GABAergic modulation of the discriminative stimulus effects of methamphetamine.

To assess whether gamma-aminobutyric acid (GABA) modulation of dopamine is important in mediation of the discriminative stimulus effects of methamphetamine, the GABA compounds chlordiazepoxide (benzodiazepine site agonist), pentobarbital (barbiturate site agonist), bicuculline and pentylenetetrazol (GABA(A) receptor antagonists) were tested in Sprague-Dawley rats trained to discriminate methamphetamine (1 mg/kg, i.p.) from saline. Each of the compounds produced modest amounts of methamphetamine-appropriate responding (20-35%) when tested alone. When tested in combination with methamphetamine, the antagonists (bicuculline and pentylenetetrazol) failed to shift the methamphetamine dose-effect curve. In contrast, chlordiazepoxide (25 mg/kg, i.p.) reduced methamphetamine-appropriate responding at each dose of methamphetamine tested, and pentobarbital (10 mg/kg, i.p.) dose-dependently decreased the discriminative stimulus effects of 1 mg/kg methamphetamine. In conclusion, GABA(A) antagonists and positive modulators likely do not produce methamphetamine-like stimulus effects. However, activation of GABA(A) receptors can interfere with the discriminative stimulus effects of methamphetamine.

Estrogen neuroprotection against the neurotoxic effects of ethanol withdrawal: potential mechanisms.

Ethanol withdrawal (EW) produces substantial neurotoxic effects, whereas estrogen is neuroprotective. Given observations that both human and nonhuman female subjects often show less impairment following EW, it is reasonable to hypothesize that estrogens may protect females from the neurotoxic effects of ethanol. This article is based on the assumption that the behavioral deficits seen following EW are produced in part by neuronal death triggered by oxidative insults produced by EW. The EW leads to activation of protein kinase C, especially PKCepsilon, which subsequently triggers apoptotic downstream events such as phosphorylation of nuclear factor-kappaB (NFkappaB) complex. On phosphorylation, active NFkappaB translocates to the nucleus, binds to DNA, and activates caspases, which trigger DNA fragmentation and apoptosis. In contrast, estrogens are antioxidant, inhibit overexpression of PKCepsilon, and suppress expression of NFkappaB and caspases. Estrogen treatment reduces the behavioral deficits seen during EW and attenuates molecular signals of apoptosis. The effects of ethanol and estrogen on each step in the signaling cascade from ethanol exposure to apoptosis are reviewed, and potential mechanisms by which estrogen could produce neuronal protection against the neurotoxicity produced by EW are identified. These studies serve as a guide for continuing research into the mechanisms of the neuroprotective effects of estrogen during EW and for the development of potential estrogen-based treatments for male and female alcoholics.

Effects of calcium channel blockers on pentylenetetrazol drug discrimination in rats.

The effects of the dihydropyridine L-type calcium channel blockers nitrendipine and nimodipine on the pentylenetetrazol (PTZ) drug discrimination, an operant model of anxiety, were investigated. Male Long-Evans rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline. Both nitrendipine (5.0-25 mg/kg, i.p.) and nimodipine (5.0-25 mg/kg, i.p.) partially substituted for the PTZ discriminative stimulus. However, pretreatment with nitrendipine (25 mg/kg, i.p.) or nimodipine (25 mg/kg, i.p.) produced no change in the PTZ dose-effect function. Rats were given a nutritionally balanced liquid diet containing 6.5% ethanol for 10 days. Rats selected the PTZ drug lever during withdrawal. Subchronic coadministration of nitrendipine (1.25-5.0 mg/kg, i.p., b.i.d.) with ethanol failed to dose-dependently reduce PTZ-lever responding, but it did reverse withdrawal signs. Acute administration of nitrendipine (5, 10, and 20 mg/kg, i.p.) produced marked suppression of lever responding, but it failed to significantly reduce levels of PTZ-lever responding. Although calcium channel blockers reduce signs of ethanol withdrawal, they also markedly reduce rates of behavior and produce no clear effects on anxiety-like behaviors induced by ethanol withdrawal.

Abecarnil and alprazolam reverse anxiety-like behaviors induced by ethanol withdrawal.

