Effects of oral cocaine on intravenous cocaine discrimination in humans.

This study was designed to evaluate the drug discrimination paradigm as a model for assessing the ability of potential agonist medications to block the effects of intravenous cocaine. Previous research has demonstrated that oral cocaine attenuated the subjective and physiological effects of intravenous cocaine injections, and in the absence of a known efficacious medication for cocaine use disorders, a proof-of-concept approach was used in which cocaine was acutely administered orally to block intravenous cocaine's discriminative-stimulus effects. During training, 11 cocaine-dependent participants were able to discriminate between intravenous saline and 20 mg/70 kg iv cocaine, and 8 of these participants completed the study. After training, participants ingested capsules containing either placebo or 300 mg/70 kg cocaine 60 min prior to the intravenous injection of different doses of cocaine during test sessions with no contingencies in place. Each cocaine dose was administered twice, once under each oral pretreatment condition. Training sessions were interspersed among the test sessions. Physiological and subjective effects were measured throughout each session. Oral cocaine moderately increased some of the subjective and physiological effects of the lower doses of intravenous cocaine, whereas effects at the higher doses were unaltered. Similar changes were seen for the discrimination results. Thus, although oral cocaine given acutely likely is not a viable treatment medication for cocaine dependence, the usefulness of the drug discrimination model in the evaluation of agonist treatment medications remains unclear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of acute pretreatment with high-dose memantine on the cardiovascular and behavioral effects of cocaine in humans.

This study examined the acute effects of pretreatment with high-dose memantine, an N-methyl-D-aspartate antagonist, on the effects of cocaine in humans. Six African American men completed this laboratory study, in which, following pretreatment with memantine (0 or 60 mg), they had 5 opportunities to smoke cocaine base (0, 12, 25, or 50 mg) or receive an alternative reinforcer ($5.00 merchandise voucher). Cocaine alone produced the well-documented dose-dependent increases in cardiovascular activity and ratings of positive mood. Maximal systolic blood pressure was elevated during memantine pretreatment days. Peak ratings of "I feel stimulated" and "I feel anxious" were also higher with memantine pretreatment. However, memantine pretreatment did not alter the choice to self-administer cocaine. These data suggest that memantine pretreatment may not be helpful in the treatment of cocaine dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Binge cocaine self-administration by humans: smoked cocaine

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.     

The effects of transnasal butorphanol on mood and psychomotor functioning in healthy volunteers

Transnasal butorphanol is effective in relieving migraine and postoperative pain. The extent to which this drug preparation impacts on cognitive and psychomotor performance, as well as mood, has not been examined. Accordingly, the cognitive and psychomotor, subjective, and physiological effects of two clinically relevant doses of transnasal butorphanol (1 and 2 mg) were compared to that of placebo, and a common analgesic drug combination given for pain relief in ambulatory settings, 600 mg of acetaminophen and 60 mg of codeine, in healthy volunteers (n = 10). The larger transnasal butorphanol dose impaired psychomotor performance for up to 2 h, and produced subjective effects for up to 3 h. The smaller dose had no psychomotor-impairing effects, but had subjective effects (including increased ratings of "sleepy"). All three active drug conditions including miosis. These laboratory results suggest that patients should use caution when using the 1-mg dose of transnasal butorphanol, and should curtail certain activities if they administer the 2-mg dose of transnasal butorphanol for analgesia.     

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

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

Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults.

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Given the purported role of the NMDA receptor in long-term potentiation, the primary purpose of the present study was to further understand the dose-related effects of ketamine on memory. The study was also designed to provide information about the relative effects of ketamine on memory versus nonmemory effects and to more fully characterize ketamine's overall pattern and time course of effects. Single intramuscular injections of ketamine (0.2 mg/kg, 0.4 mg/kg) were administered to 18 healthy adult volunteers using a double-blind, placebo-controlled, crossover design. Word lists were used to evaluate episodic memory (free recall, recognition memory, source memory) and metamemory. Working memory, time estimation, psychomotor performance, and subjective effects were assessed repeatedly for 5 hours after drug administration. Ketamine selectively impaired encoding (as measured by free recall) while sparing retrieval, working memory while sparing attention, and digit symbol substitution task speed while sparing accuracy. Ketamine did not significantly impair recognition or source memory, metamemory, or time estimation. There were no hallucinations or increases in mystical experiences with ketamine. Memory measures were less sensitive to ketamine effects than subjective or psychomotor measures. Subjective effects lasted longer than memory and most psychomotor impairments. Ketamine produces selective, transient, dose- and time-related effects. In conjunction with previous studies of drugs with different mechanisms of actions, the observed selectivity of effects enhances the understanding of the pharmacological mechanisms underlying memory, attention, psychomotor performance, and subjective experience. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans

