Effect of naltrexone and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and saccharin intake in rats

Drug craving, the desire to re-experience the effects of a psychoactive substance, may be an important influence on drug-seeking and drug-taking behaviour. In rats, drug-seeking behaviour can be operationalized as conditioned anticipatory behaviour, evidenced by frequent visits to, and an increased time spent and distance travelled in, the drug administration area prior to the availability of the reinforcer. The effects of the opioid antagonist, naltrexone, and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and drinking-associated behaviour and fluid intake during the access phase were examined. Male Wistar rats were trained to consume 0.1% saccharin and water in a distinct environment in a free-choice limited-access procedure. Naltrexone (0.3, 1 mg/kg) decreased conditioned anticipatory behaviour and drinking-associated behaviour in the saccharin zone without affecting the corresponding behaviour in the water zone. Its derivatives had different effects. Nalmefene (0.1 mg/kg) increased drinking-associated behaviour but not conditioned anticipatory behaviour, whereas naltrindole (1, 2 mg/kg) modestly decreased conditioned anticipatory behaviour but not drinking-associated behaviour. Naltrexone (0.3, 1 mg/kg) and naltrindole (1, 2 mg/kg), but not nalmefene, selectively decreased saccharin intake. These findings suggest that the blockade of selective opioid receptors may differentially alter conditioned anticipatory behaviour, drinking-associated behaviour and consumption levels, and that these behaviours can be modified separately.     

Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens

The opiate antagonist naltrexone suppresses ethanol-reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms underlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activity in the nucleus accumbens (NAcc). Simultaneous measures of the effects of naltrexone on dialysate dopamine levels in the NAcc and on operant responding for oral ethanol were used. Male Wistar rats were trained to self-administer ethanol (10-15%, w/v) in 0.2% (w/v) saccharin during daily 30 min sessions and were surgically prepared for intracranial microdialysis. Experiments began after reliable self-administration was established. Rats were injected with naltrexone (0.25 mg/kg, s.c.) or saline and 10 min later were placed inside the operant chamber for a 20 min waiting period with no ethanol available, followed by 30 min of access to ethanol. A transient rise in dialysate dopamine levels was observed during the waiting period, and this effect was not altered by naltrexone. Ethanol self-administration reliably increased dopamine levels in controls. Naltrexone significantly suppressed ethanol self-administration and prevented ethanol-induced increases in dialysate dopamine levels. Subsequent dose-effect analyses established that the latter effect was not merely a function of reduced ethanol intake but that naltrexone attenuated the efficacy of ethanol to elevate dialysate dopamine levels. These results suggest that suppression of ethanol self-administration by opiate antagonists is the result of interference with dopamine-dependent aspects of ethanol reinforcement, although possible additional effects via nondopaminergic mechanisms cannot be eliminated as a factor in opiate antagonist-induced reduction of ethanol intake.     

Chronic cadmium exposure alters cocaine self-administration in adult male rats.

Adult male rats (Rattus norvegicus) were exposed to a water supply in the home cage containing 100 ppm cadmium chloride and sodium saccharin (.65% wt/vol; cadmium group) or water containing only the saccharin amendment (group control). On Day 65 of exposure, animals from each group received jugular catheter implants and were subsequently trained over the course of 15 daily 2-hr sessions to self-administer a .25 mg/kg/infusion of cocaine HCl under a fixed ratio 1 schedule. Immediately following acquisition training, the full dose-effect function was determined for all animals by using cocaine doses of .03, .06, .125, .25, .50, and 1.0 mg/kg. Cadmium-exposed animals executed more active (cocaine) lever responses during acquisition training but were not different from controls in depressing a pharmacologically inactive lever. For dose-effect testing, cadmium exposed animals exhibited greater self-administration than controls at the higher doses of cocaine, and there was evidence that the cocaine dose that produced maximum responding was higher in cadmium-exposed than control animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Correlates of change in depressive symptomatology among gay men with AIDS

