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Director's Report to the National Advisory Council on Drug Abuse - September, 2005

Research Findings - Basic Behavioral Research

Learned Inhibition of Cocaine Seeking

It has long been known that cues predictive of drug administration, "conditioned excitors," acquire conditioned incentive value through classical conditioning. Such cues can serve to motivate drug-seeking behavior and they are one source of drug craving in human drug abusers. Treatments aimed at reducing the incentive value of conditioned excitors through the use of extinction procedures have proved only modestly successful in reducing drug seeking in animal models and craving in humans. Additional treatments with proven efficacy could be useful in reducing the motivation for drugs among drug addicts. Recently published research by NIDA grantee Stanley Weiss has described a conditioned inhibition procedure that offers some hope of eventually being translated into effective drug abuse treatments. "Conditioned inhibitors," unlike excitors, predict the absence (or unavailability) of drug. In Weiss' study, rats were trained to self-administer cocaine by pressing a lever in the presence of a tone or a clicking sound. Once rats were responding reliably, a light was introduced along with the tone, (or the click, in a counterbalanced design), and in the presence of the light/tone compound, responding did not result in cocaine administration. That is, the light was trained as a conditioned inhibitor since it signaled the absence of an otherwise expected injection of cocaine. To evaluate its ability to inhibit responding, the light was then presented during test sessions with the drug-paired auditory stimulus (e.g., click) that had previously been established as a conditioned excitor. Whereas the click occasioned vigorous responding when presented alone, the simultaneous presentation of the light attenuated responding in the presence of the click. Thus, the animals had learned that the light predicted the absence of an otherwise expected drug administration and withheld responding when it was presented. These results suggest that conditioned inhibitors might effectively neutralize the stimuli (conditioned excitors) that occasion drug seeking. Moreover, by suppressing stimulus-elicited drug craving, a conditioned inhibitor could attenuate drug seeking and avert relapse. Kearns, D.N., Weiss, S.J., Schindler, C.W., and Panlilio, L.V. Conditioned Inhibition of Cocaine Seeking in Rats. Journal of Experimental Psychology: Animal Behavior Processes, 31, pp. 247-253, 2005.

Inhibition of Dopaminergic and Serotonergic Reuptake During Gestation Has a Variety of Effects on Maternal Behavior in the Rat

Psychostimulants, antidepressants, anti-anxiety medications, and some antipsychotics all inhibit reuptake of one or more of the catecholmine neurotransmitters. Dr. Josephine Johns previously showed that gestational exposure to cocaine alters several aspects of maternal behavior and oxytocin levels in the rat, but it was not known whether this effect was mediated by cocaine-induced inhibition of catecholamine reuptake, or which neurotransmitters were involved. In this study, she systematically tested specific reuptake blockers of dopamine and serotonin during gestation, alone or in combination, to determine the effect of long-term reuptake inhibition on maternal behavior, postpartum aggression towards an intruder ("maternal aggression"), and oxytocin levels. Rat dams were treated throughout gestation with amfonelic acid, fluoxetine, or a combination of both at various doses, to investigate effects of reuptake inhibition of dopamine and serotonin systems, respectively. The more appetitive aspects of maternal behavior (nesting, licking, touching), and general activity of the dams, were increased by a low dose of amfonelic acid, a high dose of fluoxetine, or the high dose combination, more than other treatments. Maternal aggression was decreased by amfonelic acid and somewhat increased by fluoxetine. The results for crouching behavior were complex, but overall suggested both dopaminergic and serotonergic involvement. Dopamine uptake inhibition had a strong effect on hippocampal oxytocin levels, while receptor dynamics appeared to be more strongly affected by serotonin uptake inhibition. Dr. Johns is continuing her examination of oxytocin levels and receptor expression, which as recent studies suggest, may have a greater role in maternal care in humans than previously thought. Since pregnant women frequently take drugs (e.g. antidepressants, cocaine) that induce long-term reuptake inhibition of dopamine and/or serotonin, it is important to understand the effects of such drugs on behavior and biochemistry. The quantitative measures in this study indicate that long-term reuptake inhibition of dopamine or serotonin, or both, has specific and complex effects on different aspects of maternal behavior. The overall conclusion is that these treatments do not impair maternal behavior per se, but they alter it in a variety of ways that can further our understanding of alterations in human maternal behavior after perinatal exposure to drugs with the same mechanism of action. Johns, J.M., Joyner, P.W., McMurray, M.S., Elliott, D.L., Hofler, V.E., Middleton, C.L., Knupp, K., Greenhill, K.W., Lomas, L.M. and Walker, C.H. The Effects of Dopaminergic/serotonergic Reuptake Inhibition on Maternal Behavior, Maternal Aggression, and Oxytocin in the Rat. Pharmacology, Biochemistry and Behavior. July 1, 2005 [Epub ahead of print].