Attenuation of hypothalamo-pituitary-adrenal (HPA) function in laboratory rodents has been found to reduce the reinforcing effects of cocaine. To examine whether attenuation of HPA function reduces the effects of cocaine in humans, one female and seven male 'crack' cocaine abusers were pretreated with three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocorticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked cocaine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induced cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH levels were more predictive of blood pressure changes than either cocaine or cortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results support a role for the HPA axis in the cardiovascular effects of cocaine, but do not support a role for the HPA axis in the subjective effects of cocaine. To the extent that self-administration can be predicted by subjective effects, these results further argue that the HPA axis does not play a critical role in cocaine self-administration by humans.     

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

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

Opioid discrimination in humans: discriminative and subjective effects of progressively lower training dose

The purpose of this study was to examine the extent of covariation of subjective and discriminative drug effects as the dose of the discriminated training drug was progressively lowered. Six adult male volunteers with histories of opioid abuse, who were not currently physically dependent, were trained to discriminate the mu-receptor agonist hydromorphone (20 mg, oral) from placebo in daily sessions. They received financial reinforcement for correct responses. The hydromorphone training dose was then progressively reduced (20, 14, 10, 7, 5, and 3.5 mg) while the discrimination reinforcement contingencies remained in effect. Measures of subjective and physiological effects were concurrently collected during each discrimination session. As the training dose decreased, discriminative performance was generally well maintained, although the percent of drug-appropriate responses to hydromorphone did decline from 98% to 75%. The magnitude of the subjective and physiological effects of hydromorphone also decreased as the training dose decreased. At the lowest training dose, there were no physiological effects and few subjective effects of hydromorphone statistically different from placebo, although discrimination behavior remained statistically significant at all doses. These data indicate covariation of subjective effects and discrimination performance and suggest that discrimination behavior may be more sensitive for differentiating among drug conditions than traditional subjective effects measures.     

The effects of venlafaxine on the subjective, reinforcing, and cardiovascular effects of cocaine in opioid-dependent and non-opioid-dependent humans.

The effects of maintenance on venlafaxine, which blocks both norepinephrine and serotonin reuptake, on the response to smoked cocaine (0, 12, 25, or 50 mg) in 7 opioid-free and 7 methadone-maintained cocaine abusers was examined during a 42-day study. Participants received venlafaxine (225 mg daily) and placebo as part of a double-blind crossover design. Cocaine significantly increased heart rate, blood pressure, cocaine choice, cocaine ratings, and ratings of positive subjective effects (e.g., "I feel high") in both groups. Venlafaxine significantly decreased the subjective effects of cocaine by 10-20% without affecting cocaine choice or cardiovascular response in both groups. Although the reduction in cocaine's effects was small, further studies using a longer venlafaxine maintenance period or a larger venlafaxine dose are warranted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine 'D2-like' receptor agonists in combination with cocaine: absence of interactive effects on locomotor activity

This study examined interactions between cocaine and drugs that act as direct agonists at subtypes of "D2-like" dopamine receptors. The drugs 7-OH-DPAT, quinpirole and RU24213 were studied alone and in combination with cocaine for their effects on locomotor activity in non-habituated mice. Locomotor activity was measured by photobeam crossings over 140 min. At the doses given (7-OH-DPAT: 0.006-6.4 mg/kg; quinpirole: 0.001-1 mg/kg; RU24213: 0.008-8 mg/kg) all three direct agonists dose-dependently reduced locomotor activity throughout the test, whereas cocaine (0.6-20 mg/kg) produced dose-related hyperactivity. Next, for each direct agonist, a series of doses was selected (up to threshold behaviourally-active doses) as pretreatments to a sub-maximally stimulant dose of cocaine (15 mg/kg). 7-OH-DPAT and quinpirole did not modulate the effects of cocaine; RU24213 produced, at best, a very modest attenuation of the effects of cocaine. Finally, a series of cocaine doses (below stimulant threshold) was given before a single dose of each direct agonist (the lowest dose to reduce activity significantly). Cocaine did not reliably alter the hypoactivity produced by any of the D2-like agonists. By demonstrating negligible interactions between cocaine and D2-like agonists, the results fail to demonstrate any necessary involvement of D2-like receptors in one of the behavioural effects of cocaine.     