The present experiment investigated the ability of the opiate receptor antagonist naltrexone to block the increased locomotion and rearing produced acutely by amphetamine as well as the sensitization of these responses produced when this drug is administered repeatedly. Rats in different groups received an injection of amphetamine (1.5 mg/kg, i.p.) or saline preceded 30 min earlier by an injection of naltrexone (0, 0.5, 1.0, 5.0 or 10.0 mg/kg, i.p.). Naltrexone dose-dependently reduced the rearing but had no effect on the locomotion produced by this dose of amphetamine. The locomotion and rearing observed following saline were not affected. This pattern of results was observed following each of six additional pairs of injections, one pair of injections given every third day. Once, soon (2-4 days) and once, long (9-12 days) after the last injection, all animals were injected with amphetamine (0.75 mg/kg, i.p.) in the absence of naltrexone (tests for sensitization). Animals having been pre-exposed to amphetamine preceded by naltrexone showed no evidence of sensitized rearing on either test, indicating that naltrexone blocked sensitization of this response to amphetamine. These animals, however, exhibited sensitized locomotion on both tests. These results suggest an important but complex role for dopamine-opioid interactions not only in the production of acute locomotor responding to amphetamine but also in the sensitization of locomotor responding when this drug is administered repeatedly. The present findings also suggest that amphetamine-induced rearing is more dependent than locomotion on neuronal mechanisms involving dopamine-opioid interactions.     

Chronic l-alpha acetylmethadol in rhesus monkeys: discriminative stimulus and other behavioral measures of dependence and withdrawal

This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.     

A history of postponing shock does not appear to alter the discriminative stimulus effects of cocaine

Previous research has shown that the rate of punished lever pressing of monkeys is typically decreased by cocaine administration. However, cocaine increases punished responding in monkeys with a history of responding maintained by the postponement of shock presentation. This raises the question of whether other behavioral effects of cocaine differ following a history of postponing shock. The present experiment examined whether a history of postponing shock alters the discriminative stimulus effects of cocaine. Three squirrel monkeys were trained to discriminate cocaine (0.56 mg/kg, intramuscular) from saline. Presses on the left lever produced food following saline injections whereas presses on the right lever were reinforced following administration of cocaine. Occasional test sessions were conducted in which cocaine (0.1-0.56 mg/kg), midazolam (0.03-0.56 mg/kg) or pentobarbital (0.3-5.6 mg/kg) was injected prior to the session and responding on either lever was reinforced. Discrimination training was discontinued during a second experimental phase in which responding was maintained by shock postponement. Pulling a chain postponed mild shocks for 25 s, whereas shocks occurred every 5 s in the absence of responding. Next, the drug discrimination dose-response curves were redetermined. The dose-response curves for all drugs before and after the shock postponement history were similar. This outcome suggests that the influence of a history of shock postponement is specific to punished responding.     

Ethanol Palatability and Consumption by High Ethanol-Drinking Rats: Manipulation of the Opioid System With Naltrexone.

Three experiments examined the effect of acute naltrexone treatment on both taste reactivity and consumption of ethanol in high ethanol-preferring rat lines: Alko Alcohol-Accepting (AA) rats (Experiments 1 and 2) and Alcohol-Preferring (P) rats (Experiment 3). A 3.0 mg/kg naltrexone dose was ineffective at altering ethanol palatability for either line, whereas 7.5 mg/kg was effective at reducing palatability of 10% ethanol for AA, but not P, rats, as reflected by both a decrease in ingestive responding and an increase in aversive responding. The effects of naltrexone on ethanol consumption were quite consistent: At both dosages, acute naltrexone treatment significantly decreased consumption of 10% ethanol. Termination of naltrexone resulted in an immediate increase in ethanol consumption to control levels. Results show that ethanol palatability and consumption can be dissociated in the rat and that the organization of opioidergic mechanisms that mediate ethanol responses may vary between rat lines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of the benzodiazepine inverse agonist RO19-4603 alone and in combination with the benzodiazepine receptor antagonists flumazenil, ZK 93426 and CGS 8216, on ethanol intake in alcohol-preferring (P) rats