Repeated Exposure to the Abused Inhalant Toluene Alters GABAA and Glutamate Receptor Subunit Expression In Specific Brain Regions

Toluene is a commonly abused solvent found in many industrial and commercial products. The neurobiological effects of toluene remain unclear, but there is increasing evidence that many of them, like those of ethanol, are mediated by GABA and glutamate receptors. The purpose of a recent set of experiments by Dr. Steketee and his colleagues was to examine the effects of repeated toluene inhalation on the protein levels of specific subunits for GABAA, NMDA and AMPA receptors. Rats were exposed to toluene vapors (8000 ppm) or air for 10 days (30 min/day) in a protocol previously devised in Dr. Steketee's laboratory. Consistent with their previous findings, toluene exposure produced significant sedation and ataxia, mild body tremors, jerking of the legs, and nose twitching. They determined the levels of GABAA _1, NMDA NR1 and NR2B, and AMPA GluR1 and GluR2/3 receptor subunit levels in discrete brain regions. Toluene increased GABAA _1, NR1, NR2B and GluR2/3 subunits in the medial prefrontal cortex and decreased GABAA _1 and NR1 subunits in the substantia nigra compacta. It produced modest increases in GABAA _1 subunits in the striatum, as well as slight decreases in the ventral tegmental area. NR2B subunit levels were also slightly increased within the nucleus accumbens. These studies show that toluene differentially alters levels of specific GABAergic and glutamatergic receptor subunits in a regionally selective manner. The authors discuss the similarities and differences between their findings and those from studies on other drugs of abuse and alcohol. The neurobehavioral and pharmacological effects of toluene appear similar to those of classical CNS depressants such as ethanol, but regulation of the GABAA _1 subunit in this study was less widespread than that produced by ethanol. However, the pattern of changes in expression suggests that repeated toluene administration might regulate GABAA receptors to significantly alter dopaminergic transmission within brain areas important as neuroanatomical substrates for the effects of drugs of abuse. The authors also suggest that these toluene-induced changes in GABAA and glutamate receptor subunits might underlie the previously observed cross-sensitization to cocaine produced by toluene exposure. Williams, J.M., Stafford, D. and Steketee, J.D. Effects of Repeated Inhalation of Toluene on Ionotropic GABA A and Glutamate Receptor Subunit Levels in Rat Brain. Neurochemistry International, 46, pp. 1-10, 2005.

Conditioned Withdrawal From Nicotine Decreases Activity of Brain Reward Systems

Scripps Research Institute investigators studied intracranial self-stimulation thresholds in nicotine-dependent rats before and after they were presented with a light/tone conditioned stimulus and injected with the nicotinic receptor antagonist dihydro-beta-erythroidine (DhβE) on four consecutive days. On the test day, the rats were presented the conditioned stimulus but this time injected with saline. DbβE elevated reward thresholds, (indicated by increased self-stimulation thresholds) by steady increments on each successive conditioning day, suggesting a potentiation of the degree of nicotine withdrawal as the motivational significance increased. On the test day, by contrast, the reward thresholds were increased by the conditioned stimuli alone, providing the first evidence that conditioned nicotine withdrawal can occur following withdrawal-paired cues and suggesting that decreases in brain reward function may bring about a fundamental source of craving that continually contributes to the intransigence of smoking. Kenny, P.J. and Markou, A. Conditioned Nicotine Withdrawal Profoundly Decreases the Activity of Brain Reward Systems. The Journal of Neuroscience, 25(26), pp. 6208-6212, 2005.

