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Director's Report to the National Advisory Council on Drug Abuse - September, 2002

Research Findings - Behavioral Research

Research Implicates the Basolateral Amygdala (BLA) in Heroin Relapse

Researchers at the Medical University of South Carolina discovered that similar to cocaine relapse, stimuli (i.e., environmental cues) paired with heroin infusions can induce drug abuse relapse in a rodent model. In this experiment, rats were trained to press a lever to deliver intravenous heroin infusions. The heroin infusions were also paired with a change in the environment. That is, heroin infusions were paired with the presentation of a tone and a light stimulus. After rats learned to press the lever to receive heroin infusions, they were put under an "extinction" phase in which lever pressing resulted in the delivery of saline and not heroin. During this "extinction" phase responding on the lever decreased. Later, when rats were exposed to the tone and light stimuli previously paired with heroin they began to press the lever to infuse heroin, although heroin was not actually available. This phenomenon is referred to as "cue-induced" relapse. Similarly, if rats were administered a small "priming" dose of heroin following the "extinction" phase they also began to press the lever for heroin. This phenomenon is referred to "drug-induced relapse." The researchers further showed that the BLA was an important brain region for both drug- and cue-induced relapse in animals trained to self-administer this opiate drug. The BLA has previously been shown to be important for learning and in motivated behavior. These researchers showed when they inactivated this brain region temporarily with tetrodotoxin neither the cues nor the drug itself induced relapse after heroin rewarded responding had been extinguished. In the past, this same group of researchers has shown that cocaine itself does induce relapse if the BLA is inactivated. These results suggest that the BLA is an important component of the neural circuitry that underlies cue- and heroin-induced relapse. Furthermore these results suggest that different neural circuits may be critical for cocaine-induced relapse relative to heroin-induced relapse. Fuchs, R.A. and See, R.E. Psychopharmacology, 160, pp. 425-433, 2002.

Neurobiological Stress Systems Play a Role in Relapse Triggered by Drug-related Environmental Cues

Dr. Nicholas Goeders and his colleagues at the Louisiana State University Health Sciences Center in Shreveport, LA, have been studying the role of central stress systems (specifically, the hypothalamo-pituitary-adrenal axis) in drug abuse and addiction. He employs an animal model of drug self-administration with cocaine and has previously reported that corticosterone (CORT) is crucial for acquisition, and is involved in continued drug taking during maintenance. Also, the CORT synthesis inhibitor, ketoconazole, reduces 'reinstatement' to drug-seeking behavior. In the reinstatement paradigm, animals are trained to self-administer drug, and then put into extinction where their responses produce no consequences (i.v. infusions of cocaine are not delivered). Eventually, animals stop making drug-seeking responses during this extinction. Then, several different manipulations can be used to 'reinstate' drug-seeking behavior - that is, responses made on the operant lever that previously delivered cocaine. One manipulation is to provide environmental cues previously paired with cocaine during self-administration. These cues serve to signal drug reward and also take on secondary reinforcing properties of their own, thereby activating incentive motivational systems that direct behavior. For example, animals will make responses just to receive presentation of these cues - which become conditioned stimuli (CS). These experimental observations parallel reports from human drug abusers, where drug-paired stimuli induce emotional responses of arousal and anticipation, and elicit positive, 'drug-like' reports that may define human craving. In a recent report, Dr. Goeders used response-contingent cues to reinstate cocaine-seeking behavior and examined the effects of ketoconazole pretreatment in this animal model of relapse. In his study, extinguished rats reinstated responding on the drug-associated lever, just to gain access to CS previously associated with cocaine. Thus, this behavior is driven by the incentive motivational properties of the CS. Pretreatment with the CORT synthesis inhibitor ketoconazole abolished CS-induced reinstatement of responses on the cocaine lever, and a similar result was obtained by pretreating animals with a corticotropin-releasing hormone (CRH) receptor antagonist (specifically, for the CRH1 site, CP-154,526). Parallel findings with the direct receptor antagonist provide additional evidence that the HPA axis is involved in reinstatement triggered by a drug-associated CS, since activation of CRH receptors on the pituitary trigger the adrenals (through ACTH) to release CORT. Ketoconazole also decreased the rise in plasma CORT that was seen in vehicle-pretreated rats, during reinstatement (thus, reinstatement activated the HPA axis). In the present study, inhibition of CORT synthesis, or blockade of pituitary receptors that ultimately promote CORT activation, diminished the ability of an incentive motivational CS to reinstate cocaine directed behavior. Reductions of plasma CORT at the same time suggest that this attenuation in the ability of conditioned incentive stimuli to drive drug seeking may result from a blunting of CS-induced activation in the HPA axis. Goeders, N.E., and Clampitt, D.M. Potential Role for the Hypothalamo-Pituitary-Adrenal Axis in the Conditioned Reinforcer-induced Reinstatement of Extinguished Cocaine Seeking in Rats. Psychopharmacol., 161, pp. 222-232, 2002.

