Conditioned taste aversions and drugs of abuse: A reinterpretation.

A new hypothesis (and supporting data) provides a solution to the 25-yr-old paradox whereby positively reinforcing drugs of abuse also support a conditioned taste aversion (CTA). The results show that unlike LiCl-induced CTAs, morphine- and cocaine-induced suppression of conditioned stimulus (CS) intake depends on the rewarding properties of the gustatory CS. This finding argues against the long-standing CTA interpretation in favor of a new reward comparison account. That is, rats decrease intake of a gustatory CS following taste–drug pairings because the value of the CS is outweighed by that of a highly reinforcing psychoactive drug. Suppression of CS intake, then, is a consequence of the well-documented positive reinforcing, rather than the hypothetical aversive, properties of drugs of abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: Evidence for the reward comparison hypothesis.

Rats suppress intake of a saccharin conditioned stimulus (CS) when it is paired with an aversive unconditioned stimulus (UCS), an appetitive UCS, or a drug of abuse such as morphine or cocaine. It is unclear, however, whether the reduction in intake induced by these drugs is mediated by their aversive or their rewarding properties. The present set of experiments addressed this question by comparing the suppressive effects of a known aversive UCS (LiCl), a known reinforcing UCS (sucrose), and a drug of abuse (cocaine) in two strains of rats (i.e., Lewis and Fischer 344 rats) that differ in their preference for rewarding stimuli. The results show that, although both strains readily acquired a LiCl-induced conditioned taste aversion (CTA), the suppressive effects of sucrose and cocaine were robust in the drug-preferring Lewis rats and absent in the Fischer rats. These data argue against a CTA account and in favor of the reward comparison hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of the reduction of colloid oncotic pressure, with and without reduction of osmolality, on post-traumatic cerebral edema

The fact that centrally acting analgesics have abuse potential commensurate with their analgesic activity raises the question of whether these effects are related. The abuse potential of drugs depends on their ability to produce reinforcing effects, which are mediated by a neural system that includes the ventral tegmental dopamine cells and their connections with the ventral striatum. Morphine and amphetamine are both powerful analgesics and have high abuse potential. Their analgesic and reinforcing effects are mediated by similar receptors, similar sites of action, and overlapping neural substrates. These coincidences suggest that reinforcers may produce analgesia by transforming the aversive affective state evoked by pain into a more positive affective state. The implications of this hypothesis and its relation to other known mechanisms of analgesia are discussed. The hypothesis predicts that drugs with reinforcing effects should produce analgesia. A survey of drugs acting through 21 classes of receptors reveals that in 13 classes there is evidence for both analgesic and reinforcing effects that are approximately equipotent. The GABA(A) agonists were found to be the only drugs with confirmed abuse potential that lack analgesic activity. The interpretation of this and several other anomalous cases is discussed.     

Behavioral pharmacology of zolpidem relative to benzodiazepines: a review

Zolpidem, an imidazopyridine that purportedly binds selectively to certain GABA(A) receptor subtypes, is the most commonly prescribed hypnotic. The present article critically reviewed the extant experimental literature to determine whether the behavioral pharmacologic profile of zolpidem also differs from that of benzodiazepines. Specific topics that are reviewed include: 1) reinforcing effects and abuse potential, 2) discriminative-stimulus effects, 3) subject-rated drug effects, 4) performance-impairing effects, 5) tolerance-producing effects, and 6) physiological dependence-producing effects. Studies that employed both nonhumans and humans are reviewed. Based on the available literature, the most parsimonious conclusion is that despite its unique neuropharmacological profile, the behavioral effects of zolpidem are generally similar to those of benzodiazepines. However, it is important to note the dearth of perspective, experimental studies that directly compared zolpidem and a benzodiazepine. Because of the clinical relevance and paucity of published studies, future research should focus explicitly on assessing the reinforcing effects, abuse potential, performance-impairing effects, tolerance-producing effects, and dependence-producing effects of zolpidem relative to a benzodiazepine. Important issues such as the selection of an appropriate comparison drug and subject population, and the doses tested needed to be considered in these future studies.     