Cigarette Smoking May Selectively Enhance Spatial Working Memory and Attentional Deficits in Schizophrenia

High rates of cigarette smoking (upwards of 90% by some estimates) among schizophrenic patients compared to the general population (approximately 23%) have long been recognized. A neuropsychological battery of tests was administered to 25 smokers with schizophrenia and an equal number of controls, all of whom met the criteria of smoking more than 15 cigarettes per day, expired breath levels of carbon monoxide more that 10 ppm, and plasma cotinine levels greater than 150 ng/mL. The tests were administered at smoking baseline, after overnight abstinence, and after smoking reinstatement across three test weeks during which the subjects were pretreated with the nonselective nicotinic receptor antagonist mecamylamine. Abstinence reduced scores on a continuous performance test in both groups, whereas visuospatial memory was impaired in the schizophrenic group only and this effect was reversed when smoking was once again allowed. The enhanced scores on the two tests in the schizophrenic group during reinstatement were blocked by mecamylamine. Results from these studies suggest an explanation for high rates of smoking among schizophrenics, and may contribute to strategies for developing pharmacotherapies to treat both cognitive deficits and nicotine dependence in schizophrenia. Sacco, K.A., Termine, A., Seyal, A., Dudas, M.M., Vessicchio, J.C., Krishman-Sarin, S., Jatlow, P.I., Wexler, B.E. and George, T.P. Effects of Cigarette Smoking on Spatial Working Memory and Attentional Deficits in Schizophrenia: Involvement of Nicotinic Receptor Mechanisms. Archives of General Psychiatry, 62, pp. 649-659, 2005.

Validity and Reliability of the Fagerstrom Test for Nicotine Dependence in PTSD Smokers

Rates of smoking among individuals with psychiatric conditions are greater than rates seen in the general population, yet little is known about the psychometric properties of commonly used nicotine dependence instruments among psychiatric smokers. This study examined the reliability, validity, and factor structure of the Fagerstrom Test for Nicotine Dependence (FTND) among psychiatric smokers. With respect to the validity analyses, the FTND was correlated at statistically significant levels with biological and psychological measures of dependence. Results revealed that the FTND had good test-retest reliability, convergent validity, and discriminant validity. A factor-analytic examination converged on a two-factor solution, reflecting two correlated but separate processes related to nicotine dependence. The psychometric profile of the FTND in this study was at least as good as that found in psychometric studies of the FTND with nonpsychiatric smokers, validating use of the FTND with this population. Buckley, T.C., Mozley, S.L., Holohan, D.R., Walsh, K., Beckham, J.C. and Kassel, J.D. A Psychometric Evaluation of the Fagerstrom Test for Nicotine Dependence in PTSD Smokers. Addictive Behaviors, 30(5), pp. 1029-1033, 2005.

Preclinical "Binge" Model of Inhalant Abuse for Studying Prenatal Exposure Effects