The present study investigated dose dependence and time course effects of the benzodiazepine (BDZ) partial inverse agonist, RO19-4603 (0.005-0.30 mg/kg) alone, and in combination with the BDZ receptor antagonists flumazenil, ZK 93426, and CGS 8216 (20 mg/kg) in selectively bred alcohol-preferring (P) rats provided a two-bottle choice test between ethanol (EtOH) (10% v/v), and a palatable saccharin (0.0125% g/v) solution. A single dose of RO19-4603 as low as 0.009 mg/kg selectively reduced EtOH drinking during the initial 15 min of a 4 h access to 19-0% of control levels on day 1. The 0.08, 0.15 and 0.30 mg/kg doses of RO19-4603 significantly reduced total EtOH intake in the 4 h access period to 57-45% of controls on day 1. On day 2, no RO19-4603 injections were given; however, six of the seven doses of RO19-4603 (0.009, 0.02, 0.04, 0.08, 0.15, and 0.30 mg/kg) continued to reduce EtOH intake to 42-3% of control levels at the initial 15 min interval, while the 0.005, 0.009, 0.08, and 0.30 mg/kg doses reduced total 4 h EtOH intake to 60-42% of controls. Saccharin intake was either not altered by RO19-4603 or showed increases during the initial 15 min intervals and the total 4 h sessions on days 1 and 2. Food intake was also unaffected by RO19-4603. The CGS 8216, but neither flumazenil nor ZK 93426, reliably reversed the RO19-4603-induced suppression of EtOH intake on days 1 and 2. That certain BDZ inverse agonists can attenuate motivated behavior for EtOH reinforcement over a prolonged time course may provide a possible therapeutic approach to reducing EtOH consumption associated with alcoholism.     

Nalmefene causes greater hypothalamic-pituitary-adrenal axis activation than naloxone in normal volunteers: implications for the treatment of alcoholism

Among other actions, opioid antagonists modulate the control endogenous opioids exert on the hypothalamic-pituitary-adrenal (HPA) axis. Naloxone, nalmefene, and naltrexone are the opioid antagonists approved for use in man and are primarily mu-opioid selective. Naltrexone and nalmefene have been demonstrated to be useful in the treatment of alcoholism. Compared with naloxone, nalmefene has a longer half-life, is more potent at the mu-receptor, and has a higher affinity for kappa- and delta-opioid receptors. We conducted an inpatient study comparing the effects of 10 and 30 mg doses of intravenous naloxone and nalmefene in normal, nonsubstance nor alcohol-abusing, volunteers. Significant increases in ACTH and cortisol were observed after both antagonists, without an apparent dose-response relationship; however, both doses of nalmefene resulted in greater HPA axis activation than either dose of naloxone (ACTH: p <0.005). These results indicate that kappa- and delta-opioids may play important roles in the regulation of the HPA axis; nalmefene may be useful as both a probe to explore the HPA axis physiology and as a pharmacotherapeutic agent.     

Naltrexone's effects on reactivity to alcohol cues among alcoholic men.

The mechanisms of naltrexone's effects on urges to drink during abstinence are unclear. Naltrexone may suppress either urges to drink specifically or appetitive responses in general. The effects of naltrexone on cue reactivity to alcoholic and sweet nonalcoholic beverages were investigated. Alcohol-dependent men (N ?=?53) in treatment received naltrexone (50 mg) or placebo. Four hours later, they received baseline assessment, exposure to fruit juice, and exposure to their usual alcoholic beverage in 3-min trials. Naltrexone reduced urge to drink and self-reported attention to the alcohol cues, not at the initial exposure but after repeated exposures to alcohol cues. Naltrexone reduced negative affect across baseline and alcohol trials. No effects of naltrexone on responses to the nonalcoholic appetitive beverage cues were found, suggesting that general appetite suppression does not mediate the effects of naltrexone on urges. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain differences in reversal of conditional analgesia by opioid antagonists.