Dopamine D2 Receptors May Act as a "Brake" on Escalation of Cocaine Self-administration

Recent findings from human neuroimaging studies, and from non-human primates housed in a social colony, implicate basal ganglia Dopamine D2 receptor substrates both in the subjective, pleasurable response to psychostimulant drugs and to the vulnerability to begin self-administration. A recent report from Dr. S. Barak Caine and colleagues at McLean Hospital, Harvard Medical School, also implicates this substrate specifically in high dose cocaine reinforcement. Dr. Caine used a creative experimental approach where converging evidence from C57BL/6 D2 knock-out mice was evaluated along with pharmacologic probes of the D2 system in mice and in outbred rats. When D2 knock-outs were allowed to make operant responses to receive food, their rate of responding was lower than their wild type counterparts. However, in a cocaine self-administration procedure, these knock-outs took significantly more cocaine, with heterozygous animals responding at rates between those of the wild types and homozygous (knock-out) mice. A dose-response analysis revealed that knock-out mice took more cocaine only at the higher doses offered (i.e., 1.0 and 3.2 mg/kg/injection). When self-administering cocaine doses <1.0 mg/kg/injection, their response rates were no different than the other groups. When challenged with a D2 antagonist (eticlopride), wild type and heterozygous mice showed significant increases in their cocaine intake (as is usually seen with D2 antagonist treatment in cocaine self-administration studies), but the antagonist was without effect in the D2 knock-outs. Outbred rats showed a similar rightward shift in dose response function for cocaine self administration when pretreated with a more selective D2 antagonist (L-741,626). In this case, rats showed significantly greater self-administration of cocaine for doses of 3.2 mg/kg/injection, and less self-administration with lower doses (i.e., 0.3 mg/kg/injection). By contrast, drug intake was not increased following pretreatment with either a selective D3/D4 antagonist, or a D3 antagonist. Collectively, these findings implicate a D2 receptor substrate as critically important in modulating the intake of high doses of cocaine. Since continued cocaine use has been observed to progress to increasingly greater drug intake (i.e., higher doses per administration), these receptors may play an important role in escalation or transition to higher dose patterns of use. Caine, S.B., Negus, S.S., Mello, N.K., Patel, S., Bristow, L., Kulagowski, J., Vallone, D., Saiardi, A., and Borrelli, E. Role of Dopamine D2-like Receptors in Cocaine Self-administration: Studies with D2 Receptor Mutant Mice and Novel D2 Receptor Antagonists. J. Neurosci., 22, pp. 2977-2988, 2002.

Escalation Schedule Produces Changes in Central Reward Systems that May Drive Compulsive Drug-taking