LC/MS with a particle beam interface in forensic toxicology

Many instruments are used in forensic toxicology to screen biologic samples for drugs and other compounds. Many of these screening instruments (and others) are used to confirm positive screening tests. The focus of this article is the use of a high pressure liquid chromatograph/mass spectrometer (HPLC/MS) for screening forensic postmortem and human performance DWI cases. This screening procedure involves an HPLC with a particle beam interfaced to a mass spectrometer detector and a photodiode array detector. Drugs such as the antidepressants, drugs of abuse, over-the-counter cold and pain preparations, anticonvulsants, benzodiazepines, and some medications that are not available in the United States are selected at therapeutic and subtherapeutic levels. Limits of detection and extraction efficiencies are presented for many compounds. Several cases are discussed showing different drug combinations.     

Psychobiology of novelty seeking and drug seeking behavior

There is considerable evidence that high novelty seekers are at increased risk for using drugs of abuse relative to low novelty seekers. This review examines the potential biological mechanism that may help explain the relationship between novelty seeking and drug seeking behavior. Evidence is summarized to suggest that exposure to novelty activates, at least in part, the same neural substrate that mediates the rewarding effects of drugs of abuse. It is argued that individual differences in response to novelty and drugs may relate to individual differences in the mesolimbic dopamine (DA) system of the brain. Individual differences in both novelty seeking and drug seeking behavior, while under some degree of genetic control, appear to be modifiable by early development experiences and this modification may relate to alterations in activity of the mesolimbic DA system. Within the context of this biological formulation, implications for the prevention and treatment of drug abuse are discussed.     

Animal models of relapse.

This review focuses upon an animal model of relapse. The basic model is to establish that a drug is functioning as a reinforcer. Drug is then replaced with vehicle, and responding is allowed to extinguish. Exteroceptive or interoceptive stimuli are then presented to determine whether behavior that was previously reinforced by drug would be reinstated. Experimental attention has been directed toward using interoceptive stimuli (e.g.. priming injections of the self-administered drug, other drugs of abuse or potential treatment drugs) to reinstate extinguished behavior. Drugs that function as reinforcers reinstate responding (relapse), although there have been few reports of reinstatement with drugs that are not reinforcing. Reinstatement usually occurs in a dose-dependent manner with a priming injection of a drug from the same pharmacological class. Restricted feeding and stress enhance relapse in cocaine-trained rats. Relapse occurs over several days or weeks of abstinence. This model is useful for the study of drug abuse treatment by identifying methods of behaviorally extinguishing or pharmacologically blocking relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Column-switching high-performance liquid chromatographic assay for determination of apigenin and acacetin in human urine with ultraviolet absorbance detection

Postweaning social isolation can influence the sensitivity of rats to several effects of drugs of abuse. The present study investigated the influence of postweaning housing conditions on the sensitivity of rats to the aversive effects of a number of psychoactive agents using a conditioned taste aversion (CTA) test procedure. Development of a CTA was assessed by pairing administration of the drug with the consumption of a 0.05% (weight/volume) saccharin solution in water-deprived (18 h) rats in a 20 min drinking period. Saccharin consumption was then measured in 20 min test sessions over the next 4 consecutive days. Consumption of saccharin solution was significantly reduced in both isolated and enriched rats following administration of d-amphetamine (2 mg/kg), cocaine (30 mg/kg), morphine (10 mg/kg), nicotine (1.0 mg/kg), caffeine (20 mg/kg), alcohol (1.5 g/kg), and LiCl (0.15 M, 4 ml/kg). There was no significant effect of housing conditions on the CTA induced by cocaine, nicotine, alcohol, or LiCl; however, isolation-reared rats were found to be less sensitive to the aversive effects of d-amphetamine, morphine, and caffeine in this paradigm. These results suggest that rearing rats in social isolation induces an attenuation in sensitivity to the aversive effects of some psychoactive agents.     

Caffeine promotes an ethanol-induced conditioned taste aversion: A dose-dependent interaction.