The ability of both naloxone and naltrexone to block conditional analgesia produced by shock associated contextual stimuli was determined using rats from three suppliers. Naltrexone (7 mg/kg) was equally effective in reversing analgesia on the formalin test in all rats tested. Naloxone (7 mg/kg) significantly affected analgesia in Long-Evans and Holtzman Sprague-Dawley rats but had no effect on Charles River (CD) Sprague-Dawley rats. Charles River rats also differed from the other groups in the amount of time spent freezing to apparatus cues. These results indicate that genetic factors and the choice of antagonists may complicate distinctions between opioid and nonopioid analgesia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of chlordiazepoxide and food deprivation on punished and unpunished responding maintained by food.

Twelve adult rats pressed a lever in daily 1-hr sessions on a modified Geller-Seifter conflict schedule to earn a 45-mg food pellet every 2 min on the average in one component and a pellet accompanied by an incremental footshock for every response in the other component (multiple variable-interval 2-min [food] fixed ratio (FR) 1 [food plus shock]). Body weight (M?=?322 g) and baseline responding were maintained by restricting postsession food to 1 hr. Chlordiazepoxide 25 mg/kg po raised shock-suppressed responding by 79% over baseline. Omitting postsession food for 5 days reduced mean body weight by 10% and raised variable interval (VI) responding by 137% but raised shock-suppressed responding by only 25%. Results suggest that the ability of conventional anxiolytics to raise shock-suppressed responding is therapeutic-class-specific and is not based on appetite enhancement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Establishing morphine and U-50,488H as discriminative stimuli in a three-choice assay with pigeons.

Pigeons were trained in a 3-choice assay to discriminate among injections of 5.6 mg/kg U-50,488H, 5.6 mg/kg morphine, and vehicle solution. In dose-response tests, subjects rarely responded on the U-50,488H-appropriate key when morphine was administered or on the morphine-appropriate key when they received U-50,488H. A high dose of naltrexone (1.0 mg/kg) completely blocked the morphine cue but failed to block completely the U-50,488H cue. In generalization tests, d-amphetamine primarily engendered saline-appropriate responding. Ethylketazocine produced mixed results, in that moderate doses produced responding on both the morphine- and U-50,488H-appropriate keys, but 3.2 mg/kg engendered primarily morphine-appropriate responding. These results demonstrate the feasibility, but not necessarily the value, of 3-choice discrimination procedures involving mu and kappa agonists and vehicle. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amphetamine-induced withdrawal responding: effects of repeated drug administration

The first purpose of this research was to assess withdrawal haloperidol-appropriate lever responding 24 h after a single administration of 0.35, 0.75, and 1.00 mg/kg amphetamine. Rats were trained to discriminate among 0.35 mg/kg amphetamine (AM), distilled water (DW), and 0.033 mg/kg haloperidol (HA) in a three-lever drug discrimination task. An increase in HA-appropriate lever responding occurred following the 1.00 mg/kg dose of AM but not after either of the lower doses. The second purpose was to determine the effect of repeated administration of 0.75 mg/kg AM. Two groups of animals were given five administrations of drug, one at an interdose interval (IDI) of 24 h and the other at an IDI of 48 h. Control animals were given injections of DW. Increased HA-appropriate lever responding occurred in both of the AM-treated groups. The magnitude of this effect tended to be less in the 48-h IDI group. Thus, even though HA-lever responding was not evident 24 h after a single administration of 0.75 mg/kg AM, it was produced by repeated administration of this dose, even at 48-h intervals.     

