National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse

May, 1997

Research Findings

Behavioral Research

Individual Differences in Drug Discrimination

To test the effects on operant food responding via discrimination and generalization of internal amphetamine cues on high versus low behavioral responders, several different operant pre-test screening methodologies for behavioral response to novelty/stress were used. Based on measures of activity, rats were grouped into high versus low responders. Both groups were then trained to discriminate amphetamine versus saline in a two lever procedure using food maintained responding. Following this training, amphetamine generalization tests were conducted across a range of doses. In the first of these two tests, the high responders to novelty were found to be more sensitive than the low responders to the bar-press suppressant effects of amphetamine. In the second generalization test, high responders were also more sensitive to the discriminative effects of amphetamine (i.e., lower median effective dose). These results are discussed in terms of identifying the processes common to the screens (e.g. stress and novelty). Bevins, R.A., Klebaur, J.E., and Bardo, M.T. Individual Differences in Response to Novelty, Amphetamine-Induced Activity and Drug Discrimination in Rats. Behavioral Pharmacology, In press.

Drug Combinations: Caffeine + Triazolam is not Caffeine + Buspiron

The drug discrimination paradigm has become a standard method by which many behaviorally active compounds are classified in animal research. Researchers from the University of Vermont adapted this procedure to humans to ask: Can the stimulus properties of caffeine, a methylxanthine CNS stimulant, be altered by the two chemically distinct anxiolytic compounds triazolam and buspiron? They found that triazolam given in combination with caffeine blocked the subject's ability to discriminate caffeine. By contrast, buspiron given in combination with caffeine had no effect on volunteers' ability to discriminate caffeine from placebo. These results demonstrate the utility of drug discrimination paradigms for studying the effects of drug combinations in humans. Furthermore, these results suggest triazolam and caffeine share a common neurosubstrate for detection of their stimulus properties that are distinct from the neurosubstrate associated with buspiron detection. Oliveto, A.H., et al. Behavioural Pharmacology, In press.

Neonatal Withdrawal Syndrome in Infants Exposed to Cocaine and Methadone

The effect of concomitant cocaine and methadone use on neonatal withdrawal was examined in 68 infants born to methadone-maintained mothers. Fifty-three (78%) of these mothers reported regular cocaine use during pregnancy and/or had positive urine screens. Methadone dose in the last weeks of pregnancy was positively correlated with withdrawal severity. Infants exposed to both cocaine and methadone had higher first withdrawal scores; however, cocaine-exposed infants did not require more medication for withdrawal management, nor were they more likely to show retarded growth in the uterus, prematurity, or early perinatal complications. These data do not support a common view among women in methadone maintenance that cocaine will either minimize their infant's methadone withdrawal or will decrease the length of hospitalization after birth. Such incorrect beliefs may be contributing to the high frequency of cocaine use in the present sample of women. Mayes, C., & Carroll, K.M. Substance Use and Misuse, 3, pp. 241-253, 1996.

False Feedback about Work Performance Reduces Methamphetamine Intake

Researchers at Columbia University tested whether research volunteers who are told that d amphetamine impairs research task performance and reduces monetary earnings would actually decrease their d-amphetamine self-administration in the laboratory. With no performance feedback, volunteers chose d-amphetamine over placebo 78% of the time, and increased amphetamine choices when they were given feedback that their performance had improved. By contrast, d-amphetamine self-administration decreased significantly to 25% when subjects were told that it impaired their performance on work tasks and resulted in reduced earnings. In reality, d-amphetamine had little effect on work task performance. With regard to subjective effects, d amphetamine significantly increased ratings of "Stimulated" and "Good Drug Effect" and significantly decreased ratings of "Tired" and "Sleepy." These results demonstrate that d amphetamine served as a reinforcer under conditions in which drug self-administration did not influence monetary earnings, but that d-amphetamine self-administration could be modified by feedback/monetary earnings. Thus, contingencies associated with performance have important implications for drug use in the workplace. Comer, S.D., Haney, M., Foltin, R.W., Fischman, M.W., Psychopharmacology, 127, pp. 39-46, 1996.

The Noradrenergic System May Not be Involved in Morphine Discriminative Effects

Since studies suggest that the noradrenergic system is involved in the analgesic effects of opioids and in physical signs of opioid withdrawal, is the noradrenergic system involved in the discriminative effects of morphine? First, a range of doses of morphine (0.3-10.0 mg/kg) produced dose-dependent increases in morphine-appropriate responding in rats without substantial decreases in response rate. In several experiments, neither the alpha 2 agonist clonidine (0.003 0.1 mg/kg), the alpha 1 antagonist prazosin (0.1-10.0 mg/kg), the alpha 2 antagonist yohimbine (0.1-10.0 mg/kg), the beta 2 agonist salbutamol (0.03-10.0 mg/kg), nor the beta antagonist propranolol (1.0-10.0 mg/kg) substituted for morphine nor altered the discriminative-stimulus effects of morphine when administered in combination. These data suggest that the noradrenergic system is not involved in the discriminative-stimulus effects of 5.6 mg/kg morphine in rats. Hughes, C.E., Habash, T., Dykstra, L.A., Picker, M.J. Pharmacol. Biochem. Behav. 53, pp.979-986, 1996.

Gender and Vulnerability Factors in Cigarette Abstinence

Dr. David Gilbert from Southern Illinois University is investigating the role of individual differences in physiological and psychological responses to smoking abstinence among females as they relate to individual differences in personality and nicotine dependence and comparing responses of this female sample to a recently collected all-male sample. Large individual differences in response to quitting have been found to correlate with personality, psychopathology, and nicotine dependence. Preliminary data indicate that neuroticism and depressive trait measures predict degree of smoking cessation induced negative affect and depressive state. These findings are consistent with the PI's hypothesis that individuals scoring high in trait depression and neuroticism smoke to self-medicate their temperamental disposition toward negative affect. The data, when complete, will lead to new knowledge that will have implications for how to individualize smoking cessation programs to maximize successful long-term abstinence.