This study investigated the effects of a benzodiazepine partial agonist, abecarnil, and a full agonist, alprazolam, on ethanol withdrawal-induced anxiety-like behaviors in rats. Anxiety was assessed in two models: elevated plus maze and pentylenetetrazol (GABA(A) antagonist) discrimination assay. Male rats received an ethanol-containing (4.5%) liquid diet for 7 to 10 days and were tested for withdrawal symptoms 12 h after termination of the diet. In the elevated plus maze, ethanol-withdrawn rats displayed less open arm activity and total arm entries than pair-fed rats. Abecarnil (0.08-0.32 mg/kg, IP) and alprazolam (0.08-1.25 mg/kg, IP) each produced a dose-dependent, full reversal of ethanol withdrawal-induced reduction of open arm activity, but only alprazolam increased the total arm entries. In the pentylenetetrazol assay, ethanol-withdrawn rats selected the pentylenetetrazol lever (100%) over the salin-lever. Abecarnil (0.04-0.32 mg/kg, IP) and alprazolam (0.08-0.32 mg/kg, IP) dose dependently reduced pentylenetetrazol-lever responding to control levels (10-20%). Alprazolam was more potent than abecarnil in reversing ethanol withdrawal-induced decrease in open arm activities, but showed comparable potency and efficacy to abecarnil in blocking the pentylenetetrazol-like ethanol withdrawal stimulus. These results suggest that abecarnil and alprazolam may have therapeutic potential for treatment of ethanol withdrawal-induced anxiety-like symptoms.

Effects of ritanserin on ethanol withdrawal-induced anxiety in rats.

This study investigated the ability of ritanserin, a 5-HT2 antagonist, to modify ethanol withdrawal (EW) symptoms in two animal models of anxiety: the elevated plus-maze (EPM) and the pentylenetetrazol (PTZ) discrimination assay. Long-Evans hooded rats were given a nutritionally balanced liquid diet containing 4.5% ethanol for 10 days. Twelve hours after removal of the ethanol diet, rats were tested in the EPM. A significant reduction in the open-arm activity and the number of total arm entries was observed, which is indicative of EW. Acute ritanserin (0.16-0.64 mg/kg, i.p., 60 min) had no effect on EW-induced anxiety-like behavior on the EPM. Ritanserin (0.08-0.64 mg/kg, i.p., b.i.d. 12 h) administered concurrently with the last 5 days of ethanol diet produced an increase in the time spent on the open arms of the EPM and reversed the EW-induced reduction in total arm entries. Rats trained to discriminate between saline and PTZ (an anxiogenic drug), selected the PTZ lever during EW. Chronic ritanserin (0.32 mg/kg, i.p., b.i.d. ) did not block PTZ lever responding during EW. On the rotorod, ritanserin (0.32 mg/kg, i.p.) increased the motor incoordination induced by ethanol. In conclusion, coadministration of ritanserin with ethanol prevented the development of EW-induced anxiety as measured by the EPM, but not in the PTZ drug discrimination.

Sex differences in nicotine substitution to a pentylenetetrazol discriminative stimulus during ethanol withdrawal in rats.

RATIONALE: Nicotine and ethanol are frequently co-abused in men and women, but few studies compare common stimulus effects produced by these substances between males and females. OBJECTIVES: This study compared the anxiety-like behavior induced by nicotine prior to and during ethanol withdrawal in intact male, sham-operated female, and ovariectomized (OVX) rats. METHODS: Using an animal model of anxiety, the pentylenetetrazol (PTZ) drug-discrimination assay, rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline and were subjected to the following tests: (1) PTZ-lever selection at 12 h after termination of ethanol diet (4.5% for 10 days); (2) dose-response tests for nicotine (0.08-1.3 mg/kg) prior to ethanol and 1.5, 6, and 7 days after ethanol withdrawal. RESULTS: (1) During acute ethanol withdrawal (12 h), more male rats (43.4%) responded on the PTZ lever than OVX (29%) or sham female (15.3%) rats. (2) For nicotine dose-response tests, more male rats (70%) selected the PTZ lever than OVX (37.5%) or sham female (50%) rats prior to ethanol. At 1.5 days, nicotine fully generalized to the PTZ stimulus in male (100%) and OVX (90%), but only partially in sham female (50%) rats. At 6 days and 7 days after ethanol withdrawal, the PTZ-lever selection decreased, but more male rats (78%) tended to respond on a PTZ lever than OVX (63.6%) or sham female rats (62.5%). CONCLUSIONS: Acute nicotine produces anxiety-like behavior similar to that of PTZ in male and female rats, and this effect of nicotine is intensified during ethanol withdrawal in male and OVX rats, but not in sham female rats.

Sex differences in the discriminative stimulus effects of m-chlorophenylpiperazine and ethanol withdrawal.

