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National Institute on Drug Abuse

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

September, 2000

Research Findings

Behavioral Research

Environmental Context Modulates Midazolam's Behavioral Effect: Function of High Versus Low Serum Drug Concentration

Dr. John Falk and associates at Rutgers, The State University of New Jersey, have been examining the relationship between pharmacokinetic drug profiles on various behavioral assays and drug effects. With the benzodiazepine derivative midazolam, at any point in time the time course and intensity of effects on operant behavior correspond to the serum concentration of the drug. In the most recent study, under the direction of Dr. Chyan Lau, these investigators imposed delays between the administration of midazolam and the beginning of an operant test session. Some animals experienced the delay in their home cage and another group in the operant test chamber. For long delays (i.e., greater than 60-min), midazolam's effects were less disruptive if the delay was experience in the operant test chamber rather than the home cage. The researchers suggest that environmental manipulations or contextual effects may only be seen with low drug doses, (or, in this case, lower serum drug concentrations) and that at higher doses direct effects of the drug determine behavioral effects. Sun, L., Falk, J.L., Nguyen, K-N., and Lau, C.E. Behavioural Pharmacology, 11, pp. 133-142, 2000.

Active Versus Passive Drug Administration and the HPA Axis

Recent research has shown that the neurochemical and behavioral effects of cocaine depend upon whether the drug is self-administered, i.e. active administration, or delivered independently of responding, i.e. passive administration. For example, during withdrawal, both neurotransmitter levels and neurotransmitter turnover rates differ for active versus passive cocaine administration. Mortality is higher following passive delivery of cocaine. Research by R. Galici et. al. demonstrates for the first time that active and passively administered cocaine have differential effects on the physiological stress response as measured by plasma corticosterone levels. In the study conducted in the laboratory of Dr. Charles France at Louisiana State University, plasma corticosterone levels in rats were higher following active than following passive cocaine administration. Since cocaine self-administration has been shown by others to be potentiated by the activation of the HPA axis, these results suggest that the stress involved in the self-administration of a drug may contribute to the acquisition, maintenance and reinstatement of self-administration of that drug. Galici, R., Pechnick, R.N., Poland, R.E., and France, C.P. Eur. J. Neurol., 387, pp. 59-62, 2000.

Conditioned Taste Aversion to Morphine is Related to Corticosterone Response

Drugs of abuse such as the opiates and psychostimulants are readily self-administered in animal behavioral paradigms but also produce a conditioned taste aversion (CTA) suggesting that they may have aversive as well as reinforcing central effects. These self-administered drugs also activate endogenous stress systems through the hypothalamic pituitary axis (HPA) and there are data to indicate that activation enhances both the reinforcing and aversive properties of drugs of abuse. Dr. Felipe Gomez, in collaboration with Drs. Nicole Leo and Patricia Sue Grigson at Penn State College of Medicine, have noted that there are wide inter-subject differences in animals that acquire CTA when a unique taste/solution is paired with morphine. In this procedure, the investigators subsequently assess intake of a solution (saccharin) previously paired with morphine. Rats with similar baseline corticosterone were separated into two groups, one that showed a strong post-pairing (drug + saccharin) suppression of intake (or an avoidance of saccharin) and one that did not. Both groups received the same number of morphine administrations. Rats showing CTA had greater elevations of plasma corticosterone following saccharin exposure. The researchers suggest that this difference is related to the conditioning or learning process and that saccharin, as a 'conditioned stimulus' takes on the ability to elicit a drug-induced activation of the HPA. Gomez, F., Leo, N.A. and Grigson, P.S. Brain Research, 863, pp. 52-58, 2000.

Acute Dependence Revealed by Progressive Ratio Procedures with Intra-Cranial Self-Stimulation

Investigators in the laboratory of Dr. Stephen Holtzman at Emory University School of Medicine in Atlanta, Georgia have been studying physical dependence after acute opiate administration. This phenomenon can be demonstrated using sensitive behavioral baselines and the technique of precipitated withdrawal. Thus, rats responding for intra-cranial self-stimulation (ICSS) using an autotitration procedure to assess threshold for reward show a greater suppression of responding for ICSS if they had received naltrexone than if they had received an acute morphine administration. This is interpreted as reflecting a subjective dysphoria during the withdrawal state. A recent study was conducted to extend these findings to a progressive ratio (PR) procedure of ICSS wherein the number of responses an animal is willing to make in order to receive stimulation is taken as the dependent measure. This measure proved incredibly sensitive to detecting precipitated withdrawal, as the ED25 for decreasing response rate was 850-fold lower in animals that had received a prior acute morphine treatment. Interestingly, the investigators compared these findings to those for animals treated acutely with benzodiazepines (BZ) and then challenged with a BZ antagonist before the ICSS session. While other measures of operant behavior have revealed signs of precipitated withdrawal from BZs, none were seen using PR ICSS as an indicator. Dr. Holtzman and his colleagues infer that the processes underlying dependence with acute drug administration of these two drug classes may be fundamentally different. Easterling, K.W., Plovnick, R.M. and Holtzman, S.G. Psychopharmacology, 148, pp. 263-271, 2000.