The present study examined whether caffeine administered within a dose range previously shown to promote ethanol drinking would also alter an ethanol-induced conditioned taste aversion (CTA). The results revealed a dose-dependent interaction between caffeine and ethanol where caffeine (2.5 and 10 mg/kg) promoted an ethanol-induced CTA at a low ethanol dose (1.0 g/kg) but had no effect in blocking CTA at the higher ethanol dose (1.5 g1kg). These results were found to be unrelated to an alteration in ethanol metabolism, as caffeine had no effect in altering blood ethanol levels at the doses tested. In agreement with the reward comparison hypothesis, the present results suggest that rather than attenuate ethanol's "aversive" effects, caffeine may have promoted an ethanol-induced CTA by increasing the reinforcing efficacy of ethanol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

New drugs of 1997

OBJECTIVE: To provide information regarding the most important properties of the new therapeutic agents marketed in 1997. DATA SOURCES: Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS: A record-setting number of 45 new therapeutic agents were marketed in 1997. The indications and information on dosage and administration for each new agent are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 1997 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.     

Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance

For cytotoxic agents to have an effect on tumor cells, drugs must first be transported into the cell, potentially be metabolized to an active form, and interact appropriately with target molecules. A final common pathway of cytotoxic agents is usually the initiation of programmed cell death, or apoptosis. Tumor cells overcome the effects of cytotoxic agents at one or more of these levels. The classic multidrug-resistance (MDR) phenotype, as mediated by the drug efflux pump, P-glycoprotein, is one of the most extensively studied mechanisms of drug resistance. Additional drug transporters, such as the multidrug resistance-associated proteins (MRPs), have also been identified and can convey drug-resistance phenotypes. Important questions remain as to how and whether such transport systems can be specifically measured and effectively targeted to improve therapeutic outcomes. Furthermore, alterations in drug targets, drug metabolism, repair of DNA damage caused by drugs, and the inability to initiate programmed cell death can all contribute to drug resistance and must be ultimately considered in the explanation of tumor-cell resistance to therapy. Continued exploration of the pharmacologic methods to circumvent drug resistance, as well as strategies that involve targeted therapy and immunomodulation, should increase the specificity and efficacy of treatments for patients with cancer.     

Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/hypoglycemia

OBJECTIVE: To compile and assess the English-language literature on drug-induced nightmares, excluding nightmares secondary to drug withdrawal or drug-associated night terrors. DATA SOURCES: Published articles, letters, case reports, and abstracts in English were identified by MEDLINE (1966-May 1998) searches using the search term nightmares, chemically induced. Additional articles were obtained from bibliographies of retrieved articles. DATA EXTRACTION: All case reports of drug-induced nightmares were evaluated using the Naranjo algorithm for causality. Clinical studies of drugs that reported nightmares as an adverse effect were assessed for frequency of occurrence. DATA SYNTHESIS: Nightmares, defined as nocturnal episodes of intense anxiety and fear associated with a vivid, emotionally charged dream experience, are generally classified as a parasomnia. Possible pharmacologic mechanisms for drug-induced nightmares, such as REM suppression and dopamine receptor stimulation, are reviewed. However, the vast majority of therapeutic agents implicated in causing nightmares have no obvious pharmacologic mechanism. CONCLUSIONS: Assessing causality with an event such as a nightmare is difficult because of the high incidence of nightmares in the healthy population. Using qualitative, quantitative, and possible pharmacologic mechanism criteria, it appears that sedative/hypnotics, beta-blockers, and amphetamines are the therapeutic modalities most frequently associated with nightmares. These drug classes have a plausible pharmacologic mechanism to explain this effect. Dopamine agonists also have evidence of causality, with dopamine receptor stimulation as a possible pharmacologic mechanism.     