NIDA-funded investigators Drs. George Koob and Athina Markou from the Scripps Research Institute, in collaboration with Drs. Serge Ahmed and Paul Kenny, recently provided evidence that repeated binge cycles of cocaine self-administration in the rat produce a persistent dampening of central reward mechanisms indexed by intra-cranial self-stimulation (ICSS). These researchers trained animals to self-administer cocaine over 12 daily sessions that were either one or six hours long. Six hours of self-administration availability has been previously shown to be associated with escalated drug intake in this model. ICSS thresholds, as a measure of reward sensitivity, were assessed 17-22 hours after each daily self-administration session. On these test days, animals made a discrete response to receive reinforcing electrical stimulation delivered to the posterior lateral hypothalamus and thresholds were measured from current-intensity profiles. Over 12 days, rats in the long access group (LgA) showed increased ICSS reward thresholds, whereas those in the one hour exposure group (short access, ShA) and others who did not self-administer cocaine had stable thresholds. Over the course of these 12 days, there was also a significant escalation in number of cocaine injections per drug self-administration session in LgA animals only. In fact, the authors report a high correlation between the slope of reward thresholds and the slope of this escalated drug self-administration for the LgA group. Daily cocaine intake was also positively correlated with daily ICSS thresholds from LgA rats, and ICSS thresholds continued to be elevated for eight days following this long access testing (i.e., during subsequent days when LgA rats were switched to a ShA procedure). All animals were also assessed for acute effects of cocaine on ICSS thresholds at the end of the 12 days of self-administration. Cocaine normally lowers reward thresholds for ICSS and this measure has been proposed as an index for a drug's central reinforcing effects. However, because reward thresholds remained elevated for LgA rats over the 12 days, an acute cocaine probe did not lower ICSS thresholds in these animals to as great an extent as seen in the other groups. These observations suggest that central reward systems are blunted over the course of escalation to excessive cocaine intake and that continued drug-seeking and drug-taking, in the face of a newly established reward "set point" in the system, may represent an attempt to recapture previous reinforcing effects of the drug. Ahmed, S.H., Kenny, P.J., Koob G.F., and Markou A. Neurobiological Evidence for Hedonic Allostasis Associated with Escalating Cocaine Use. Nature Neurosci., 5, pp. 625-626, 2002.

Acute Marijuana Produces Deficits in Adaptation to Changing Reinforcement Contingencies

Acute administration of delta9-THC (THC, the active pharmacological component of marijuana) impairs performance on a variety of different learning tasks and in human subjects decreases rate of "working" to receive experimenter delivered rewards. Drs. Scott Lane and Don Cherek recently tested human marijuana users in a laboratory-based study to measure sensitivity to reinforcement frequency. Subjects of this study presented with clean urine samples for THC and were tested on three to four multiple random interval operant schedules each day to earn monetary rewards. On drug days, all subjects were tested immediately following smoked THC for one session of a concurrent random interval schedule that offered two response choices and required them to continue to switch to a "least preferred" option over the course of the session in order to maximize money earned. That is, if volunteers preferred one option over the other the overall amount of money earned decreased. THC was self-administered by smoking one of four doses: One placebo cigarette, one-half of a 1.77% (w/w) THC cigarette plus one-half of a placebo cigarette, one 1.77% THC cigarette, and 3.58% THC cigarette. Doses were tested in counter-balanced order. Under placebo conditions, subjects switched between the two response option and maximized monetary gain. However, this pattern of behavior decreased as a function of THC dose. Behavioral differences were noted between placebo versus 3.58% THC, and placebo versus 1.77% THC conditions. Thus, after smoking a cigarette with these THC doses, subjects allocated more responses to the decreasing option, and switched less despite diminishing monetary returns. Differences were not attributable to overall decreases in response rates. Adaptive response strategies on this task require the volunteers to discriminate a change in reinforcement frequency and to shift their responses to the higher frequency option. These findings reveal that an acute dose of self-administered THC results in an insensitivity to changing reward frequency. The authors suggest that this impairment might be manifest as a deficit in adaptability to changing environmental or social demands. Whether the observed behavior can be attributed to blunted central reinforcement processes, an inability to shift responses, or impaired learning and memory processes remains to be determined. Lane, S.D., and Cherek D.R. Marijuana Effects on Sensitivity to Reinforcement in Humans. Neuropsychopharmacol., 26, pp. 520-529, 2002.