Laboratory-Based Classical Conditioning of Stimuli Paired with Drugs

Drs. Richard Foltin and Margaret Haney of the New York State Psychiatric Institute and Columbia University have shown that neutral stimuli paired with the administration of smoked cocaine (CS+) versus the administration of a placebo (CS-) acquire emergent stimulus effects, including conditioned reinforcing effects. Eight experienced cocaine smokers were studied over 22 experimental sessions conducted while the subjects resided in a Clinical Research Center. The CS + and CS- were compound stimuli containing visual, olfactory and auditory elements. Pairing cocaine with the CS+ served to increase cocaine's heart rate-increasing effects and ratings of "anxious." Following training trials with CS+ and CS- seven of the eight subjects exhibited preference for the CS+ indicating that the CS+ had acquired conditioning reinforcing effects. During extinction in which the CS+ was presented without cocaine, there was an increase in heart rate, systolic pressure, and ratings of "anxious" and "tired" as well as an increase in craving ("I want cocaine") and a decrease in skin temperature. The CS- produced no behavioral or physiological effects either during training or extinction. This is the first laboratory-based study to show that neutral stimuli paired with the administration of smoked cocaine acquire emergent stimulus effects, including conditioned reinforcing effects. Foltin, R.W., and Haney, M. Conditioned Effects of Environmental Stimuli Paired with Smoked Cocaine in Humans. Psychopharmacology, 149, pp. 24-33, 2000.

Sex Differences in Language Production in 24-Month-Old Inner City Children Exposed In Utero to Cocaine

Researchers at the Yale Child Study Center compared the language abilities at age 24 months of 47 inner-city children exposed prenatally to cocaine with those of 30 inner-city children not exposed prenatally to cocaine. The sample was recruited prenatally. While both groups of children evidenced some delays in language development, the non-cocaine-exposed children produced more complex language, including longer utterances, a richer vocabulary, and more complex grammatical structure than the cocaine-exposed children were able to do. The effect, however, was largely in girls. Malakoff, M.E., Mayes, L.C., Schottenfeld, R., and Howell, S. Language Production in 24 Month Old Inner City Children Exposed In Utero to Cocaine. Journal of Applied Developmental Psychology, 20, pp. 159-180, 2000.

Contingent Versus Non-Contingent Cocaine, the HPA Axis, and Sex Differences

Researchers at the University of Michigan Medical School and at Washington University have shown in rhesus monkeys that cocaine-produced increases in cortisol and ACTH release are greater and more dose-dependent when the cocaine (0.01-, 0.03-, 0.1-, and 0.3-mg/kg/injection) is delivered response-contingently than when it is delivered non-contingently. Under both procedures, the cortisol response was higher in males than in females; there were no sex differences in the ACTH response. A single large dose infusion of cocaine (1 mg/kg) produced a substantially larger ACTH response in males than in females; there were no sex differences in the cortisol response to the large dose. Broadbear, J. H., Winger, W., Cicero, T., and Woods, J.H. Effect of Response Contingent and Non-contingent Cocaine Injection on Hypothalamic-Pituitary-Adrenal Activity in Rhesus Monkeys. Journal of Pharmacology and Experimental Therapeutics, 290, pp. 393-402, 1999.

Buprenorphine Blocks Mood and Other Effects of Opiates

One of the aims of medicating drug dependent patients with a mu opioid agonist or putting them on antagonist maintenance is to attenuate the effects of illicit opioids such as heroin. This study asked whether buprenorphine, as compared to naltrexone or placebo, attenuates opioid effects at the start and end of treatment. Opioid-experienced volunteers (n = eight) participated in this ten-week, inpatient, double blind, within subject, crossover study. Buprenorphine alone (2 and 8 mg, sublingually) produced dose-related typical agonist effects during induction (i.e., positive mood, respiratory depression, miosis); tolerance developed only to the subjective effects. Buprenorphine at 2 mg partially attenuated the effects of hydromorphone, while nearly complete attenuation was observed with buprenorphine at 8 mg and that lasted up to 72 hours after discontinuation. Naltrexone (25 and 100 mg, PO) produced complete hydromorphone blockade after a single dose. Five days after discontinuation of naltrexone at 100 mg, blockade of the behavioral but not the physiological effects persisted. These data suggest that buprenorphine at 2 mg is a sub-therapeutic maintenance dose; both buprenorphine at 8 mg and naltrexone at 100 mg produce an immediate and efficacious opioid blockade; and adequate protection against illicit opioids may be achieved with less-than-daily dosing. Schuh, K.J., Walsh, S.L., Stitzer, M.L. Psychopharmacology, 145, pp.162-74, 1999.

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