RATIONALE: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. OBJECTIVES: This study examined sex differences in the anxiogenic stimuli induced by a serotonin (5-HT)(1b,2) agonist, meta-chlorophenylpiperazine (mCPP), prior to ethanol and during EW. METHODS: Gonadectomized or sham-operated adult male and female rats and 17beta-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0-1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. RESULTS: Fewer sham female and beta-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and beta-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. CONCLUSIONS: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and beta-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.

Effects of benzodiazepines on acute and chronic ethanol-induced nociception in rats.

BACKGROUND: Acute and chronic ethanol produces antinociception, and ethanol withdrawal induces hyperalgesia. METHODS: A radiant heat tail-flick assay was used to assess the effects of benzodiazepine ligands on ethanol-induced changes in nociception in rats. Acute activity of cumulative doses of ethanol (0.5-2.0 g/kg) and diazepam (0.1-10 mg/kg), a benzodiazepine agonist, was tested alone and after pretreatment with flumazenil (1.0-10 mg/kg), a benzodiazepine antagonist. Chronic effects of ethanol were tested in three groups of rats that received a liquid diet for 10 days. One group received ethanol alone; one group received ethanol and twice-daily injections of flumazenil (10 mg/kg); and one received a dextrin control diet. Acute withdrawal was tested at 12 hr after removal of the liquid diet. Effects of cumulative doses of diazepam (1.0-10 mg/kg) were tested during withdrawal (12 hr) in the ethanol-alone group. RESULTS: Acute doses of ethanol produced a small but significant degree of antinociception, which was fully suppressed by flumazenil. Acute doses of diazepam did not produce antinociception. Chronic exposure to ethanol produced antinociception on days 2 through 8. Tolerance developed by day 10, and hyperalgesia was seen 12 hr after removal of ethanol. Administration of diazepam or ethanol during withdrawal reversed the hyperalgesia induced by ethanol withdrawal. However, flumazenil (10-50 mg/kg) failed to reverse the antihyperalgesic effect of either diazepam or ethanol. No antinociception was seen in either the ethanol/flumazenil or dextrin control groups. CONCLUSIONS: These results suggest that the antinociceptive effects of both acute and chronic ethanol are at least partially mediated by GABA receptors, and that diazepam's antihyperalgesic effects may not be mediated by the GABA acid receptor.

Effects of NMDA antagonists on ethanol-withdrawal induced "anxiety" in the elevated plus maze.

The anxiolytic effects of NMDA antagonists during ethanol withdrawal were assessed in Long-Evans rats. Anxiety was measured by the elevated plus maze. Male rats were exposed to ethanol (6.5%) in a liquid diet for 10 days. Behavioral testing took place 12 h after withdrawal of ethanol. The competitive NMDA antagonists, AP-7 (0.02-0.32 mg/kg) and CGP-37849 (0.64-10 mg/kg), at least partially reversed the anxiety-like effects induced by withdrawal from ethanol. Both drugs produced a small increase in total arm entries, and a much larger increase in the percentage of open arm entries. AP-7, but not CGP-37849, also increased the percentage of open arm time. In contrast, the NMDA channel blocker, dizocilpine (MK-801; 0.08-0.32 mg/kg), produced only a small increase in the percentage of open arm entries and of open arm time. HA-966, a glycine-site antagonist, also failed to produce changes in ethanol withdrawal induced changes in anxiety at the doses tested. These results suggest that competitive NMDA antagonists may be useful for reduction of signs of anxiety during ethanol withdrawal.

Sex differences in the pentylenetetrazol-like stimulus induced by ethanol withdrawal.

This study investigated sex differences in responding to the pentylenetetrazol (PTZ, a gamma-aminobutyric acid A antagonist) discriminative stimulus and to substitution to PTZ during ethanol withdrawal. The PTZ stimulus has served as an anxiogenic stimulus in numerous studies. Adult male and female rats were trained to discriminate PTZ (16 mg/kg i.p.) from saline in a two-lever food-reinforced task. They were then gonadectomized or sham-operated. Ovariectomized (OVX) rats were also tested during 17beta-estradiol (2.5 mg, 21 days release, s.c.) replacement. The PTZ dose response (0-16 mg/kg i.p.) was tested in all groups. In general, fewer females than males responded to PTZ. Diazepam (DZP; 0-10 mg/kg i.p.) injected before PTZ (16 mg/kg) decreased the number of rats selecting the PTZ lever. This effect was greater in sham female and estradiol-replaced-OVX rats than in male or OVX rats. Rats then received chronic ethanol diet (6.5%) for 10 days. During ethanol withdrawal (12 h after termination of the ethanol diet), they were tested for PTZ lever selection. PTZ lever selection differed between groups: sham or castrated male rats > OVX > sham female or estradiol-replaced-OVX rats. In sham female rats, estradiol concentrations showed a cyclic pattern with an estradiol surge that did not influence their PTZ discrimination performance. After i.p. injection of ethanol (2 g/kg), blood ethanol concentrations were not different in male and female rats. These findings suggest that 1) female rats are less sensitive to the anxiogenic effects of PTZ; 2) female rats are less sensitive to the anxiogenic effects of ethanol withdrawal; and 3) estrogen plays some role in mediation of these sex differences.