Sensitization Produced by d-amphetamine Increases "Willingness" to Work for Drug

When animals are treated repeatedly with a psychostimulant, such as cocaine or amphetamine (amp), they show greater locomotor activation to a subsequent acute challenge of these drugs and enhanced dopamine (DA) release in the nucleus accumbens (NAS). This sensitization process has been linked to a substrate in the ventral tegmental area (VTA -- the cell body region for the mesocorticolimbic DA projection system). Animals pretreated with psychostimulants also more readily acquire self-administration behavior for these drugs. But we know little about what the phenomenon of sensitization has to do with features of addiction such as escalation in use, transition to compulsion, or "willingness to work" to obtain drug. Dr. Paul Vezina at the University of Chicago has addressed this question by testing amp sensitized rats in an operant procedure that requires them to make progressively more and more bar press responses, over the course of a session, to obtain an infusion of drug. When compared to animals receiving saline during a pre-exposure phase, rats repeatedly treated with amp (amp pre-exposed) responded the same under a requirement of 10 responses per amp infusion. However, when subjected to increasing response requirements under a progressive ratio (PR) operant schedule to receive i.v. amp, rats pre-exposed to amp emitted threefold to fivefold more responses to receive drug. This effect was observed over a range of self-administered amp doses, and in animals that had been pre-exposed to amp via an intraperitoneal route of administration, or via direct amp infusion into the VTA. When measuring concomitant DA release from the NAS in these groups, the investigator found greater DA efflux from amp pre-exposed rats. Over the session, DA became depleted in saline pre-exposed animals and they stopped responding for drug. However, at the same time, and under the same increasing response demands, DA continued to be released in amp pre-exposed rats. The last study in this series addressed the question of relapse, using a reinstatement procedure where animals are withdrawn (i.e., bar presses no longer result in delivery of drug) and receive a 'priming' injection of amp to stimulate drug-seeking behavior. In this procedure, amp pre-exposed (thus, 'sensitized') animals emitted more drug seeking bar press responses and had a significantly greater DA efflux in response to the amp prime than saline pre-exposed rats. Collectively, these findings implicate previously observed behavioral and neurochemical changes, that are signatures for psychostimulant-induced sensitization, are evident during drug maintenance and relapse phases of the addictive process. Vezina, P., Lorrain, D.S., Arnold, G.M., Austin, J.D., and Suto, N. Sensitization of Midbrain Dopamine Neuron Reactivity Promotes the Pursuit of Amphetamine. J. Neurosci., 22, pp. 4654-4662, 2002.

Acute Cocaine Alters Oxytocin Levels in the Medial Preoptic Area and Amygdala in Lactating Rat Dams

Child abuse and neglect are strongly correlated with drug abuse in women. Prior research by Dr. Josephine Johns at the University of North Carolina at Chapel Hill, using an animal model of maternal neglect, has shown that chronic cocaine treatment during pregnancy and acute cocaine treatment in postpartum dams both increase maternal neglect, defined as the disruption of pup-directed maternal behavior. Chronic cocaine during pregnancy also increases postpartum maternal aggression toward intruders, but does so to the extent that pups are injured. On the other hand, acute cocaine treatment after partuition decreases the protection of pups from intruders. In humans, lower levels of the peptide oxytocin (OT) and cocaine use in pregnancy have been associated with general feelings of anger and hostility and difficulty in establishing infant attachment. Dr. Johns rodent work has shown that chronic gestational cocaine treatment reduces OT in the medial preoptic area (MPOA) on postpartum day 1 (PPD1), a time at which maternal behavior disruptions were observed, and in the amydala on PPD6 when increases in maternal aggression were observed. OT is a peptide that is associated with sexual behavior, onset of maternal behavior, and maternal aggression in rats. Dr. Johns has now extended these prior findings by showing that acute cocaine treatment during lactation also alters OT. Thirty mg/kg cocaine delivered on PPD1 resulted in a significant reduction of OT in the MPOA, consistent with the effect of gestational cocaine on OT. On PPD6, cocaine resulted in significant increases in OT levels in the amygdala, in contrast to the reduction in OT in the amydala previously observed on PP6 following gestational cocaine. Future work by Dr. Johns will explore the role of OT in chronic and acute cocaine effects on maternal behavior. Elliot, J.C., Lubin, D.A., Walker, C.H. and Johns, J.M. Acute Cocaine Alters Oxytocin Levels in the Medial Preoptic Area and Amygdala in Lactating Rat Dams: Implications for Cocaine-induced Changes in Maternal Behavior and Maternal Aggression. Neuropeptides, 35(2), pp. 127-134, 2001.

