Robert L. Balster

The behavioral pharmacology of NMDA receptor antagonists

There is considerable interest in the development of NMDA antagonists as potential therapeutic agents in the treatment of convulsant, neurodegenerative and anxiety disorders. Because the clinical use of phencyclidine (PCP) has been precluded by its psychotomimetic effects and abuse potential, there has been concern that other NMDA antagonists including those acting competitively might produce similar untoward effects. However, the studies in animals, reviewed here by Joyce Willetts, Robert Balster and David Leander, suggest that while there are certain similarities in the behavioral effects of PCP-like and competitive antagonists, there are also differences. These differences have implications for the development of NMDA antagonists with less likelihood for producing PCP-like side-effects.

Neural basis of inhalant abuse

It should be apparent from this review that far less is known about the neural basis for inhalant abuse than for other forms of drug abuse. This reflects a lack of research interest in this area (Balster, 1997). Indeed, conclusions are difficult to draw. In the case of the volatile alkyl nitrites, the most reasonable hypothesis at this time is that the cellular basis for their abuse resides in their actions on smooth muscles to produce vasodilation and relaxation, however, direct effects on the brain cannot be ruled out. Although there is some evidence that analgesic effects of nitrous oxide may involve opiate systems, even this conclusion is controversial. There is no evidence that opiate systems play a role in nitrous oxide intoxication or reinforcement. The mechanisms for these effects are unknown. They may reflect the same actions on lipid membranes or on hydrophobic sites on unspecified proteins that have been proposed as mechanisms for nitrous oxide anesthesia. In the case of the volatile solvents, fuels and anesthetics we are faced with a wide variety of specific chemicals which may produce different profiles of pharmacological effects. There is evidence that the prototypic abused solvents toluene and trichloroethane produce acute effects similar to subanesthetic concentrations of general anesthetics, as well as to the effects of classical CNS depressant drugs, such as alcohol and the barbiturates. For the anesthetics, evidence suggests that enhancement of GABAergic inhibition may be an important cellular target for their acute effects, just as it is for alcohol and other depressant drugs. For toluene, as with alcohol, recent evidence suggests a possible role for inhibition of glutamatergic neurotransmission involving NMDA receptors. Toluene has also been shown to have some dopaminergic effects which may be important to its abuse. As for the large number of other abused vapors, practically no information can be found on their cellular actions, and certainly not on actions that may be relevant to their abuse. This entire area would seem an important direction for future research.

CNS depressant effects of volatile organic solvents

Volatile chemicals used widely as solvents can produce acute effects on the nervous system and behavior after inhalation exposure, and many are subject to abuse. This review considers the nature of the acute effects of volatile organic solvents by comparing their actions to those of classical CNS depressant drugs such as the barbiturates, benzodiazepines and ethanol. Like CNS depressant drugs, selected inhalants have been shown to have biphasic effects on motor activity, disrupt psychomotor performance, have anticonvulsant effects, produce biphasic drug-like effects on rates of schedule-controlled operant behavior, increase rates of punished responding, enhance the effects of depressant drugs, serve as reinforcers in self-administration studies and share discriminative stimulus effects with barbiturates and ethanol. Toluene and 1,1,1-trichloroethane, as well as subanesthetic concentrations of halothane, have been the most extensively studied; however, it is unclear whether important differences may exist among solvents in their ability to produce a depressant profile of acute effects. The possibility that selected solvents can have acute effects similar to those of depressant drugs may shed light on the nature of their acute behavioral toxicology and on their abuse.

GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects

Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of ‘metaplasticity’ by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.

Initial tobacco use episodes in children and adolescents: current knowledge, future directions

Approximately three-quarters of adult tobacco users report that their first tobacco use occurred between ages 11 and 17, while many adults who do not regularly use tobacco report that they experimented with it as adolescents. Surprisingly little is known about the effects of these initial tobacco use episodes and their influence on adult tobacco use patterns. In particular, understanding the role that nicotine plays in these early tobacco use experiences may be important in understanding the development of regular tobacco use and concomitant nicotine dependence. One goal of this review is to summarize current knowledge regarding the effects of initial tobacco use episodes in adolescents and to discuss nicotine exposure in initial tobacco use episodes. Another goal is to outline a research agenda designed to learn more about initial tobacco use episodes and the effects of nicotine in children. An ethical rationale and some potential methods for this research agenda are presented.