Dr. Scott Bowen at Wayne State University has developed a binge model for exposing animals to abused inhalants. In his static exposure chambers, animals receive high concentrations of solvents over relatively brief exposure periods, mimicking the typical pattern of solvent abuse in humans. Previous exposure paradigms have employed long-term, relatively low levels of inhalant treatment, but with this model, the investigator attempts to produce repeated and rapidly resolved high-peak blood solvent concentrations. Recently he has used this procedure to study the teratogenic impact of toluene exposure during gestational days eight through 20 in the rat. Solvent abuse in adolescent females of childbearing age is a concern because rates of first-time solvent use among young people between 18 and 25 rose 243% during the 1990s and toluene-related embryopathy and malformations have been reported, with high levels of exposure linked to gross morphological teratogenicity. Moreover, follow-up evaluations reveal developmental delays and language impairment, among other neurological pathologies, and retardation in physical growth. In the present study, timed-pregnant females were exposed twice per day for 15 min to either 8000 (L) or 12,000 (H) ppm toluene. There was also an "air-only" control group (C) that was placed in the chambers twice daily for an equal amount of time. Pups were assessed on measures of early neonatal growth, perinatal outcome, and neurobehavioral development. From whole litter assessments of reflex development, strength and motor coordination, the investigators note a greater number of weaker pups in the highest dose group on post-natal (PN) day 16 (i.e., close to half the animals from the H group were at or below the 25th percentile of the C group). There were also significant effects of solvent exposure on negative geotaxis, with longer latencies for both concentration groups on PN days 6-8. On PN1, H litters weighed significantly less than the other two groups. However, between PN12-21, H pups gained relatively more weight than control animals, showing "catch up" growth. The authors also observed a dose relationship for gross malformations, external soft tissue malformations, number of pups classified as "runts", and neonatal mortality: The percentage of litters affected by these three kinds of outcomes was 12.5, 29.4 and 52.9 for the CF, L and H exposure conditions, respectively. These differences were seen with similar maternal weights and maternal weight gains across the three groups. There were also no significant between group differences in total litter size or mean gestational length. It appears that this procedure, using high dose, binge exposure conditions, may better reproduce the key pharmacodynamic features of inhalant abuse in humans and provide a more valid characterization of toluene embryopathy than studies employing longer, lower dose exposure. Bowen, S.E., Batis, J.C., Mohammadi, M.H. and Hannigan, J.H. Abuse Pattern of Gestational Toluene Exposure and Early Postnatal Development in Rats. Neurotoxicology and Teratology, 27, pp. 105-116, 2005.

A Metabotropic Glutamate Receptor 5 Antagonist Suppresses Cocaine Intake, Subjective Effects and Relapse

Ionotropic glutamate receptors have been implicated in the behavioral effects of cocaine in animal studies. For example, these receptors are involved in cocaine self-administration, reinstatement of drug seeking, and behavioral sensitization. Recently, an important role for metabotropic glutamate receptors (mGluRs) has been identified, following reports that mice lacking the mGluR5 subtype do not self-administer cocaine; and that a selective mGluR5 antagonist (2-methyl-6(phenyethynyl)-pyridine or MPEP) attenuates cocaine self-administration at doses not affecting food reinforced operant behavior. While these observations suggest that MPEP may be acting as a functional cocaine antagonist, these prior studies have been conducted in rodent models. The present study by Dr. Roger Spealman and colleagues examined MPEP effects on squirrel monkeys responding for i.v. cocaine, and compared these effects with the NMDA antatongist, dizocilpine. Animals self-administered cocaine under a second-order schedule and were then withdrawn so that responses were no longer reinforced by i.v. cocaine. Once responding on the drug lever was extinguished (i.e., responding on the lever no longer produced cocaine injections), drug seeking was measured following a cocaine "priming" injection to reinstate the behavior. In a separate study, monkeys were trained to discriminate cocaine from saline by making responses on a drug- or saline-appropriate lever, after injection of either the drug or the vehicle. Other animals were observed following MPEP or dizocilpine to assess antagonist effects on a number of spontaneous behaviors including locomotion, object exploration, foraging, self-grooming, and vocalizations. The data show that pretreatment with either 0.1 to 1.0 mg/kg MPEP, or 0.003 to 0.03 mg/kg dizocilpine, to animals responding for 0.1 to 0.3 mg/kg cocaine, produced dose-related decreases in response rates. When MPEP pretreatment was tested before cocaine priming in animals extinguished from lever pressing, with either 0.3 or 1.0 mg/kg cocaine as the prime, both 0.3 and 1.0 mg/kg MPEP significantly attenuated reinstatement. However, higher doses of MPEP were required to reduce seeking primed with 1.0 mg/kg cocaine, suggesting that the cocaine-antagonist effects of this mGluR5 drug are surmountable. Surmountable antagonism was also observed for the attenuation of discriminative cue properties of cocaine, as MPEP produced an overall rightward shift in the cocaine dose-response function in this paradigm. In contrast, the NMDA antagonist had little effect on drug seeking in the test for reinstatement, and rather than blocking discriminative cue properties of cocaine, had either no effect or enhanced cocaine discrimination. Behavioral observations revealed that MPEP significantly reduced overall locomotion but was without effects on foraging, exploration or grooming, whereas dizocilpine had no behavioral effects except that it increased muscle resistance. As MPEP did not disrupt spontaneous behavior, and also did not disrupt operant responding in drug discrimination testing, this mGluR5 antagonist may be a promising candidate to explore for the treatment of cocaine addiction. Moreover, the observed differences between this antagonist and dizocilpine suggest that the observed antagonism is independent from MPEP's interaction with the glutamate NMDA receptor. Lee, B., Platt, D.M., Rowlett, J.K., Adewale, A. and Spealman, R.D. Attenuation of Behavioral Effects of Cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-methyl-6-(phenylethynyl)-pyridine in Squirrel Monkeys: Comparison with Dizocilpine. The Journal of Pharmacology and Experimental Therapeutics, 312, pp. 1232-1240, 2005.