Comparing the subjective, psychomotor and physiological effects of intravenous nalbuphine and morphine in healthy volunteers

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of nalbuphine in healthy non-drug abusing volunteers and to compare and contrast the effects of equianalgesic doses of nalbuphine and morphine. Subjects (12 males, 4 females) without histories of opiate dependence were injected in an upper extremity vein with 0, 2.5, 5.0 or 10 mg/70 kg nalbuphine, or with 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. The 10-mg doses of nalbuphine and morphine are considered equianalgesic and are doses commonly given for relief of postoperative pain. Subjective effects of nalbuphine included increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and the Lysergic Acid Diethylamide scale of the Addiction Research Center Inventory; increased adjective checklist ratings of "nodding," "numb" and "sweating"; increased visual analog scale ratings of "coasting or spaced out," "high" and "sleepy" and increased "feel drug effect" and drug-liking ratings. Ten milligrams of nalbuphine had subjective effects similar, and similar in magnitude, to those of 10 mg of morphine. Nalbuphine produced exophoria and impairment on the Digit Symbol Substitution Test in a dose-related fashion. Ten milligrams of morphine produced exophoria but did not affect performance on the Digit Symbol Substitution Test. Both nalbuphine and morphine induced miosis and decreases in respiration rate. The results of the present study demonstrate that 2.5 to 10 mg nalbuphine had orderly, dose-related effects on subjective, psychomotor and physiological variables. The results also indicate that 10 mg of nalbuphine produces a profile of subjective, psychomotor and physiological effects similar to that of an equianalgesic dose of morphine (10 mg). The similarity in profiles between drugs at this dose is consistent with both infrahuman studies, which suggests that nalbuphine is a mu agonist, and studies with nondependent opioid abusers, in which relatively low doses of nalbuphine (such as 10 mg) produce morphine-like effects.     

Intravenous cocaine discrimination in humans.

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20 mg/70 kg cocaine. During the first session, saline and cocaine injections were alternated twice, with each separated by 1 hr. The injections were identified by letter codes. During the next 3 sessions, 12 trials were conducted, with saline and cocaine administered 6 times each in pseudorandom order. Thirty minutes following each injection, participants were asked to identify the injection by letter code. Seven of the 10 learned the discrimination (at least 10 trials correct). To evaluate sensitivity, the investigators tested participants with different doses of cocaine in test sessions. In the next phase, methamphetamine (5 and 10 mg/70 kg) and pentobarbital (50 and 100 mg/70 kg) were given intravenously during test sessions to determine whether the discrimination exhibited pharmacological class selectivity. During the evaluation of sensitivity and selectivity, training sessions were interspersed. As dose of cocaine increased, the number of participants identifying the test dose as cocaine increased, demonstrating sensitivity. The higher doses of methamphetamine and pentobarbital substituted for cocaine. The physiological and subjective effects of cocaine and methamphetamine were stimulant-like and dose related. Pentobarbital produced no physiological changes but increased Visual Analog Scale ratings of Sedation, Good Drug Effect, and High. This failure to demonstrate pharmacological selectivity may be related to participants' learning a drug-vs.-no-drug discrimination, and thus it may be necessary to alter training procedures in future studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A comparison between low-magnitude voucher and buprenorphine medication contingencies in promoting abstinence from opioids and cocaine.

