensitization to cocaine, suggesting that the local anesthetic properties of cocaine were not responsible for the inability of intra-VTA cocaine to induce sensitization. In summary, the data suggest that sensitization to cocaine may involve mechanisms different from amphetamine.     

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.     

Autonomic mechanisms in the acute cardiovascular effects of cocaine in conscious rats

We studied the differential involvement of central dopaminergic activation and autonomic nervous system regulatory mechanisms in the cardiovascular responses to cocaine in conscious rats. Sprague-Dawley rats, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were instrumented with catheters in the jugular vein and abdominal aorta at least 5 days before the experiment. Intravenous administration of cocaine (0.1-3.0 mg/kg) caused a dose-dependent increase in blood pressure that was biphasic, with a large and rapid increase peaking at 10 s, followed by a mild sustained pressor response. Pressor responses to cocaine were significantly greater in SHR when compared to WKY rats. However, pretreatment with dopamine D1 receptor antagonist SCH 23390 or the D2 receptor antagonist raclopride did not influence the effects of cocaine. Pretreatment with the alpha-adrenoceptor antagonist phentolamine or the ganglion blocker pentolinium blocked the peak response and reversed the more sustained response into a depressor effect. While pretreatment with propranolol alone did not alter the responses to cocaine, in rats pretreated with phentolamine and propranolol neither a pressor response nor a depressor response was observed. In conclusion, cocaine administration caused marked, but short lasting pressor responses that were mediated by sympathetic activation and alpha-adrenoceptor vasoconstriction with little involvement of central dopaminergic mechanisms. The rapid return of blood pressure towards baseline may be mediated by sympathoinhibition and beta-adrenoceptor-mediated vasodilatation, the latter of which being particularly prominent when alpha-adrenoceptor activation was prevented.     

Interaction of buprenorphine with cocaine-morphine combinations.

Sixteen nonheroin dependent drug abusers, who identified intravenous cocaine and heroin as their drug combination of choice, participated in a study assessing the efficacy of buprenorphine in altering the subjective and cardiovascular effects of such combinations. A sublingual dose of buprenorphine (none, 2, or 4 mg) was administered 50 min before the intravenous administration of morphine sulfate (0, 5, or 10 mg/70 kg) in combination with cocaine hydrochloride (0, 8, or 32 mg/70 kg). Buprenorphine had minimal effects on the response to cocaine alone but decreased cardiovascular activity produced by morphine alone. Buprenorphine decreased ratings of drug liking when given before combinations of 32 mg of cocaine and morphine. The greater effect of buprenorphine on cocaine-morphine combinations suggests that buprenorphine may be effective as a treatment medication for individuals who use such combinations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine as a conditioned stimulus: Impact of attention-deficit/hyperactivity disorder medications.

People diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk to start smoking and have greater difficulty quitting. Nicotine, one of the principal addictive components of tobacco smoke, functioned as a conditioned stimulus (CS) for intermittent sucrose delivery in a Pavlovian drug discrimination task with rats. This study compared the ability of commonly prescribed ADHD medications (i.e., methylphenidate, atomoxetine, and bupropion) and additional dopamine reuptake inhibitors (i.e., cocaine and GBR 12909) to substitute for the CS effects of nicotine. Atomoxetine was also used to antagonize these CS effects. Rats acquired the discrimination as evidenced by increased dipper entries in nicotine (0.2 mg base/kg) sessions as compared with saline sessions. Nicotine generalization was dose dependent. Bupropion (10 and 20 mg/kg), methylphenidate (10 mg/kg), and cocaine (5 and 10 mg/kg) partially substituted for the 0.2 mg/kg nicotine CS. Atomoxetine did not substitute for the nicotine CS; however, atomoxetine (1 to 10 mg/kg) partially blocked nicotine's CS effects. These results suggest that atomoxetine, bupropion, and/or methylphenidate may be effective treatments for people diagnosed with ADHD and addicted to nicotine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anxiolytic effects of dopamine receptor ligands: I. Involvement of dopamine autoreceptors

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg/kg), quinelorane (0.01 mg/kg), quinpirole (0.04 mg/kg), pramipexole (0.09 mg/kg), roxindole (0.04 mg/kg), talipexole (0.04 mg/kg), (+/-)-7-OH-DPAT (0.05 mg/kg), (+/-)-PPHT (0.03 mg/kg), (-)-TNPA (0.06 mg/kg), PD128907 (0.13 mg/kg). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(-)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.     

Professor Matthew Stewart: asbestosis research 1929-1934

The chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without changing dopamine transporter binding. In order to examine more closely the dopaminergic contribution to this effect, the selective dopamine uptake inhibitor GBR 12,909 (30 mg/kg/day), cocaine (50 mg/kg/day), or vehicle, were continuously infused via osmotic minipump, and their effects on the dopamine transporter examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and removed after seven days. [3H]WIN 35,428 binding and [3H]dopamine uptake were measured in caudate putamen and nucleus accumbens at varying intervals after pump removal. The Bmax for [3H]WIN 35,428 binding was decreased by approximately 75% in the caudate putamen and by 40% in the nucleus accumbens of GBR 12,909-treated rats both 1 and 4 days after pump removal, and was still significantly decreased after 10 days, but had returned to normal by 20 days post-treatment. In contrast, cocaine did not significantly alter [3H]WIN 35,428 binding. GBR 12,909 produced both tolerance to the inhibition of [3H]dopamine uptake by cocaine, and a decrease in total uptake of dopamine, in the caudate putamen, with no change in the nucleus accumbens. The persistent reduction of [3H]WIN 35,428 binding following continuous GBR 12,909 does not appear to result from residual drug binding. These findings suggest that GBR 12,909 and cocaine may bind to and regulate the dopamine transporter in different ways.     

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.     

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.     

Discriminative characteristics of high and low cocaine administration: effect of other psychostimulants

Two groups of N/Nih male rats were trained to discriminate saline vehicle from either 2.0 mg/kg (n = 10) or 10.0 mg/kg (n = 10) cocaine in a food-motivated, two-lever operant paradigm. The rats trained at the low-dose cocaine took a significantly longer training period to reach criterion performance than did the high-dose cocaine group. In addition, the ED50 value for the 2.0 mg/kg cocaine-trained animals (0.465 mg/kg) was significantly lower than the ED50 value (2.105 mg/kg) for those animals trained at the 10.0 mg/kg dose of cocaine. This correlation of ED50 values for stimulus generalization decreasing with reduction in training dose was in contrast to the time-course of the two groups when tested from 15 to 240 min post-injection; this experimentation indicated that there was a non-significant difference in half-life for the 2.0 mg/kg (t1/2: 97.1 min) vs. that of the 10.0 mg/kg cocaine-trained group (t1/2: 83.4 min). Generalization tests with other purportedly dopaminergically-active drugs of abuse including 0.05-0.8 mg/kg d-amphetamine, 0.125-1.5 mg/kg methamphetamine and 0.125-1.0 mg/kg methcathinone indicated that the highest doses of each produced generalization and, with the exception of methcathinone, the ED50 values were significantly lower in the low-cocaine trained group. The stimulus properties of cocaine, as they generalize to amphetamine, methamphetamine and methcathinone, can be explained by effects upon central dopaminergic neurons and may be qualitatively different in low-and high-dose trained rats.