The effects of adenosine ligands R-PIA and CPT on ethanol withdrawal.

The potential anxiogenic or anxiolytic effects of R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), an adenosine agonist, and 8-cyclopentyl-1,3,dimethylxanthine (CPT), an adenosine antagonist, were tested during chronic exposure to ethanol and to ethanol-induced withdrawal in rats. Effects on anxiety were measured by the elevated plus maze and dark-light box. Ethanol consumption and preference was tested in an additional experiment. In testing of elevated plus maze performance during withdrawal from ethanol, R-PIA produced no change in the anxiety-related behaviors of total arm entries and percent open arm entries, but produced a significant decrease in percent open arm time. CPT produced at least partial recovery from the anxiogenic effects of ethanol withdrawal on all three measures of elevated plus maze performance, although peak effects were seen at the intermediate dose of CPT (0.08 mg/kg) for total arm entries and percent open arm time. CPT also showed anxiolytic effects at low to intermediate doses (0.04, 0.08 mg/kg) in the dark-light box. CPT did not reduce the preference for ethanol over water or the total consumption of ethanol over a range of ethanol doses. In summary, the adenosine agonist, R-PIA, exacerbated the effects of ethanol withdrawal, whereas the adenosine antagonist, CPT, at least partially blocked the anxiogenic effects produced by ethanol withdrawal. These results suggest that adenosine antagonists, at least at some doses, may be useful for ameliorating the anxiogenic effects produced by ethanol withdrawal, although it does not appear useful for reducing consumption.

Effects of ethanol and ethanol withdrawal on nociception in rats.

The effect of acute and chronic administration of ethanol and ethanol withdrawal on a radiant heat tail-flick assay of nociception was examined in rats. Acute administration of ethanol (2.0 g/kg, i.p.) produced peak antinociception (68% of maximum) by 30 min, and effects were gone by 120 min. Cumulative doses of ethanol (0.5-2.0 g/kg, i.p.) produced dose-dependent increases in latencies to 49% of maximum. During chronic administration, a liquid diet containing ethanol (6.5%) was given for 10 days. Tail-flick latencies were measured on day 0 (baseline), day 2, 4, 6, 8, and 10 of chronic ethanol and at 3, 6, 12, and 36 hr after removal of ethanol. To test for behavioral tolerance, both between- and within-group designs were used. In both between- and within-group experiments, the antinociceptive effects of chronic ethanol peaked by day 4 of exposure to the liquid diet, and tolerance developed by day 10. When the liquid diet was removed, hyperalgesia was detected at 6 and 12 hr after withdrawal, and was gone by 36 hr after withdrawal. When cumulative doses of ethanol (0.5-2.0 g/kg) were administered starting 12 hr after withdrawal, ethanol (0.5 g/kg) fully reversed the hyperalgesia induced by ethanol withdrawal, even though this dose was without antinociceptive effect in the absence of withdrawal. Higher doses of ethanol during ethanol withdrawal did not increase tail-flick latencies over baseline. In summary: (1) ethanol produces antinociception when administered acutely or chronically; (2) tolerance to the antinociceptive effects develops during chronic administration; (3) ethanol withdrawal induced hyperalgesia, which was reversed by ethanol; and (4) repeated testing did not produce behavioral tolerance.

Antinociceptive effects of cocaine in rhesus monkeys.