Heavy Marijuana Smoking in Adolescents is Associated With Reduced Motivation

In A Laboratory Measure Of "Work" Dr. Scott Lane and his colleagues have developed a computer based "work" task that uses progressive ratio (PR) schedules of reinforcement with money, to assess motivation in the laboratory. In this procedure, subjects have the option of responding on the PR schedule, which increases number of responses required to receive monetary reward over sequential segments of the experimental session, or switching to a fixed time (FT) schedule that delivers money without a work requirement. However, the FT schedule delivers less money than the PR, so it is advantageous to continue to "work" on the PR schedule. Early session switching to the non-work, FT option is considered an indication of reduced motivation. Previously, these researchers have found that adults smoking marijuana in the laboratory show reduced motivation on this task. Until the present study, however, the task had not been used to assess motivation in adolescent subjects who may be especially vulnerable to the cognitive and motivational effects of THC. In this study, 14-18 years who regularly smoked marijuana (at least 4 days/wk) and met DSM-IV criteria for marijuana abuse or dependence (MJ+) were compared with a control group of 14-18 year olds who reported no current illicit drug use (MJ-). The dependent measures assessed were: largest PR completed in the increasing sequence of greater response requirements, and percent earnings from the non-work option. The data indicate that control subjects completed a larger average PR on both test days, and as expected, the MJ+ group derived proportionally more earnings from the FT option. Pearson correlation coefficients were calculated to examine the relationship between urinary cannabinoid levels and these behavioral measures. While there was no relationship between drug concentration and the largest PR completed, a significant correlation was detected between the biochemical measure and percent of earnings from the FT option. These findings are consistent with "amotivational" effects of marijuana as previously reported from this laboratory. However, the authors caution that other variables might have contributed to these behavioral differences (e.g., socio-demographic, past marijuana use by control subjects, attention, efficacy of the reinforcer, etc.). Lane, S.D., Cherek, D.R., Pietras, C.J. and Steinberg, J.L. Performance of Heavy Marijuana-smoking Adolescents on a Laboratory Measure of Motivation. Addictive Behaviors, 30, pp. 815-828, 2005.