Methadone-Cocaine Combinations are Preferred Over These Drugs Alone in Rhesus Monkeys

Methadone maintenance effectively decreases opioid use, increases retention in drug treatment programs, reduces criminal behavior, and slows the spread of HIV. These benefits of maintenance, however, are often undermined by concurrent cocaine use. While cocaine use is problematic among methadone maintenance patients, and while concurrent use of heroin and cocaine ("speedball") is prevalent among drug addicts, little laboratory research has been devoted to the study of opiate-cocaine combinations. Dr. Richard Meisch and his colleagues at the University of Texas Health Science Center have developed an animal model of oral self-administration using the rhesus monkey that permits assessment of choice between the combination of heroin and cocaine and the component drugs alone. When given concurrent access to the combination and one of the component drugs, subjects typically preferred the combination. In cases where the two options were equally preferred, the researchers found that increasing the response requirement (cost) for these options resulted in a shift to preference for the cocaine-heroin combination. Further investigations with this animal model could have implications for the use of methadone in the treatment of comorbid opiate and cocaine dependence. Wang, N.S., Brown, V.L., Grabowski, J., and Meisch, R.A. Reinforcement by Orally Delivered Methadone, Cocaine, and Methadone-Cocaine Combinations in Rhesus Monkeys: Are the Combinations Better Reinforcers? Psychopharmacology, 156, pp. 63-72, 2001.

Context Dependence of Amphetamine-induced Psychomotor Sensitization Involves Inhibitory As Well As Excitatory Processes

Behavioral sensitization - a progressive and long-lasting increase in drug-induced motor responses - is observed when repeated doses of psychostimulant drugs are administered to an animal. This phenomenon is of interest because the underlying neuroadaptations are thought to contribute to addiction and to persistent brain changes that may be involved in relapse. Under some circumstances, sensitization is "context dependent:" an increased response to a challenge dose of a drug occurs only in the environment where the repeated doses were previously given, whereas a challenge dose in other environments produces a smaller response (i.e., similar to what is observed in drug-na•ve animals). A new study by Anagnostaras et al. reveals that context specificity depends, in part, on inhibition of sensitization in the unfamiliar context, rather than on facilitation of drug-induced responses in the familiar context. In the present study, animals with unilateral (6-hydroxydopamine-induced) dopamine depletions were given repeated doses of d-amphetamine (AMPH) in group-specific environments, and rotational behavior was used as the measure of psychomotor activation. Some animals then received electroconvulsive shock (ECS) in their drug-associated environment. Since ECS produces retrograde amnesia, it was expected that upon return to this previously drug-paired environment, memories evoked of the drug experience would be vulnerable to disruption by the shock procedure. Surprisingly, animals given ECS and, later, a challenge dose in the same drug-paired environment continued to show sensitization. However, animals given ECS in their drug-paired environment and then tested in a different environment, where they had never before received AMPH, now showed a robust sensitization. These results, in conjunction with previous findings, indicate that repeated psychostimulant administration sensitizes the neural substrate that mediates a non-associative, unconditioned responses to these drugs, but that the behavioral expression of sensitization can be blocked in contexts where the drug is not expected. By these processes, drug-associated contexts can come to gain powerful associative control over behavioral sensitization, and perhaps also over craving and relapse. Anagnostaras, S.G., Schallert T., and Robinson T.E. Memory Processes Governing Amphetamine-induced Psychomotor Sensitization. Neuropsychopharmacology, 26, pp. 703-715, 2002.

Mood, Stress, and Physiological Reactivity in Withdrawal from Nicotine

A recent study by NIDA investigator Dr. M. al'Absi and colleagues was designed to evaluate the effects of short-term abstinence from smoking on psychophysiological activity and mood changes during rest and following behavioral challenge. Subjective reports indicate that abstinence from smoking leads to anxiety, depression, restlessness, irritability and distractibility that may produce impairments in cognitive performance. These symptoms are reported to occur within 4-24 hr after smoking cessation and may contribute to relapse risk. Moreover, withdrawal symptoms after abstinence may be exacerbated by stressors and subsequently may then contribute to early relapse. The current study investigated the effects of short-term abstinence (18-21 hours) from smoking on psychophysiological activity and responses to brief behavioral challenges evaluated by withdrawal symptoms in male and female habitual smokers (mean years smoking = 4; mean number cigarettes/day = 19.5). Thirty habitual smokers (15 women and 15 men) participated in two sessions conducted after abstinence and after ad lib smoking (in counterbalanced order). Saliva cotinine concentrations and expired carbon monoxide were measured in both conditions. A subset of the sample (8 men and 8 women) provided saliva samples after 18 hr abstinence and after ad lib smoking while outside the laboratory setting (ambulatory controls). Abstinence produced significant withdrawal symptoms in all participants, with women reporting greater desire to smoke than men. Participants showed greater systolic BP responses to a behavioral challenge (fast-paced mental arithmetic tasks) in the abstinence condition than in the control condition. They also showed worse cognitive performance on the challenges in the abstinence than in the ad-lib condition. Salivary cotinine was greater in the ad lib than the abstinence condition, confirming the effectiveness of the abstinence manipulation. Men had greater salivary cortisol levels than women and both men and women showed the expected decline in cortisol levels across time. However, there were no differences in cortisol levels as a function of abstinence or ad lib smoking conditions in either the laboratory or ambulatory measurements. These results show that abstinence alters mood, performance and BP responses, but not adrenocortical responses, seen upon acute challenge. It is possible that these changes contribute to stress-related vulnerability to smoking relapse. On the other hand, absence of effects of abstinence on salivary cortisol production during the ambulatory measurements and in response to the laboratory challenges does not support the hypothesis that abstinence is associated with enhanced adrenocortical activity. al'Absi , M., Amunrud, T., and Wittmers, L.E. Psychophysiological Effects of Nicotine Abstinence and Behavioral Challenges in Habitual Smokers. Pharmacology, Biochemistry and Behavior, 72, pp. 707-716, 2002.