Guidelines and methodological reviews concerning drug abuse liability assessment

Regulatory control of drugs with abuse liability is an important component of drug control policy and is believed to help prevent nonmedical use. To be maximally effective, this requires a scientific assessment of abuse liability of drugs considered for regulatory control. These assessments have relied extensively on laboratory-based animal and human testing, but also utilize information from clinical trials, actual abuse and other sources. Here, we discuss recommendations and guidelines that have been proposed for abuse liability assessment and describe important review papers and conference proceedings that have addressed this matter, focusing primarily on drugs with medical usefulness. Historically, there is substantial consensus about how to approach abuse liability evaluation of drugs with actions similar to those of abused opiates, stimulants, depressants, and to a somewhat lesser extent, cannabinoids and hallucinogens, and much of what has been recommended for abuse potential assessment in the past remains valid and useful. On the other hand, novel CNS-active medications which cannot be readily classified with these traditional drugs of abuse are increasingly under development. In addition, advances in the science of abuse liability assessment need to be incorporated into future guidelines and recommendations on this subject. Developers of new medications need guidance on how to utilize scientific research to maximize therapeutic benefit while minimizing risk for abuse. Thus, another goal of this review has been to identify areas where critical thinking and new guideline development are needed.

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central α1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil,l-ephedrine andd-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by α1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil andl-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil required very high doses: modafinil was over 200 times less potent thand-amphetamine and was also less potent thanl-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.

Inhalant abuse in pregnancy

Information from a variety of sources suggests the possibility of adverse effects of maternal inhalant abuse, although a well-controlled, prospective study in this area has not been conducted. One source of this concern is the data from occupational exposure to some of the abused solvents, specifically toluene and TCE, with numerous reports suggesting increased spontaneous abortion and fetal malformations. There are also data suggesting decreased fertility and an increased risk for spontaneous abortion in health care workers exposed to nitrous oxide. The relevance of these studies to problems of inhalant abuse is not clear. Although the chemicals involved are the same, there are many differences in the exposure parameters, the populations exposed, and the types of associated risk factors. Nonetheless, there are more than 100 cases reported in the literature of children born to solvent-abusing mothers. Many of these children were small at birth, and some have craniofacial abnormalities not unlike that seen in children with FAS. In the few studies reporting the findings of follow-up in these children, some evidence has been obtained for retardation in growth and development and for residual deficits in cognitive, speech, and motor skills. Clearly, more research is needed to rule out the concomitant risk factors and to identify specific chemicals and patterns of use associated with adverse effects. Animal studies provide more direct evidence that prenatal exposure to toluene or TCE can produce reduced birth weights, occasional skeletal abnormalities, and delayed neurobehavioral development, even under conditions designed to mimic inhalant abuse patterns. Additional research is needed to identify other chemicals with adverse effects, critical periods of exposure, effects of combinations of inhalants, or interactions with drugs of abuse. The research literature seems sufficient to alert clinicians to possible problems in patients who abuse inhalants while pregnant. Diagnosis and good prenatal care for these women are important. The evidence for neonatal withdrawal is limited at this time; however, infants born to women who have recently used inhalants should be observed carefully for an alcohol-like withdrawal syndrome. Although it is not possible to link a specific birth defect or developmental problem in the child of an inhalant abuser to prenatal exposure to a specific chemical, it is clear that inhalant abuse and its associated lifestyle place children at increased risk. A wider appreciation of this is needed among health care professionals and the general public.

Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys.

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and (+/-)-3,4-methylenedioxymethamphetamine (MDMA; 3-300 micrograms/kg per infusion) during daily 1-h sessions. From four to over nine times more cocaine infusions were obtained than saline infusions during baseline sessions. When MDMA was substituted for cocaine, at least one dose was self-administered in 3 of the 4 monkeys at rates that exceeded the range of saline infusions. In fact, two of the monkeys self-administered a dose of MDMA at a greater rate than cocaine. These results demonstrate that MDMA can serve as a positive reinforcer for rhesus monkeys and, taken together with other preclinical behavioral studies, suggest a potential for recreational use of MDMA by humans.

Opioids: similarity between evaluations of subjective effects and animal self-administration results.

Abuse potential studies of 33 morphine‐like analgesics were compared in humans and monkeys. The results of intravenous self‐administration studies in rhesus monkeys were correlated with measures of morphine‐like signs, symptoms, and subjective effects in ex‐addicts. Each set of data was assigned to a position in a 3 × 3 contingency table dependent upon whether the results were yes, no, or equivocal. Of the 33 drugs, 29 were given identical classifications in both the human and animal test procedures. This good concordance between the human and animal results further validates each procedure and suggests the possibility that both the human and animal procedures are measuring a common underlying pharmacological property which relates to abuse potential of drugs.