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.     

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)     

Zolpidem is differentiated from triazolam in humans using a three-response drug discrimination procedure

The discriminative stimulus effects of the imidazopyridine hypnotic zolpidem and the classic benzodiazepine hypnotic triazolam were examined in seven healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 20 mg/70 kg zolpidem, and 0.5 mg/70 kg triazolam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made 3.75 h after drug administration. Five out of seven subjects acquired the three-response discrimination. Analyses of standardized and unstructured self-report questionnaires revealed that zolpidem and triazolam produced different profiles of effects; zolpidem was associated with a number of negative somatic symptoms including nausea, blurred vision, visual images/hallucinations, and heavy limbs, whereas triazolam was associated with greater sedative effects. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for zolpidem, relative to triazolam, which is consistent with its somewhat distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure for detecting between-drug differences.     

The influence of caffeine on nicotine's discriminative stimulus, subjective, and reinforcing effects.

Caffeine may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining the association of coffee intake with smoking status. In this study, smokers were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0). Then, generalization of nicotine discrimination was tested, using both 2- and 3-choice ("novel" option) procedures, across a range of doses (0-20 μg/kg) following pretreatment with 0, 2.5, and 5.0 mg/kg caffeine p.o. Nicotine reinforcement was assessed after the end of generalization testing using a choice procedure. Caffeine pretreatment did not alter nicotine discrimination and self-administration. Caffeine and nicotine influenced some subjective and cardiovascular responses, but there were no interaction effects except for diastolic blood pressure. These results do not support the notion that caffeine acutely alters nicotine's discriminative stimulus, subjective, or reinforcing effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans

This study evaluated the effects of i.v. cocaine, hydromorphone and their combination, and assessed the ability of oral naltrexone, an opioid antagonist, to modulate these effects. Volunteers with cocaine and heroin abuse histories (n = 8) participated in this placebo-controlled, cross-over study while residing on a closed research unit. Daily treatment with capsules containing placebo or naltrexone in ascending doses (3.125, 12.5, 50 and 200 mg) were given for 7-day periods. In thrice weekly experimental sessions, cocaine, hydromorphone and their combination were given in random order. Drug doses were given in an ascending order 1 hr apart as follows: cocaine at 0,20 and 40 mg, hydromorphone at 0, 1.5 and 3.0 mg, and the combination of 0 and 0 mg, 20 mg cocaine and 1.5 mg hydromorphone and 40 mg cocaine and 3.0 mg hydromorphone. Hydromorphone and cocaine produced distinct pharmacodynamic profiles, and the combination produced effects similar to both drugs. In some cases, the magnitude of effects produced by the combination was greater than that produced by either drug alone. Naltrexone produced dose-related blockade of hydromorphone effects, but did not after any of the physiological or subjective effects of cocaine. All naltrexone doses partially attenuated the effects of the combination and this appeared to be attributable to selective opioid blockade. These data do not support the use of naltrexone as a treatment for cocaine abuse, but suggest it may be useful for treating patients with concurrent cocaine and heroin abuse.     

Effects of abused drugs on psychomotor performance.

Some abused drugs have been reported to alter performance on naturalistic tasks such as driving and also on laboratory tasks. The performance effects of several drug classes were examined using a repeated measures design. Eight volunteers were administered 2 doses of ethanol, marijuana, amphetamine, hydromorphone, pentobarbital, or placebo on separate days. The larger dose of each increased subjective drug strength; however, only ethanol and pentobarbital impaired performance on circular lights, digit symbol substitution, and serial math tasks. Both ethanol and pentobarbital impaired performance on card-sorting tasks; impairment was evident at lower doses as the cognitive load increased. Results illustrate differences among drugs in producing performance impairment at doses that cause subjective effects. Increasing cognitive requirements uncovered performance impairment at lower doses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Mycotic sinusitis

Previous drug discrimination studies have elucidated the importance of gamma-aminobutyric acidA (GABAA), N-methyl-D-aspartate (NMDA) glutamate, and serotonin (5-HT) receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice operant drug discrimination procedure in an attempt to determine if salient GABAergic effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate pentobarbital (10.0 mg/kg; intragastrically (i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Stimulus substitution tests were conducted following the administration of allopregnanolone (1.0-17.0 mg/kg; intraperitoneally (i.p.)), diazepam (0.1-7.3 mg/kg; i.p.), midazolam (0.0056-17.0 mg/kg; i.p.), dizocilpine (0.01-0.56 mg/kg; i.p.), phencyclidine (1.0-5.6 mg/kg; i.p.), CGS 12066B (3-30 mg/kg; i.p.), RU 24969 (0.1-5.6 mg/kg; i.p.) and morphine (1 or 3.0 mg/kg; i.p.). Within the group, allopregnanolone and midazolam completely substituted (> 80%), and diazepam partly substituted (67%) for the discriminative stimulus effects of pentobarbital. Dizocilpine and phencyclidine partly substituted (58 and 57%, respectively) for ethanol without substantial pentobarbital-appropriate responding. RU 24969, CGS 12066B and morphine did not result in complete substitution for either ethanol or pentobarbital, although RU 24969 resulted in partial (68%) pentobarbital substitution. The ability to train the present three-choice discrimination in rats indicates that the discriminative stimulus effects of 10.0 mg/kg pentobarbital were separable from those of 2.0 g/kg ethanol. The results suggest that the pharmacological effects of ethanol, which can control behavior, may seemingly be modified by training conditions (two-versus three-choice discrimination procedures), to the extent that a receptor system prominently linked to the behavioral activity of ethanol (i.e. GABAA) appears no longer to be involved in the interoceptive effects of the drug.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Continuous extrapleural intercostal nerve block for post thoracotomy analgesia in children