The antinociceptive effects of (-)cocaine, (+)cocaine, and cocaine methiodide administered alone and in combination with the mu-opioid agonist morphine were evaluated in rhesus monkeys. The shaved tails of four rhesus monkeys were exposed to warm water (42, 46, 50, and 54 degrees C), and tail-withdrawal latencies (20-s maximum) from each temperature were determined. (-)Cocaine (0.032-1.8 mg/kg, s.c.) produced dose-dependent antinociceptive effects and enhanced the antinociceptive effects of morphine. Neither (+)cocaine nor cocaine methiodide (0.1-10 mg/kg, s.c.) produced antinociception or altered the effects of morphine. Pretreatment with the serotonin receptor antagonist mianserin (0.1-04).32 mg/kg, i.m.) produced dose-dependent rightward shifts in the dose-effect curve for (-)cocaine alone, and attenuated (-)cocaine-induced enhancement of the antinociceptive effects of morphine. However, mianserin (0.32 mg/kg, i.m.) did not alter the antinociceptive effects of morphine alone. These results suggest that in rhesus monkeys, the effects of cocaine on nociception may be stereoselective and centrally mediated. These findings further suggest that the antinociceptive effects of cocaine in primates may be mediated at least in part by cocaine's effects on serotonergic systems.

Training and characterization of a quinine taste discrimination in rhesus monkeys.

There is a limited amount of information available about taste as a discriminative stimulus in non-human primates. The objective of this study was to establish a bitter taste (quinine sulfate) as a cue for lever selection and food reward in rhesus monkeys. Training took place in a series of steps that culminated in a schedule in which five lip contacts on a spout produced either quinine solution or water, followed by an opportunity to earn a food pellet by completing 20 presses on one of two levers. Responses on one of the levers resulted in food delivery if the solution contained quinine; responses on the other lever resulted in food delivery if the solution was water. A single session consisted of 100 randomly ordered taste trials with a 60-s interval between each trial. All of the animals acquired the discrimination, and the lowest quinine concentration that maintained consistent behavior was 0.3 mg/ml. To assess the specificity of the discrimination, compounds from other human taste categories were tested. A series of compounds that are detected as "bitter" by humans (caffeine, 1.5x10(-3) M; strychnine, 9x10(-4) M; PTC, 6x10(-5) M, denatonium benzoate, 2.24x10(-4) M; and urea, 3.0x10(-1) M) produced full generalization to the quinine sulfate discriminative stimulus, while "sweet" (sucrose, 2.9x10(-2) M) and "salty" (sodium chloride, 1.4 M) stimuli did not. There was individual variation among animals in response to "sour" compounds; acetic acid did not generalize to quinine, but HCl acid produced full generalization in one of three animals. These results suggest that a "bitter" taste cue is controlling the quinine discrimination.

Pharmacological treatment of alcoholism.

1. Pharmacological treatments are effective as part of a treatment plan that includes substantial education, psychological therapy and social support. This paper reviews recent literature on animal models of and treatment for alcohol abuse under seven categories: agents to block craving or reduce alcohol intake, agents to induce aversion to alcohol, agents to treat acute alcohol withdrawal, agents to treat protracted alcohol withdrawal, agents to diminish drinking by treating associated psychiatric pathology, agents to decrease drinking by treating associated drug abuse, and agents to induce sobriety in intoxicated individuals. 2. The benzodiazepines provide safe and effective treatment for detoxification, although current research focuses on finding drugs with a smaller likelihood of dependence. As yet, there are no drugs that effectively reverse the intoxicating effects of alcohol. 3. Currently, only two major groups of drugs that are relatively safe have shown any effect at reducing alcohol consumption: aversives such as disulfiram, and opioid antagonists such as naltrexone. 4. Finally, it is important to customize therapy for each patient rather than putting everyone through a standard treatment plan, especially in regards to the use of antidepressant or antipsychotic medications. Tailoring the program to the patient's needs dramatically improves the outcome of therapy and reduces the risk of adverse effects.

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.

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.

Effects of heroin/cocaine combinations in rats trained to discriminate heroin or cocaine from saline.

