Keith A. Trujillo

Excitatory amino acids and drugs of abuse: a role for N-methyl-d-aspartate receptors in drug tolerance, sensitization and physical dependence

N-methyl-D-aspartate (NMDA) receptors have been implicated in several types of neural and behavioral plasticity ranging from development to learning. The present paper reviews evidence suggesting that these receptors might also be involved in the neural and behavioral changes resulting from chronic administration of drugs of abuse. NMDA receptor antagonists have been found to interfere with tolerance, sensitization, physical dependence and conditioning to a variety of self-administered drugs, including psychomotor stimulants, opiates, ethanol and nicotine. The results indicate a broad role for NMDA receptors in drug-induced neural and behavioral plasticity, including changes in the brain and behavior that may lead to compulsive drug use, and suggest that drugs acting at the NMDA receptor complex may be clinically useful.

Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? A review of preclinical studies.

Abstract Rationale: Research over the past decade demonstrating that NMDA receptor antagonists have the ability to inhibit opiate tolerance, sensitization and physical dependence has led to the suggestion that NMDA receptors may have a critical role in opiate-induced neural and behavioral plasticity. However, there have been suggestions that the effects of NMDA receptor antagonists on these phenomena result from non-specific behavioral or pharmacological effects, rather than from a specific inhibition of plasticity. Objectives: To review the literature in order to explore whether the effects of NMDA receptor antagonists on opiate-induced changes in behavior are best accounted for by an inhibition of neural and behavioral plasticity, or if alternative explanations might better account for the results. Results: The effects of NMDA receptor antagonists on the development of tolerance to opiate analgesia and the development of opiate physical dependence do not appear to be due to confounding behavioral effects produced by high doses of NMDA receptor antagonists, ”side-effects” of a particular drug or drug class, blockade of associative learning processes, or state-dependency. Results on tolerance and sensitization to the locomotor effects of morphine are more mixed and controversial; however, there is evidence suggesting that NMDA receptor antagonists may inhibit these phenomena in a similar manner. Conclusions: NMDA receptor antagonists appear to inhibit the neural plasticity underlying some forms of opiate tolerance, sensitization and physical dependence, suggesting that NMDA receptors are involved in the development of these drug-induced changes in behavior. Further research will help to determine the neural mechanisms responsible for these phenomena, and the therapeutic potential for drugs acting on the NMDA receptor complex in the treatment of pain and addiction.

Motivational Properties of Oxytocin in the Conditioned Place Preference Paradigm

We hypothesized that oxytocin might have intrinsic reinforcing properties and studied it using a conditioned place preference. Three studies examining motivational properties of oxytocin in nonpreferred, preferred, and balance designs were performed utilizing two compartment apparatus. On alternate days, compartments were paired with subcutaneously injected oxytocin (6 mg/kg) or saline, and animal pre- and post-conditioning place preference was compared. Whereas in animals paired with saline there was a shift to a lack of preference, oxytocin-treated animals reversed their preference, spending more time in a previously unpreferred, compartment. In preferred compartment design, oxytocin-treated animals further increased their preference, whereas saline-treated animals decreased their preference toward a nonpreference for either compartment. Our results demonstrate that oxytocin produces a reliable and robust preference for the environment with which it is repeatedly associated, and has rewarding or potentially anti-aversive properties. Future studies are needed to distinguish among these possibilities.

The neurobiology of opiate tolerance, dependence and sensitization: Mechanisms of NMDA receptor-dependent synaptic plasticity

Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-d-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.

Increased Response to Ketamine Following Treatment at Long Intervals: Implications for Intermittent Use

BACKGROUND Ketamine has been used for many years as a dissociative anesthetic; however, there is evidence of increasing abuse, especially at dance clubs and raves. In addition, there is increasing interest in the use of subanesthetic doses of ketamine for the treatment of pain and depression, as well as for clinical research on schizophrenia. Despite growing use, relatively little is known about the consequences of repeated administration of low doses of ketamine. METHODS To determine the changes in response to repeated administration, ketamine (20 mg/kg or 50 mg/kg intraperitoneal [IP]) was administered once weekly to laboratory rats and the locomotor response was assessed following each injection. RESULTS Repeated administration of ketamine led to an escalation in the stimulant effects of the drug, characteristic of behavioral sensitization. The development of sensitization was greater when ketamine was repeatedly administered in the presence of distinct environmental cues. CONCLUSIONS Intermittent administration of ketamine at weekly intervals leads to the development of locomotor sensitization. These results suggest caution in the repeated use of ketamine for recreational or clinical purposes.