The influence of the nicotine antagonist dihydro-beta-erythroidine (DH beta E) was examined on various behavioural effects of nicotine in rats. Motor activity was recorded in photocell cages whereas discriminative stimulus effects were examined using two-lever drug discrimination procedures with a tandem schedule of food reinforcement (n = 8 throughout). DH beta E (0.1-3.2 mg/kg) failed to antagonise the decreases in motor activity that nicotine (0.4-0.6 mg/kg) produced in experimentally naive rats, whereas mecamylamine (1.5 mg/kg) completely blocked this effect of nicotine. DH beta E (0.1-3.2 mg/kg) antagonised the increases in motor activity that nicotine (0.4 mg/kg) produced in rats with extensive previous exposure to both nicotine and the photocell apparatus. In rats trained to discriminate either 0.1 or 0.4 mg/kg nicotine from saline, DH beta E (0.1-3.2 mg/kg) blocked the discriminative stimulus effect of nicotine. The block of the discriminative effect could be reversed by increasing the dose of nicotine; DH beta E (1.6 mg/kg) shifted the dose-response curve for nicotine discrimination to the right by a factor of 9.4. In addition, nicotine in doses of 0.32-0.64 mg/kg decreased the overall rate of lever pressing but DH beta E (1.6 mg/kg) did not influence the dose-response curve for this effect. Thus, DH beta E potently blocked the locomotor activating and discriminative stimulus effects of nicotine at doses that did not antagonise its locomotor depressant and operant response rate-reducing effects. This selective blockade supports the involvement of different subtypes of nicotinic receptor in the mediation of diverse behavioural effects. Furthermore, the rightward shift of the dose-response curve for nicotine discrimination suggested a competitive mode of action for DH beta E.     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Home visitors'' beliefs and practices regarding childhood injury prevention

Although the discriminative properties of cocaine have been examined extensively in rats, and to a lesser extent in other species, there are currently no reports on cocaine discrimination by mice. In one of our experiments, C57BL/6 (C57) mice acquired cocaine discrimination (10 mg/kg training dose) and exhibited dose responsive generalization to lower doses of the drug, which was similar to previous reports using rats. In addition, mazindol, a general monoamine uptake inhibitor similar to cocaine, and nomifensine, which is relatively specific for the dopamine transporter, substituted completely for cocaine, as described for rats. In contrast, there was little substitution evidenced by monoamine uptake inhibitors relatively specific for the norepinephrine transporter (nisoxetine) or for the serotonin transporter (fluoxetine), or by the local anesthetics procaine or lidocaine. In our second experiment, neither cocaine nor mazindol substituted for procaine in animals trained to discriminate the local anesthetic (100 mg/kg) although lidocaine substituted completely for the procaine cue. These experiments emphasize the importance of the dopamine transporter in mediating the discriminative stimulus effects of cocaine in C57 mice. The lack of cross generalization between cocaine and procaine suggests that the anesthetic properties of cocaine contribute little toward its discrimination by this mouse strain.     

Hazardous materials and work safety in veterinary practice. 1: Hazardous material definition and characterization, practice documentation and general rules for handling

The role of the nicotinic acetylcholine receptor (nAChR) in the discriminative and aversive stimulus effects of ethanol was studied in rats. In the operant drug discrimination procedure the rats were trained to discriminate between 1.0 g/kg ethanol and saline under the FR10 schedule of sweetened milk reinforcement. Neither the nAChR agonist, nicotine (0.1-0.6 mg/kg) nor the nAChR antagonist, mecamylamine (3.0-6.0 mg/kg) substituted for the ethanol stimulus. Moreover, mecamylamine (0.5-6.0 mg/kg) did not antagonise the ethanol stimulus. The cross-familiarisation conditioned taste aversion procedure was used as an alternative method to study stimulus resemblance between ethanol and nicotine. Six daily injections of nicotine (0.6 mg/kg) significantly decreased a subsequent ethanol-induced taste aversion conditioning. The aversive stimulus effects of ethanol were investigated with the conditioned taste aversion (CTA) paradigm. Mecamylamine (1.0-3.0 mg/kg) did not attenuate an ethanol-induced CTA. These results suggest that: (1) nAChRs are not primarily involved in the discriminative stimulus effects of ethanol when studied with the operant drug discrimination test; (2) nAChRs are not critically involved in the ethanol-induced CTA.     