Discriminative stimulus effects on enadoline in pigeons

The discriminative stimulus effects of enadoline were characterized in pigeons responding under a fixed-ratio 20 schedule of food presentation and discriminating between intramuscular injections of the kappa opioid agonist enadoline and saline. Cumulative doses of enadoline dose-dependently increased drug-key responding with the training dose of enadoline (0.178 mg/kg) producing > or = 90% drug key responding (% DR). In time course studies, doses of enadoline larger than 0.32 mg/kg produced > or = 90% DR for more than 40 min. Naltrexone antagonized both the discriminative stimulus and the rate-decreasing effects of enadoline (pA2 = 6.79 and 6.73, respectively); in some pigeons, naltrexone produced an unsurmountable antagonism of the enadoline discriminative stimulus. Substitution tests using the kappa agonists U-50,488, spiradoline, U-69,593 and ethylketocyclazocine resulted in > or = 90% DR in most, but not all, pigeons; at larger doses, all compounds markedly decreased response rates. Up to rate-decreasing doses, nalorphine, dynorphin A(1-13) amide (DYN), nalbuphine, butorphanol, morphine and ketamine failed to occasion > or = 90% DR; nalbuphine, nalorphine, butorphanol, but not DYN, antagonized the discriminative stimulus and the rate-decreasing effects of enadoline. This study established stimulus control with enadoline in pigeons and results from substitution studies in these pigeons support the view that the enadoline discriminative stimulus is mediated by kappa opioid receptors; these results further demonstrate that nalbuphine and butorphanol have kappa antagonist actions in pigeons. The negative results obtained with DYN are in contrast to previous demonstrations of kappa agonist effects for DYN and might provide support for the hypothesized importance of nonopioid systems in the effects of this peptide.     

Effects of nalmefene, CG3703, tirilazad, or dopamine on cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and hemorrhage

Hemorrhage after traumatic brain injury (TBI) in cats produces significant decreases in cerebral oxygen delivery (DcereO2) and electroencephalographic (EEG) activity. To determine whether effective treatments for the separate insults of TBI and hemorrhagic shock would also prove effective after the clinically relevant combination of the two, we measured the effects of a kappa-opiate antagonist (nalmefene), an inhibitor of lipid peroxidation (tirilazad), a thyrotropin-releasing hormone analog (CG3703), a clinically useful pressor agent (dopamine) or a saline placebo on cerebral blood flow (CBF), and EEG activity after TBI and mild hemorrhagic hypotension. Cats (n = 40, 8 per group) were anesthetized with 1.6% isoflurane in N2O:O2 (70:30) and prepared for fluid-percussion TBI and microsphere measurements of CBF. Cats were randomized to receive nalmefene (1 mg/kg), tirilazad (5 mg/kg), CG3703 (2 mg/kg), dopamine (20 microg x kg(-1) x min[-1]) or a saline placebo (2 ml, 0.9% NaCl). Animals were injured (2.2 atm), hemorrhaged to 70% of preinjury blood volume, treated as just described and resuscitated with a volume of 10% hydroxyethyl starch equal to shed blood. CBF was determined and EEG activity recorded before injury, after hemorrhage, and 0, 60, and 120 min after resuscitation (R0, R60, and R120). CBF increased significantly after resuscitation (R0) in the nalmefene- and CG3703-treated groups. CBF did not differ significantly from baseline in any group at R60 or R120. DcereO2 was significantly less than baseline in the saline-, dopamine-, and tirilazad-treated groups at R60 and in the dopamine-, tirilazad-, and CG3703-treated groups at R120. EEG activity remained unchanged in the nalmefene-treated group but deteriorated significantly at R60 or R120 compared to baseline in the other groups. Nalmefene and CG3703 preserved the hyperemic response to hemodilution (otherwise antagonized by TBI), and nalmefene prevented the deterioration in DcereO2 and EEG activity that occurs after TBI and hemorrhage.     