Effects of NMDA receptor antagonists on acute μ-opioid analgesia in the rat

Mixed research findings have led to a debate regarding the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on opiate analgesia. NMDA antagonists have been found in various studies to enhance, to inhibit, or to have no effect on opiate analgesia. The present research used a single protocol to explore the effects of six NMDA receptor antagonists on acute morphine (3.0 mg/kg s.c.) and fentanyl (0.05 mg/kg s.c.) analgesia in adult male Sprague-Dawley rats. NMDA receptor antagonists were selected based on their abilities to block various sites on the NMDA receptor complex, including the noncompetitive antagonists MK-801 (0.1 and 0.3 mg/kg i.p.), dextromethorphan (10.0 and 30.0 mg/kg i.p.), and memantine (3.0 and 10.0 mg/kg i.p.), a glycine site antagonist, (+)-HA-966 (10.0 and 30.0 mg/kg i.p.), a competitive antagonist, LY235959 (1.0 and 3.0 mg/kg i.p.), and a polyamine site antagonist, ifenprodil (1.0 and 3.0 mg/kg i.p.). Analgesia was assessed using the tail-flick test. A single dose of each opiate was used. The low doses of the antagonists, which are known to produce significant neural and behavioral actions at NMDA receptors, had no effect on morphine or fentanyl analgesia. At the higher doses, morphine analgesia was significantly enhanced by LY235959 (3.0 mg/kg), and fentanyl analgesia was significantly enhanced by LY235959 (3.0 mg/kg), dextromethorphan (30.0 mg/kg), and (+)-HA-966 (30.0 mg/kg). Enhancement of analgesia occurred without any apparent adverse side effects. None of the NMDA antagonists affected tail-flick responses on their own, except the higher dose of LY235959 (3.0 mg/kg), which produced a mild analgesic effect. Because no consistent effects were observed, the data suggest that NMDA receptors are not involved in acute mu-opioid analgesia. The mechanisms underlying the enhancement of opiate analgesia by selected NMDA antagonists, such as LY235959, dextromethorphan, and (+)-HA-966, remain to be determined.

Neuroanatomical and Neurochemical Substrates of Drug-Seeking Behavior: Overview and Future Directions

The focus of this volume, Molecular and Cellular Aspects of the Drug Addictions, addresses but one perspective of an admittedly complex biological, psychological, and social phenomenon: the administration of drugs for nonmedical reasons. It is readily acknowledged that, in the human, “drug abuse” and “addiction” involve interactions between biological, psychological, and social dimensions. However, it is also readily apparent from both human and animal research that much can be discussed concerning the biological dimension; drugs are self-administered because of their effects on biological systems in the brain. Moreover, research is leading us steadily closer to the specific neurochemical, neuroanatomical, molecular, and cellular actions that are important in the self-administration of drugs.

Cellular and Molecular Mechanisms of Opioid Tolerance and Dependence Progress and Pitfalls

Recent cellular models of opioid tolerance and dependence have incorporated the idea that excitatory amino acid systems may have an important role in these phenomena. Fundytus and Coderre have developed a model that suggests a prominent role for metabotropic glutamate receptors in the initiation and the development of opioid tolerance and dependence. This Commentary briefly reviews Fundytus and Coderres model of tolerance and dependence, offering comparisons and contrasts with the model of Mao, Price, and Mayer, which suggests a central role for N-methyl-D-aspartate receptors. Strengths and weaknesses of these models are discussed, as well as potential revisions that may lead to a more complete model of these phenomena.

Continuous administration of opioids produces locomotor sensitization

Sensitization, a behavioral phenomenon characterized by an escalating pattern of drug response following repeated administration, is thought to be involved in the development of addiction. Research on certain drugs of abuse, most notably the psychomotor stimulants amphetamine and cocaine, suggests that two factors are important to the development of sensitization: (1) drugs must be administered intermittently, rather than continuously, and (2) drugs must be administered in association with specific environmental cues. The present studies were performed to determine if the same requirements exist for opioid sensitization. If sensitization occurs following continuous infusion of the drugs, then neither intermittent administration nor specific environmental cues can be critical. Morphine was administered continuously with pellets (2 x 75 mg) or osmotic pumps (20 mg/kg/day), and fentanyl was administered continuously with osmotic pumps (0.2 mg/kg/day) to male Sprague-Dawley rats. Continuous infusion of either morphine or fentanyl led to an escalating pattern of activity that is characteristic of sensitization to the locomotor effects of the drugs. The escalation of activity was evident across different measures of activity, and persisted beyond continuous administration. The results suggest that, unlike sensitization to cocaine or amphetamine, intermittent administration and environmental specificity are not critical to opioid sensitization. These findings may have implications for the treatment of pain and addiction.

The Neurobehavioral Pharmacology of Ketamine: Implications for Drug Abuse, Addiction, and Psychiatric Disorders

Ketamine was developed in the early 1960s as an anesthetic and has been used for medical and veterinary procedures since then. Its unique profile of effects has led to its use at subanesthetic doses for a variety of other purposes: it is an effective analgesic and can prevent certain types of pathological pain; it produces schizophrenia-like effects and so is used in both clinical studies and preclinical animal models to better understand this disorder; it has rapid-acting and long-lasting antidepressant effects; and it is popular as a drug of abuse both among young people at dance parties and raves and among spiritual seekers. In this article we summarize recent research that provides insight into the myriad uses of ketamine. Clinical research is discussed, but the focus is on preclinical animal research, including recent findings from our own laboratory. Of particular note, although ketamine is normally considered a locomotor stimulant at subanesthetic doses, we have found locomotor depressant effects at very low subanesthetic doses. Thus, rather than a monotonic dose-dependent increase in activity, ketamine produces a more complex dose response. Additional work explores the mechanism of action of ketamine, ketamine-induced neuroadaptations, and ketamine reward. The findings described will inform future research on ketamine and lead to a better understanding of both its clinical uses and its abuse.