NMDA-receptor antagonists: new pharmacological agents to control the subjective and motivational effects of narcotics]

The effects of N-methyl-D-aspartate. (NMDA) receptor antagonists on the development of long-term adaptation to abused drugs (tolerance, sensitization, dependence) were studied, NMDA receptor antagonists were shown to suppress subjective (including an aversion-motivation component) signs of the opiate withdrawal syndrome and to diminish the secondary reinforcing effects of morphine, cocaine, and electrical brain stimulation rewards of the brain regions. The results obtained indicate the potential efficiency of this new class of pharmacological agents in the context of treatment and prevention of recurrent drug abuse.     

Investigating the pharmacological and nonpharmacological factors that modulate drug reinforcement.

Drug use is driven by principles of reinforcement and is sensitive to influences in the environmental context in which it occurs. Although a wide range of factors has been shown to directly influence the reinforcing effects of commonly abused drugs, 2 general types include pharmacological and nonpharmacological factors. Both can assert a powerful impact on a drug's reinforcing effects and, therefore, the degree to which a particular drug comes to be used and abused. This invited review seeks to briefly describe some of the current psychopharmacology research on the interactions between these factors and drug abuse. Several pharmacological influences on drug use will be discussed, including the interactions between psychomotor stimulants and recent advances in the development of pharmacotherapies for opioid abuse. With regard to nonpharmacological factors, there is a large body of research demonstrating that nondrug reinforcers can exert a powerful influence on the reinforcing effects of commonly abused drugs. More specifically, identifying alternative nondrug sources of reinforcement can, if made available contingent on drug abstinence, produce robust decreases in drug self-administration. Presented here is a very brief review of some recent scientific efforts to develop and extend behavioral interventions targeting drug use across a wide range of clinical populations. In summary, understanding the interactions among the variables present in the context of drug use is critical to understanding risk factors for substance use disorders as well as developing efficacious treatments for drug dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatment of drug abuse syndromes

This article serves as an introduction to the treatment of the various drug abuse syndromes. The theoretical concept underlying all diagnoses in drug dependence is presented first in detail, along with an extensive discussion of how these diagnoses are operationalized. Tolerance and dependence among the various drugs of abuse are considered. The review of treatment approaches divides drugs of abuse into pharmacologic categories and treatment into time segments, acute detoxification, intermediate-term, and long-term treatment. Pharmacotherapies for each of the categories of substance abuse and for each of the time periods are presented in a treatment-oriented fashion. Drug substitution therapy is considered. Individual and group therapy are discussed, as is education in the form of group process and peer feedback. The role of peer support groups is stressed. Finally, patient placement criteria across levels of care are explained.     

Re-examination of amphetamine-induced conditioned suppression of tastant intake in rats: The task-dependent drug effects hypothesis.

This study reexamined Grigson's reward comparison hypothesis (1997), which claimed to have resolved the paradox of addictive, rewarding drugs manifesting an aversive effect in the conditioned taste aversion (CTA) paradigm. Here, the authors compared the conditioned suppression effects of lithium chloride (LiCl) and amphetamine in a series of three experiments. In Experiment 1, the concentrations of saccharin solution (conditioned stimulus [CS]) and the doses of amphetamine or LiCl (unconditioned stimulus [US]) were manipulated. In Experiment 2, the effects of employing backward versus forward pairings of the CS and US were compared. Finally, in Experiment 3, the additivity of amphetamine's reward property and LiCl's aversive property was examined. The results of these experiments, respectively, indicated that: (1) manipulating saccharin solution concentrations does not distinguish the suppression effect caused by rewarding or aversive effects when amphetamine or LiCl served as the US; (2) both backward and forward pairings produced suppression of saccharin solution intake regardless of whether amphetamine or LiCl was used as the US; and (3) combining amphetamine and LiCl did not diminish the suppression effect, as would be expected if they had opposing mechanisms for the effects; instead, an additive effect occurred. Taken together, these results suggest that the drug of abuse amphetamine and the emetic drug LiCl both possess aversive properties in the CTA paradigm. No rewarding effects of amphetamine were detected in our experimental data. In all, our results do not support the Grigson's reward comparison hypothesis (1997) and a new "task-dependent drug effects hypothesis" is proposed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacological determinants of the reinforcing effects of psychostimulants: Relation to agonist substitution treatment.