Self-administration of Heroin Alters Immune Function More than Passive Administration

There is considerable evidence that opioids such as morphine induce immunomodulation. Morphine has been shown to induce dose-dependent, naltrexone-reversible suppression of natural-killer cell activity, proliferation of lymphocytes, anti-body production and the production of interferon. Morphine has also been shown to reduce the stimulated production of nitric oxide. In contrast to what is known about morphine, there is very little information available about heroin's immunomodulatory effects. Yet, the high incidence of bacterial, viral and fungal infections among human heroin abusers suggests that heroin use might alter infectious disease resistance. Nitric oxide has been shown to play a critical role in immune processes including resistance to infectious disease. The enzyme responsible for producing nitric oxide is nitric oxide synthase (NOS) and previous work from Dr. Lysle's laboratory has demonstrated that a single heroin injection reduces lipopolysaccharide (LPS)-induced expression of inducible NOS (iNOS) mRNA in spleen, liver and lung. The purpose of the present study was to extend the investigation of heroin's effects on LPS-induced iNOS expression using a self-administration paradigm. A typical triadic design was used: Animals in the self-administration group learned to lever press for infusions of heroin, in 2-hr sessions; each animal in the second group was yoked to an animal in the self-administration group and received a passive infusion of heroin whenever the first group self-administered heroin; each animal in the saline control group was yoked to an animal in the self-administration group and received a passive infusion of saline whenever the first group self-administered heroin. The experiment sought to determine [1] whether animals would self-administer a sufficient quantity of heroin to induce alterations in the expression of iNOS; and [2] whether self-administration of heroin would have different immunomodulatory consequences from the same dose of heroin infused passively. Heroin self-administration lasted 16 days. Following the last training session, animals were injected with LPS and euthanized 6 hr later. The production of nitric oxide was determined by measuring iNOS mRNA protein in spleen, liver and lung. In addition, accumulation of nitrite/nitrate was measured in plasma. Results indicated that animals acquired self-administration that leveled off at approximately 26 lever presses per animal during the 2 hr session. The mean dose of heroin thus administered was 1.59 mg/kg per animal in each session. The biochemical assays indicated that heroin administered in this manner induced significant, widespread reductions in the expression of iNOS in spleen, lung and liver, as well as in the accumulation of plasma nitrite/nitrate. Moreover, there was a trend toward greater reductions in nitric oxide production by self-administering animals compared to yoked controls receiving heroin in six out of seven measures, but only one achieved statistical significance (iNOS mRNA expression in the liver). The importance of nitric oxide as an antimicrobial agent, as well as its role in immune system regulation, makes it a critical molecule to understand. The demonstration that animals will self-administer sufficient quantities of heroin to induce widespread iNOS expression may have implications for the increased incidence of infectious diseases among heroin abusers. Lanier, R.K., Ijames, S.G., Carrigan, K.A., Carelli, R.M., and Lysle, D.T. Self-Administration of Heroin Produces Alterations in the Expression of Inducible Nitric Oxide Synthase. Drug and Alcohol Dependence, 66, pp. 225-233, 2002.