Behavioral Methods for Cigarette Smoking Cessation

Dr. Maxine Stitzer at Johns Hopkins University conducted a study to understand the role of nicotine in the maintenance of cigarette smoking. Volunteers compared their own brand (mean nicotine yield = 1.07 mg; mean tar = 15.8 mg), a "light" cigarette (nicotine yield = 0.7 mg; tar = 10 mg), or a denicotinized cigarette (nicotine <0.1; tar = 10.8 mg) in random order on three separate days. Subjective ratings for the denicotinized and light cigarettes were comparable. They were rated as similar in strength and satisfaction (both were rated as lower than their own brand). Desire to smoke scores declined after smoking and rose gradually over the next 90 mins with similar profiles across the three cigarette types. The results suggest that acute subjective effects of smoking in experienced smokers may be determined more by tar and/or sensory characteristics than by nicotine levels. Pharmacology, Biochemistry and Behavior, In press.

Gender Differences in Psychiatric and Substance Use Comorbidity among Treatment-Seeking Opioid Abusers

Psychiatric and substance use comorbidity was assessed in 716 opioid abusers (47.2% women) seeking methadone maintenance during a 5-year period. Rates of co-occurring mental disorders and personality traits were compared by gender. Although rates of comorbidity were similar in women and men (47% vs 48%), women were less likely than men to have a DSM-III-R personality disorder (28.4% vs 40.5%) or an antisocial personality (15.4% vs 33.9%) but more likely to have a mood disorder (27.5 % vs 11.4%) and 7 times more likely to have a borderline personality (9.5% vs 1.3%). Although all patients had at least one substance use diagnosis beyond opioid dependence, most often cocaine dependence, women were less likely than men to have a life-time cannabis, alcohol, or hallucinogen disorder or a current cannabis (12.1% vs 19.8%) or alcohol dependence (19.5% vs 29.4%). Brooner, R.K., King, V.L., Kidorf, M., Schmidt, C.W., and Bigelow, G.E. Psychiatric and Substance Use Comorbidity Among Treatment-Seeking Opioid Abusers. Arch. Gen. Psychiatry, 54(1), pp. 71 80, 1997.

Contingent Reinforcement of Group Participation Versus Abstinence in a Methadone Maintenance Program

This study evaluated the relative efficacy of two strategies for reducing illicit substance use in a methadone maintenance setting: urinalysis-contingent reinforcement versus participation in Training in Interpersonal Problem Solving groups (TIPS), an 8 week manualized psychoeducational group designed to promote problem-solving skills. Three months after admission, 66 methadone patients were randomly assigned to either the Urinalysis contingent condition in which take-home medication doses were received based on drug free urines or to the psychoeducational group in which take-home medication doses were received based on group attendance. During the 24 week intervention period, the urinalysis-contingent group showed greater improvement in rates of abstinence from illicit drugs and better met criteria for clinical improvement than the psychoeducational group. It appears that reinforcement of the psychoeducational group attendance is not as effective for reducing illicit drug use among methadone maintenance patients as is urinalysis-contingent reinforcement. These findings support the efficacy of contingency interventions targeted specifically at the drug using behavior. Iguchi, M. et al., Journal of Experimental and Clinical Psychopharmacology, 4(3), pp. 315-321, 1996.

Reinforcing Operants Other Than Abstinence in Drug Abuse Treatment: An Effective Alternative for Reducing Drug Use

This study evaluated the efficacy of Treatment Plan Based Reinforcement (a task-oriented behavioral intervention) compared with a standard treatment control and a more traditional contingency management intervention in reinforcing the provision of drug-free urines. Following a six-week stabilization phase, 103 subjects in methadone maintenance treatment were randomly assigned to either the standard treatment control, the urinalysis-based reinforcement or the treatment plan reinforcement. The intervention period lasted 12 weeks. Participants in the Treatment Plan group earned vouchers for completing objectively defined and clearly verifiable treatment plan tasks and were not reinforced for the provision of drug-free urines. The vouchers had an exchange value of 50 cents and could only be redeemed for expenses related to treatment plan goals (maximum value, $15 per week). The Treatment Plan group earned more vouchers than the Urinalysis-Contingent group and the number of vouchers earned bore a direct relationship to the number of drug free urines submitted. Only the Treatment plan group demonstrated improvement in abstinence rates that were maintained after the intervention was discontinued. The results from this study suggest that reinforcement of clearly defined behavioral tasks targeted to treatment plan goals increases involvement in behaviors inconsistent with drug use among methadone maintenance patients. Iguchi, M. et al. Journal of Consulting and Clinical Psychology, In press.

The NIDA Collaborative Cocaine Treatment Study

Investigators recently reported on the prevalence and pretreatment psychiatric, drug use, and demographic correlates of DSM-III-R personality disorders in a sample of 289 cocaine dependent outpatients accepted into the pilot phase of a randomized, multisite, clinical trial comparing different psychotherapy and drug counseling treatments. Results showed that 48% of the patients had at least one personality disorder and 18% had two or more. Of those with a personality disorder, 65% had a cluster B disorder with antisocial and borderline personality disorders being the most common. Men were significantly more likely to be diagnosed with antisocial personality disorder than women. Patients with personality disorders were significantly more likely to receive an another Axis 1 diagnosis and to have more severe psychiatric symptoms. However, the groups did not differ on other measures of drug use severity or demographic variables. While the prognostic significance of these findings is yet to be determined, the results suggest that personality disorders are apt to play an important role in the treatment of cocaine dependence.

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