This study compared the relative efficacy of low-magnitude, contingent monetary vouchers, contingent buprenorphine medication, and standard counseling in promoting abstinence from illicit opioids and cocaine among opioid-dependent adults. Following an 8-week baseline period during which participants received buprenorphine maintenance treatment with no contingencies in place, 60 participants were randomly assigned to one of 3 treatment groups for 12 weeks: (a) Participants in the voucher group earned vouchers for each opioid- and cocaine-negative urine sample, in accordance with an escalating schedule. Continuous abstinence resulted in voucher earnings equivalent to a total of $269, which participants could exchange for material reinforcers of their choice. (b) Participants in the medication contingency group received half their scheduled buprenorphine dose for clinic attendance and the other half for remaining abstinent from opiates and cocaine. Thus, they received only half of their scheduled dose on submission of an opioid- and/or cocaine-positive urine sample. (c) Participants in standard treatment did not receive programmed consequences contingent on urinalysis results. All participants were maintained with buprenorphine according to a 3-times-per-week dosing regimen and participated in behavioral drug counseling. Retention rate did not significantly differ across the groups; however, participants in the medication contingency group achieved significantly more weeks of continuous abstinence from opiates and cocaine compared with participants in the voucher group (Ms = 5.95 and 2.90, respectively). Results suggest that the use of medication-based contingencies in combination with behavioral therapy in promoting drug abstinence may have clinical utility. Limitations of the study are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1–4 & Days 9–12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5–8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13–40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Abuse liability of flunitrazepam among methadone-maintained patients

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4mg caused euphoria-related effects as measured by increases in ARCI-MBG and "high" scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential.     

The dose-dependent effects of oral premedication with midazolam

OBJECTIVE: The aim of this study was to examine the psychological effects, well-being and side effects after various doses of oral midazolam medication. METHODS: After informed consent has been obtained and following the approval by the institutional ethical committee, 80 adult patients in the ASA physical status I and II were randomly assigned to one of five different premedication groups: 3.75, 7.5, 11.25, 15 mg midazolam, and placebo. The medication was given in a double-blind fashion 60 min before induction of general anaesthesia for various surgical procedures. At 3 definite stages (before premedication, 30 and 60 min after premedication), blood pressure, heart rate, transcutaneous oxygen saturation and respiratory rate were measured. Sedation and well-being were graded according to a 5-point scale, and the subjective anxiety level was assessed according a visual analogue scale (range 0-100 mm). Anterograde and retrograde amnesia were measured by recall of auditive and visual stimuli. Finally, patients were asked whether in case of future surgery they would prefer the same or a different medication. RESULTS: Demographic data were similar in all groups. There was no significant difference in respiratory rate, oxygen saturation, blood pressure or heart rate. Alertness declined only after 60 min in the groups treated with 7.5 mg and more midazolam. During the entire measurement period, anxiolysis was not different from placebo in any of the midazolam groups. In comparison to placebo, all midazolam groups showed a statistically significant and dose dependent anterograde amnesia for visual stimuli. Subjective well-being scores showed no differences between the groups. Only few side effects were seen following doses of 7.5 mg and higher, including ptosis, strabismus, diplopia, speech disorders, disorientation and vertigo. The majority of patients in all groups indicated a wish for the same medication in case of future anaesthesia for surgical interventions. CONCLUSIONS: Midazolam administered orally prior to surgical procedures showed marked interindividual variability. Sedation and amnesia were dose-dependent and were evaluated by the patients as acceptable. Anxiolysis was not significantly different from placebo. A dose of 7.5 mg midazolam showed the best relation between desirable and undesirable effects. Adequate attention given to the patient by the anaesthesiologist prior to surgery seems to be as important and beneficial as oral medication with midazolam.     

Cardiovascular and subjective effects of intravenous cocaine administration in humans

Nine volunteer subjects were tested with intravenously administered cocaine hydrochloride in doses ranging from 4 to 32 mg, as well as 10 mg of dextroamphetamine sulfate. Measures of cardiovascular and subjective effects were made. Generally parallel dose-effect functions were obtained for heart rate, blood pressure, Addiction Research Center Inventory scores, Profile of Mood Scales, and subject ratings. A substantial effect on each of these variables was recorded after 8 mg of cocaine. The increase continued and peaked at approximately 16 mg after which it usually leveled off. Ten milligrams of dextroamphetamine generally had an effect comparable to 8 to 16 mg of cocaine.     

Activation of CTP:phosphocholine cytidylyltransferase by hypochlorite-oxidized phosphatidylcholines

The acute psychomotor response and development of sensitization to amphetamine is attenuated if i.p. injections are given in the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore, when the environmental cues predicting i.p. injections are completely eliminated by using remotely activated i.v. injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if i.v. injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to i.v. cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated i.v. administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when i.v. administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration.     

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)