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.     

High-dose transdermal nicotine and naltrexone: Effects on nicotine withdrawal, urges, smoking, and effects of smoking.

Although treatment with transdermal nicotine replacement (TNR) has improved smoking abstinence rates, higher doses of TNR could improve effects on urge to smoke, nicotine withdrawal, and reinforcement from smoking, and naltrexone might further reduce reinforcement and urges. A laboratory investigation with 134 smokers using a 3 × 2 parallel-group design evaluated the effects of TNR (42-mg, 21-mg, or 0-mg patch) as crossed with a single dose of naltrexone (50 mg) versus placebo on urge to smoke, withdrawal, and responses to an opportunity to smoke (intake, subjective effects) after 10 hr of deprivation. Urge and withdrawal were assessed both prior to and after cigarette cue exposure. Only 42 mg TNR, not 21 mg, prevented urge to smoke, heart rate change, and cue-elicited increase in withdrawal. Both 21 and 42 mg TNR blocked cue-elicited drop in heart rate and arterial pressure. Naltrexone reduced cue-elicited withdrawal symptoms but not urges to smoke or deprivation-induced withdrawal prior to cue exposure. Neither medication significantly affected carbon monoxide intake or subjective effects of smoking except that 42 mg TNR resulted in lower subjective physiological activation. No interaction effects were found, and no results differed by gender. Results suggest that starting smokers with 42 mg TNR may increase comfort during initial abstinence, but limited support is seen for naltrexone during smoking abstinence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of "unwanted" signals and d-amphetamine sulfate on observer responses.

The effects of unwanted signals and d-amphetamine sulfate on observer responses (OR) in a 2-hour vigilance task were studied. Scope observation was contingent on a lever press (OR). 8 different schedule of frequency and regularity of unwanted conditions were used involving 8 independent groups of 4 Ss each. The effects of oral ingestion of placebo and drug were also tested. Increasing the frequency and irregulants of unwanted signals without drugs markedly increased frequency and rate of OR. This effect was enhanced under placebo and drug. Variance due to individual differences lessened as reinforcement from unwanted signals and drugs increased. Hypotheses based on activation theory emphasizing arousal aspects of vigilance behavior were verified. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of age and ritalin dosage on the mother–child interactions of hyperactive children.

Observed interactions between mothers and 54 hyperactive children in 3 age groups (4 yrs to 5 yrs 11 mo, 6 yrs to 7 yrs 11 mo, and 8 yrs to 9 yrs 11 mo) during a drug–placebo evaluation of 2 daily dosages (0.3 and 1.0 mg/kg) of Ritalin (methylphenidate). Results indicate few age or drug effects on social interactions during free play; however, numerous age and drug effects were seen in the task period. With age, children increased their compliance and decreased their negative behavior, and their mothers decreased their levels of control and management. Both doses of methylphenidate increased child compliance equally, but only at the higher dose were significant drug effects found on mothers' behavior: Mothers decreased their control and negative behavior toward children during the high-dose condition. Drug effects on these interactions were not affected by children's ages. It is concluded that although the parent–child interactions of hyperactive children improve with age, methylphenidate produces further improvements in task-related interactions. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans

BACKGROUND: Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressive behavioral response. Although animal models of sensitization are well established, the phenomenon has been relatively little studied in humans. In a previous study, we reported enhanced responses following a second as compared to a first amphetamine dose in eye-blink rate and ratings of increased motor activity/energy, increased speech, and elevated mood in normal human volunteers. This current study extends those findings in a new sample of normal volunteers. METHODS: Eleven normal human volunteers were administered three single oral doses of d-amphetamine (0.25 mg/kg) at 48-hour intervals, alternating with matched placebo in a randomized, double-blind trial. Hourly behavioral ratings included eye-blink rate, symptoms (elevated mood, increased speech, increased motor activity/energy), and subjective drug effects. RESULTS: Eye-blink rate and increased motor activity/energy ratings progressively increased following each challenge with the third amphetamine dose response significantly greater than all other conditions 4 hours postadministration. Similar, although less pronounced, responses were observed for elevated mood and subjective drug effect. CONCLUSIONS: These results provide further evidence for sensitization of some amphetamine-induced behaviors in human subjects.     

The observing-response procedure: A novel method to study drug-associated conditioned reinforcement.

In this experiment, the observing-response procedure was adapted for use with drug self-administration. Rats' responding for oral ethanol was sometimes reinforced on a random-ratio schedule, whereas at other times it had no effect (i.e., extinction). Behavior producing stimuli associated with the otherwise unsignaled random-ratio and extinction periods (i.e., observing behavior) was acquired and maintained. In a vehicle control condition, both self-administration and observing behavior decreased, but observing decreased less rapidly proportionally to baseline than vehicle consumption. Thus, conditioned reinforcers may have persistent effects that are relatively independent of the current status of the primary reinforcer. The procedure allows long-term study of drug-associated conditioned reinforcement and provides independent indexes of the conditioned reinforcing and discriminative stimulus effects of drug stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)