Illicit use of psychostimulants, such as cocaine and methamphetamine, continues to pose a significant public health concern. On the basis of the relative success at treating opiate and tobacco users with agonist substitution treatments, this strategy has been pursued in the search for a pharmacotherapy for psychostimulant addiction. The reinforcing effects of drugs are central to their abuse liability; therefore, gaining a better understanding of the factors that determine the reinforcing effects of psychostimulants should inform the development of an effective treatment. Although the reinforcing effects of drugs are known to be multiply determined, the author's dissertation research focused on pharmacological factors. This review presents results from that research as well as findings reported in the extant literature, suggesting that the reinforcing effects of psychostimulant drugs are determined both by their pharmacodynamic and pharmacokinetic profiles. There is evidence to support the conclusion that affinity for dopamine transporters appears to be of critical importance, whereas serotonin transporters seem to serve a modulatory function. A more rapid rate of onset may enhance a drug's reinforcing effects, but a drug with a slow onset can still maintain self-administration. A drug's duration of action may only influence the rate but not the strength of responding that is maintained. Slow-onset, long-acting monoamine transporter ligands can be expected to have reinforcing effects and therefore abuse liability, which has implications for the use of these drugs as pharmacotherapies. Nonetheless, on the basis of promising preclinical and clinical findings, this appears to represent a viable treatment strategy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transgenerational effects of maternal exposure to chemicals on the functional development of the brain in the offspring

In order to prevent health risk from environmental chemicals, particularly for progeny, we have been performing a risk assessment for various chemicals including therapeutic agents. This paper reports the functional effects of maternal exposure to psychoactive drugs, anticancer drugs, or herbicides on the offspring of rats. Maternal exposure to imipramine in a dose equivalent to the therapeutic dose per unit body weight induced hyperthermic response to chlorpromazine in the male offspring, while normal control rats showed a marked hypothermia. Exposure to ethosuximide resulted in an increase in play fighting behavior in young offspring that was fostered by lactating normal mothers. Single exposures to nimustine or cisplatin, anticancer drugs, at a different gestational stage resulted in an acceleration of growth when exposed at the earlier stage of gestation. Moreover, cisplatin-exposed rats were emotionally unstable, showing a short latent time to the first line-crossing in an open-field during infantile period. The rats exposed to glufosinate ammonium, an herbicide, during the time of neurogenesis in the hippocampus showed a decrease in the wet-dog shakes response to kainic acid at six weeks of age. These results suggest that maternal exposure to chemicals during pregnancy induces a variety of functional abnormalities in the brain of the offspring dependent on the pharmacologic action of chemicals and the stage of gestation even with a single exposure.     

Biological effects of central nervous system stimulants

In both animals and man, stimulants such as the amphetamines and cocaine are reinforcing and thus motivate repeated drug-taking behaviour and leading to abuse. Although this class of drugs seems to act by different biological mechanisms in the central nervous system, it has been suggested that their action to increase dopaminergic neurotransmission is crucial to the reinforcing properties of these compounds. However, increasing evidence suggests that a number of other neurotransmitters/neuroregulators, possibly in conjunction with dopamine, are part of the complex neurochemical systems which underlies various aspects of stimulant abuse behaviours. Examples of possible influences of noradrenaline and corticosterone will be discussed.     

A viewpoint on drugs that prolong the QTc interval

Insufficient evidence exists to suggest that prolongation of the QT interval corrected for heart rate (QTc) is necessarily beneficial. In all but life-threatening situations, QTc prolongation resulting from pharmacologic agents must be considered a risk. Because dose-response relations for torsades de pointes cannot be established and because prolongation of the QTc interval is thought to precede the development of torsades, it is reasonable to assume that the QTc prolongation itself constitutes the marker of risk. An assessment of the relation between the dose of a given drug and its effect on the QTc interval will aid in making the judgment that the potential benefit outweighs the risk. Ideally, a drug should demonstrate as wide a safety margin as possible, as reflected in a large separation between the ED50 value associated with therapeutic benefit and that associated with QTc prolongation.