Effects of d-amphetamine on responding of squirrel monkeys maintained under second-order schedules of food presentation, electric shock presentation or stimulus-shock termination

The effects of d-amphetamine (0.01-5.6 mg/kg i.m.) were studied on lever pressing of squirrel monkeys maintained under various second-order schedules by a visual stimulus (S) that, with separate monkeys, was occasionally paired with the presentation of either food, electric shock or with the termination of a stimulus in the presence of which shocks occurred. Under one condition, the first response after 5 min produced a 3-sec stimulus change and the fourth stimulus change was followed immediately by food delivery, electric shock presentation or by the termination of a stimulus in the presence of which shocks occurred [fixed-ratio (FR); fixed-interval (FI) [FR 4 (FI 5-min:S)]. The effects of d-amphetamine were also studied under the food- and shock-presentation schedules when food or shock occurred only once, at the end of each session, after completion of 53n 3-min fixed-intervals all of which ended with a brief stimulus change [FR 10 (FI 3-min : S)]. Under a third condition, each thirtieth response produced the 3-sec brief stimulus (FR 30 : S) and the first FR 30 completed after 5 min elapsed produced the stimulus followed by food or, with separate monkeys, electric shock [FI 5-min (FR 30:S)]. Low to intermediate doses of d-amphetamine (0.03-0.3 mg/kg) generally increased and higher doses (0.56-5.6 mg/kg) decreased responding under all conditions. The effects of d-amphetamine on responding maintained by brief stimuli under different types of second-order schedules are generally similar, regardless of the type of reinforcing event or particular second-order schedule.     

Experiences of 23 patients > or = 90 years of age treated with radiation therapy

Previous studies showed that the 5-HT2 receptor antagonist, amperozide, is somewhat more potent than the opiate antagonist, naltrexone, in reducing alcohol drinking in high alcohol-preferring (P) rats. The purpose of this study was to determine in the P rat whether the effect of either drug could be due, in part, to an alteration in gustatory function. In an unlimited, 24-h free choice paradigm, P rats were offered water simultaneously with either a highly palatable 0.1% saccharin solution or a 1:4 dilution of Nestlé Sweet Success chocolate drink. Throughout all phases of the study, the P rats always consumed significantly greater volumes of the chocolate drink than of the saccharin solution, i.e., 526 ml/kg vs. 181 ml/kg, respectively. Successive 12-day experimental periods consisted of three phases: a 4-day predrug control interval; 4 days of administration of saline control vehicle or either drug; and a final 4 day postdrug interval. In a counterbalance design, saline, amperozide (1.0 or 5.0 mg/kg) or naltrexone (2.5 or 5.0 mg/kg) was administered subcutaneously twice daily at 1600 and 2200 h for 4 days. Amperozide and naltrexone significantly reduced the drinking of chocolate in a dose-dependent manner. Conversely, only the two higher doses of amperozide and naltrexone decreased the intake of saccharin significantly. Thus, these findings suggest that different populations of central serotonin and opioid receptors concurrently underpin, in part, the preferences for both palatable and/or nutrient fluids. Finally, because both the opiate and 5-HT2A antagonists reduce the ingestion of saccharin and chocolate solutions differentially, it is apparent that preferences for alternative palatable fluids should be examined when candidate drugs are screened for suppressing alcohol drinking and ultimately the treatment of alcohol abuse.     

Assessment of agonist and antagonist effects of tramadol in opioid-dependent humans.

The subjective, behavioral, and physiologic effects of racemic tramadol, an analgesic with low abuse liability and dual mu-opioid agonist and monoamine reuptake actions, were evaluated in 2 clinical pharmacology studies in dependent opioid abusers. In the withdrawal precipitation study, participants (N = 8) were maintained on methadone 60 mg/day orally and challenged with intramuscular tramadol, hydromorphone, naloxone, and placebo 20 hr after methadone administration. In the withdrawal suppression study, participants (N = 6) were maintained on hydromorphone given orally 10 mg 4 times daily, and spontaneous opioid withdrawal was produced by withholding doses for 23 hr. During the experimentally induced withdrawal, oral tramadol, hydromorphone, naltrexone, and placebo were given. In both studies a comprehensive panel of participant-rated, observer-rated, and physiologic measures were collected. In both studies, naloxone and naltrexone significantly increased measures of opioid withdrawal, whereas tramadol showed no discernible antagonist effects. In contrast, tramadol's pattern of effects was more similar to that of hydromorphone and suggestive of mild opioid-agonist effects (withdrawal suppression), though not to a statistically significant degree. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)