Drug Onset Cues Elicit Compensatory Conditioned Responses that Mediate Morphine Tolerance

Recent evidence from many laboratories indicates that associative learning processes are important for regulating some aspects of drug addiction. In particular, Pavlovian conditioning mechanisms have been hypothesized to mediate drug tolerance. According to this analysis, cues present at the time of drug administration come to function as conditioned stimuli (CSs) capable of contributing to subsequent behavioral reactivity to drug administration. The direct effect of the drug constitutes the unconditioned stimulus (UCS), which prior to any learning elicits unconditioned responses (UCRs) that compensate for drug-induced disturbances. After paired presentations of the CS and UCS, drug compensatory responses come to be elicited by pre-drug cues (i.e., CSs). These conditioned compensatory responses (CCRs) mediate the development of tolerance by counteracting the drug effect. For example, in rats tolerant to the analgesic effect of morphine, presentation of a drug-associated CS, in the absence of morphine administration, elicits a CCR of hyperalgesia. Although many drug associated CSs are exteroceptive, another source of drug associated CSs can be found in the early, drug-onset cues (DOCs) that precede and signal later, maximal drug effects. The present experiments evaluated the contribution of DOCs to morphine tolerance in rats. It was hypothesized that DOCs would elicit CCRs in the form of hyperalgesia. In these experiments, rats were made tolerant to a 5mg/kg infusion of morphine and tested for pain sensitivity using tail flick responses to radiant heat as a measure of analgesia. Drug infusions were gradual - each infusion was about 30 min in duration. When rats displayed tolerance to analgesic effects of the drug, they were tested with a probe morphine infusion, consisting of the first 10% of the morphine infusion used during tolerance development; i.e., 0.5 mg/kg infused over a period of 3 min. In three experiments, Siegel and his colleagues demonstrated that DOCs indeed elicit hyperalgesia. Thus, a small dose of a drug can serve as a cue for a larger dose of that drug and can function as CSs to elicit CCRs that contribute to tolerance. Recognition that associations formed to interoceptive effects of early drug onset can contribute to drug effects has important implications for theories of tolerance. Expanding our understanding of drug-paired associations to interoceptive drug cues may also inform the design of conditioning-based treatments for drug addiction, which are based on extinguishing associations between predrug exteroceptive cues and the drug administration. The present success of learning based treatment approaches may be limited by the fact that they do not include explicit extinction of such DOCs. Sokolowska, M., Siegel, S., and Kim, J.A. Intraadministration Associations: Conditional Hyperalgesia Elicited by Morphine Onset Cues. Journal of Experimental Psychology: Animal Behavior Processes, 28(3), pp. 309-320, 2001.

Anti-opioid Peptide Appears to Mediate Conditioned Compensatory Responding and Morphine Tolerance in Rats

As described above, Pavlovian conditioning mechanisms have been hypothesized to mediate drug tolerance: Cues present at the time of drug administration come to serve as conditioned stimuli (CSs) that can be observed in the absence of drug administration. After paired presentations of a CS and drug (the unconditioned stimulus, UCS), drug compensatory responses (CCRs) come to be elicited by pre-drug cues (i.e., CSs). These CCRs then mediate the development of tolerance by counteracting the drug's unconditioned effect. For example, in rats tolerant to the analgesic effect of morphine, presentation of drug-associated CSs elicit a CCR of hyperalgesia. The present experiment examined conditioned CCRs to morphine in the form of early drug onset cues to evaluate the hypothesis that this CCR of hyperalgesia can be related to an increase in brain cholecystokinin (CCK) activity. According to this hypothesis, blocking CCK activity should block the expression of behavioral hyperalgesia and tolerance. CCK was of interest because of its potential role as an endogenous "anti-opioid peptide." Two experiments were conducted using tail-flick latency to evaluate this hypothesis. In Experiment 1, rats received eight daily gradual intravenous infusions of either morphine (5 mg/kg) or saline during the tolerance acquisition phase. On a subsequent test, all rats received an injection of a "probe" morphine infusion (the putative CS), which consists of the approximately first one-tenth of the usual morphine infusion. Prior to this probe infusion, half of the animals in morphine and saline-treated groups received an injection of vehicle and half were injected with the CCK2 receptor antagonist, PD135,158. Analgesia was evident in rats given morphine and across days, tolerance developed to morphine analgesia. On the test day, morphine tolerance was still evident in the morphine treated rats that had been pretreated with saline, but in those morphine animals pretreated with the CCK antagonist, tolerance was significantly attenuated. That is, the CCK antagonist blocked the expression of the CCR and tolerance. Experiment 2 was conducted like Experiment 1, except that on the test day, the same morphine dose as used during tolerance development was administered (5 mg/kg), preceded by either saline or PD135,158. Thus, whereas Experiment 1 was an assessment of the CCK antagonist's effectiveness in attenuating the CCR, Experiment 2 investigated the CCK antagonist's ability to attenuate the display of tolerance seen with the full dose. The results indicated that morphine treated animals were tolerant to morphine analgesia, but that analgesic tolerance was significantly attenuated in animals tested under PD135,158. Together, these results suggest that a CCK2 receptor antagonist attenuates both the expression of opiate tolerance and the conditioned compensatory response hypothesized to mediate such tolerance. Kim, J.A. and Siegel, S. The Role of Cholecystokinin in Conditional Compensatory Responding and Morphine Tolerance in Rats. Behavioral Neuroscience, 115, pp. 704-709, 2001.