Deficits in Memory Induced by the Cannabinoid _9-THC Can be Reversed by Treatment With a GABAA Antagonist

Recent studies in brain slices have indicated that one important effect of cannabinoids is to modulate the release of the inhibitory neurotransmitter GABA from neural terminals. Indeed, a large proportion of brain cannabinoid receptors (CB1 receptors) are located on GABAergic terminals, especially in brain areas that are important for learning and memory. Dr. Aaron Lichtman and his colleagues hypothesized that the memory disrupting effects of the exogenous cannabinoid _9-tetrahydrocannabinol (_9-THC) are mediated by its effect on GABA release. They tested this hypothesis by evaluating whether GABA antagonists would ameliorate the behavioral effects of _9-THC-induced deficits seen on two different tests of working memory in the mouse. That is, if _9-THC disrupts working memory by decreasing GABA release, then a GABA antagonist should counteract the disruption. The two memory tests they used were the Morris water maze task and an alternating T-mast task. The first of these requires spatial memory, whereas the second task relies on the animal remembering its previous action. The two tasks also differ in motivation (escape vs. hunger) and in the reinforcer provided (safety platform vs. food reward), and in several other respects. Thus, by using both tasks, the investigators were able to assess cognitive processes per se, and control, to some extent, for motoric or motivational factors. They found that the GABAA antagonist bicuculline completely reversed the deficits in the water maze task resulting from _9-THC treatment and also blocked the disruptive effects of _9-THC in the T-maze task. They also tested the GABAB antagonist CGP 36742 in the first task and found no effect. Furthermore, bicuculline did not reverse non-mnemonic effects of _9-THC, including analgesia, hypothermia, or catalepsy. These results support the hypothesis that activation of GABAA receptors plays a critical role in _9-THC-induced memory impairment and is the first demonstration that GABAA receptors appear to play a necessary role in _9-THC-induced memory impairment in whole animals. This study furthers our understanding of how cannabinoids modulate memory and could lead to improved strategies for treating cannabis-related disorders. Varvel, S.A, Anum, E., Niyuhire F., Wise L.E. and Lichtman, A. H. _9-THC-induced Cognitive Deficits in Mice are Reversed by the GABAA Antagonist Bicuculline. Psychopharmacology, 178, pp. 317-327, 2005.

Decreased Motivation to Obtain Cocaine Following Extended Access: Effects of Sex and Ovarian Hormones

As described in the September 2004 Director's Report to Council, Drs. Wendy Lynch and Jane Taylor reported sex differences in cocaine self-administration (1.5 mg/kg/infusion) under a 24-hour access procedure in which rats received four 10-min discrete trials per hour for seven days -- a procedure which produces escalation of cocaine intake in a binge-abstinence pattern. Drs. Lynch and Taylor found that compared to males, females self-administered more cocaine, self-administered for longer periods of time, and exhibited greater disruption in the diurnal control over cocaine intake. In an assessment of long-term changes in cocaine motivation, conducted following a 10-day forced abstinence period, females exhibited an increase in motivation for cocaine as measured by behavior under a progressive ratio schedule, whereas males did not. (Lynch, W.J. and Tavlor, J.R. Sex Differences in the Behavioral Effects of 24-hr Access to Cocaine Under a Discrete Trial Procedure. Neuropsychopharmacology, 29, pp. 943-951, 2004). In a recent follow-up study, these researchers examined more immediate changes in cocaine motivation by testing 1, 2, and 3 days following the 7-day discrete trial procedure. Whereas males showed no change in cocaine motivation over the three test days, as assessed by progressive ratio performance, females exhibited a marked reduction in motivation. By comparing ovariectomized females with and without estrogen replacement, the researchers found that estrogen modulated the motivation for cocaine. Taken together, these two studies indicate that at 1, 2, 3, and 10 days following seven days of high access to cocaine, males exhibit no change in cocaine motivation, whereas females exhibit a reduction at 1, 2, and 3 days, and an increase at 10 days. These outcomes, along with earlier research using variations of the 24-hr discrete trials procedure with only male rats, illustrate male-female differences in the development and time course of cocaine motivation during and following extended access to cocaine. These data add to a growing body of human and animal literature indicating sex differences in cocaine addiction. Lynch, W.J. and Taylor, J.R. Decreased Motivation Following Cocaine Self-administration Under Extended Access Conditions: Effects of Sex and Ovarian Hormones. Neuropsychopharmacology, 30, pp. 927-935, 2005.


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