The effects of heroin and cocaine administered alone or in combination were examined in rats trained to discriminate either heroin (0.56 mg/kg i.p.; n = 6) or cocaine (5.6 mg/kg i.p.; n = 6) from saline. Heroin (0.032-1.8 mg/kg) substituted completely for the heroin training stimulus in all six heroin-trained rats, but failed to substitute for cocaine in any of the cocaine-trained rats. Cocaine (0.1-32 mg/kg) substituted completely for the cocaine training stimulus in all six cocaine-trained rats, and substituted for heroin in two of six heroin-trained rats. The opioid antagonist naltrexone (0.01-1.0 mg/kg) antagonized the discriminative stimulus effects of heroin, but naltrexone at doses up to 10 mg/kg had no effect on the discriminative stimulus effects of cocaine. The dopamine receptor antagonist flupenthixol (0.032-0.56 mg/kg) attenuated the discriminative stimulus effects of heroin and completely blocked the discriminative stimulus effects of cocaine. When heroin-cocaine combinations were administered to the heroin-trained rats, cocaine (1-5.6 mg/kg) did not significantly alter the mean heroin dose-effect curve. Similarly, in the cocaine-trained rats, heroin (0.1-0.56 mg/kg) did not significantly alter the mean cocaine dose-effect curve. These results suggest that combinations of heroin and cocaine usually produce discriminative stimulus effects similar to either heroin or cocaine alone.

Effects of mu opioid agonists alone and in combination with cocaine and D-amphetamine in rhesus monkeys trained to discriminate cocaine.

Psychomotor stimulants and mu opioid agonists are often used together by polydrug abusers, and it has been suggested that this form of polydrug abuse may result from the ability of stimulants and mu agonists to enhance each other's abuse-related effects. To investigate this possibility, the present study examined stimulant-opioid interactions in rhesus monkeys trained to discriminate cocaine. Specifically, the effects of the mu opioid agonists heroin, alfentanil, fentanyl, and morphine administered alone or in combination with cocaine or d-amphetamine were examined in five monkeys trained to discriminate 0.4 mg/kg cocaine (IM) from saline in a two-lever, food-reinforced drug discrimination procedure. When administered alone, the rapid onset mu agonists heroin (0.032-0.32 mg/kg) and alfentanil (0.01-0.1 mg/kg) substituted completely for cocaine in three of five monkeys but produced primarily saline-appropriate responding in the other two monkeys. The slower onset mu agonists fentanyl (0.0056-0.056 mg/kg) and morphine (0.56-10 mg/kg) substituted for cocaine in only one of five monkeys. When administered as pretreatments to cocaine, morphine and fentanyl increased levels of cocaine-appropriate responding produced by low doses of cocaine in some monkeys. Morphine pretreatment also increased levels of cocaine-appropriate responding produced by low doses of amphetamine in some monkeys. However, in other monkeys, morphine and fentanyl pretreatment did not alter the discriminative stimulus effects of cocaine or amphetamine. These results indicate that there are substantial individual difference in the effects of mu agonists in cocaine-discriminating rhesus monkeys. In some monkeys, mu agonists mimic or enhance the discriminative stimulus of cocaine, whereas in other monkeys, mu agonists neither mimic nor enhance the effects of stimulants.

Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys.

Cocaine, which non-selectively blocks the reuptake of the monoamines serotonin, dopamine and norepinephrine, produces weak antinociceptive effects and increases the antinociceptive effects of low- to intermediate-efficacy mu opioid agonists in rhesus monkeys. In the present study, the antinociceptive effects of more selective monoamine reuptake inhibitors administered alone and in combination with mu opioid agonists were evaluated in rhesus monkeys using a warm-water tail-withdrawal assay of thermal nociception. Like cocaine, the selective serotonin reuptake inhibitors clomipramine (0.01-3.2 mg/kg) and fluoxetine (0.1-10 mg/kg) produced weak antinociceptive effects. Pretreatment with the serotonin receptor antagonist mianserin (0.032-0.32 mg/kg) produced rightward and downward shifts in the clomipramine dose-effect curve, suggesting that the effects of clomipramine were mediated by serotonin receptors. Combination of clomipramine with the low efficacy mu agonist nalbuphine or the intermediate efficacy mu agonist morphine produced more antinociception than did the mu agonists alone. Fluoxetine also produced a small leftward shift in the morphine dose-effect curve. The selective norepinephrine reuptake inhibitors nisoxetine (0.1-10 mg/kg) and tomoxetine (0.1-10 mg/kg) and the selective dopamine reuptake inhibitors bupropion (0.032-3.2 mg/kg) and GBR 12909 (0.1-10 mg/kg) did not produce antinociception or increase antinociception induced by nalbuphine or morphine. In fact, GBR 12909 produced dose-dependent allodynia and reduced the maximal antinociceptive effects of morphine. These results suggest that inhibition of serotonin reuptake is sufficient to produce weak antinociceptive effects and enhance the antinociceptive effects of low efficacy mu opioid agonists. These results also suggest that the effects of cocaine on serotonin reuptake may contribute to cocaine's antinociceptive effects in rhesus monkeys.