Gender and Phenotype Interact Differently in the Vulnerability to Acquire Heroin or Cocaine Self-administration

Rats that have high preference for sweet-tasting solutions have been shown to acquire self-administration of amphetamine, ethanol, and morphine more rapidly than rats with low preference. Dr. Marilyn Carroll and colleagues sought to extend this observation to cocaine and heroin i.v. self-administration using male and female rats selectively bred for high (HiS) or low (LoS) preference for saccharin. They report that for cocaine, in females, but not males, the HiS subjects met an acquisition criterion of 100 cocaine infusions during 6-hr sessions over 5 consecutive days more rapidly than LoS subjects. In both phenotype groups, females met the criterion more rapidly than males and a higher percentage of females met the criterion for acquisition within 30 days. For heroin, phenotype had no effect on acquisition of self-administration, for which the criterion was 20 infusions during 6-hr sessions over 5 consecutive days; however, females in both phenotype groups acquired more quickly than males, and in the HiS group, females administered more infusions than males. The cocaine subjects were subsequently tested under a progressive ratio schedule whereby successive cocaine infusions requires more and more bar presses until responding ceases, i.e., a breakpoint occurs. The breakpoint was unaffected by phenotype, but was larger in females than males. This work indicates that both saccharin-preference phenotype and sex are determinants of acquisition of drug self-administration; however, sex appears to be a stronger factor than saccharin-preference phenotype. Carroll, M.E., Morgan, A.D., Lynch, W.J., Campbell, U.C., and Dess, N.K. Intravenous Cocaine and Heroin Self-administration in Rats Selectively Bred for Differential Saccharin Intake: Phenotypes and Sex Differences. Psychopharmacology, 161, pp. 304-313, 2002.

Prescription Medications Interact to Alter the Subjective Effects of Phencylidine

Dr. Robert Balster at the Medical College of Virginia has been studying the discriminative cue properties of the dissociative anesthetic, phencylidine (PCP) and characterized the receptor profile for subjective effects of this drug in an animal model. Some second generation tetracycline antibiotics, (such as doxycycline and minocycline), have been noted to have NMDA antagonist-like effects in regard to their CNS side effects and neuroprotective properties. NMDA is a glutamatergic receptor and channel blockade at this site has been associated with subjective effects of PCP on drug discrimination procedures in the rat. These investigators recently published that minocycline and doxycycline did not substitute for PCP in rats trained to discriminate PCP from saline. This finding suggests that the antibiotics may bind at a different site on the receptor complex than does PCP. However, both drugs shifted PCP dose response curves for discriminative cue effects to the left, indicating a potentiation of PCP's subjective effects in this animal model. While the authors suggest that the mechanism of this enhancement may be via inhibition of nitric oxide synthases, the interesting observation at the behavioral level is that prescription drug medications - in clinically used dose ranges - may significantly alter the subjective effects of drugs of abuse. This is especially noteworthy in that these tetracyclines have no known abuse liability themselves and are not recognized as having psychotropic effects. Munzar P., Hua L., Nicholson K.L., Wiley J.L., and Balster R.L. Enhancement of the Discriminative Stimulus Effects of Phencyclidine by the Tetracycline Antibiotics Doxycycline and Minocycline in Rats. Psychopharmacol., 160, pp. 331-336, 2002.


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