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1.
Pharmacol Biochem Behav ; 203: 173129, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33515586

RESUMO

Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.

4.
Behav Brain Res ; 378: 112271, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31593791

RESUMO

Ketamine is a dissociative anesthetic first developed in the 1960s but is increasingly used at subanesthetic doses for both clinical and non-clinical purposes. There is evidence from human recreational users of compulsive use and addiction. Sensitization is an increase in an effect of a drug with repeated use that is thought to be important in the development of addiction. Research on psychomotor stimulants has shown the development of sensitization in laboratory animals to be modified by factors that influence addiction. In the current paper we describe four experiments on the development of sensitization in laboratory rats aimed at determining if ketamine sensitization is also influenced by factors thought to be important in addiction. Adult, male Sprague-Dawley rats received ketamine (5, 10, 20 or 50 mg/kg i.p.) for five or more days and the development of locomotor sensitization was followed. Experiment 1 examined the ability of low doses of ketamine to produce sensitization and found sensitization at 5, 10 and 20 mg/kg. Experiment 2 examined the influence of environmental context and found that ketamine sensitization (20 mg/kg) was greater when administration occurred in a novel environment (the experimental apparatus) than in home cages. Experiment 3 found that ketamine sensitization (20 mg/kg) did not occur when animals were housed in social isolation but occurred readily in pair-housed animals. Finally, Experiment 4 found that ketamine sensitization (20 or 50 mg/kg) was similar whether drug was administered daily or at 3-day intervals. Together, the results demonstrate that ketamine sensitization is robust and reliable, occurring under a variety of circumstances. Moreover, ketamine sensitization is influenced by factors that influence the development of addiction in humans. The current results may lead to a better understanding of ketamine abuse and addiction and may help inform clinical use of the drug.

5.
Behav Brain Res ; 369: 111928, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31034850

RESUMO

Initiation of ketamine use often occurs in adolescence, yet little is known about long-term consequences when use begins in this developmental period. The current experiments were designed to examine the effects of repeated exposure to ketamine in adolescence on behavior in adulthood. We examined locomotor activity, as well as cognitive function, in animals that received repeated administration of ketamine. Groups of adolescent and adult male rats were treated with ketamine (25 mg/kg) once daily for 10 days. Locomotor activity was assessed following the first injection, following 10 days of injection, and following 20 days of abstinence. Acute locomotor effects and locomotor sensitization were compared in adolescents and adults; cross-sensitization to dextromethorphan, another dissociative with abusive potential, was also examined. In a separate group of animals cognitive deficits were assessed following the 20 day abstinence period in spatial learning and novel object recognition tasks. The locomotor stimulant effect of ketamine was much greater in adolescents than adults. Animals that were repeatedly administered ketamine demonstrated locomotor sensitization immediately after the final injection. However, sensitization only persisted after the abstinence period in animals treated as adults. No cross-sensitization to dextromethorphan was evident. Ketamine failed to produce statistically significant cognitive deficits in either age group, although drug-treated adults showed a trend towards deficits in spatial learning. Repeated use of ketamine produces long-lasting neuroadaptations that may contribute to addiction. Mild lasting memory deficits may occur in adults, although further work is necessary to confirm these findings. The results extend the understanding of potential long-term consequences of ketamine use in adolescents and adults.


Assuntos
Ketamina/efeitos adversos , Ketamina/farmacologia , Locomoção/efeitos dos fármacos , Fatores Etários , Animais , Atenção/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Dextrometorfano/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Percepção Visual/efeitos dos fármacos
6.
Neurotoxicology ; 73: 58-80, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30836127

RESUMO

Lead is a neurotoxin that produces long-term, perhaps irreversible, effects on health and well-being. This article summarizes clinical and preclinical studies that have employed a variety of research techniques to examine the neurotoxic effects of low levels of lead exposure. A historical perspective is presented, followed by an overview of studies that examined behavioral and cognitive outcomes. In addition, a short summary of potential mechanisms of action is provided with a focus on calcium-dependent processes. The current level of concern, or reference level, set by the CDC is 5 µg/dL of lead in blood and a revision to 3.5 µg/dL has been suggested. However, levels of lead below 3 µg/dL have been shown to produce diminished cognitive function and maladaptive behavior in humans and animal models. Because much of the research has focused on higher concentrations of lead, work on low concentrations is needed to better understand the neurobehavioral effects and mechanisms of action of this neurotoxic metal.


Assuntos
Comportamento do Adolescente/efeitos dos fármacos , Desenvolvimento do Adolescente/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Comportamento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo em Adultos , Intoxicação do Sistema Nervoso por Chumbo na Infância , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Encéfalo/crescimento & desenvolvimento , Criança , Pré-Escolar , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , História do Século XX , História do Século XXI , Humanos , Intoxicação do Sistema Nervoso por Chumbo em Adultos/história , Intoxicação do Sistema Nervoso por Chumbo em Adultos/fisiopatologia , Intoxicação do Sistema Nervoso por Chumbo em Adultos/psicologia , Intoxicação do Sistema Nervoso por Chumbo na Infância/história , Intoxicação do Sistema Nervoso por Chumbo na Infância/fisiopatologia , Intoxicação do Sistema Nervoso por Chumbo na Infância/psicologia , Camundongos , Pessoa de Meia-Idade , Ratos , Medição de Risco , Fatores de Risco , Testes de Toxicidade , Adulto Jovem
7.
Pharmacol Biochem Behav ; 157: 24-34, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28442368

RESUMO

Adolescence is a phase of development during which many physiological and behavioral changes occur, including increased novelty seeking and risk taking. In humans, this is reflected in experimentation with drugs. Research demonstrates that drug use that begins during adolescence is more likely to lead to addiction than drug use that begins later in life. Despite this, relatively little is known of the effects of drugs in adolescence, and differences in response between adolescents and adults. PCP and ketamine are popular club drugs, both possessing rewarding properties that could lead to escalating use. Drug sensitization (or reverse tolerance), which refers to an increase in an effect of a drug following repeated use, has been linked with the development of drug cravings that is a hallmark of addiction. The current work investigated the acute response and the development of sensitization to PCP and ketamine in adolescent and adult rats. Periadolescent Sprague-Dawley rats (30days or 38days of age), and young adults (60days of age) received PCP (6mg/kg IP) or ketamine (20mg/kg IP) once every three days, for a total of five drug injections. Adolescents and adults showed a stimulant response to the first injection of either drug, however the response was considerably greater in the youngest adolescents and lowest in the adults. With repeated administration, adults showed a robust escalation in activity that was indicative of the development of sensitization. Adolescents showed a flatter trajectory, with similar high levels of activity following an acute treatment and after five drug treatments. The results demonstrate important distinctions between adolescents and adults in the acute and repeated effects of PCP and ketamine.


Assuntos
Ketamina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Movimento/efeitos dos fármacos , Fenciclidina/administração & dosagem , Fatores Etários , Anestésicos Dissociativos/administração & dosagem , Animais , Esquema de Medicação , Alucinógenos/administração & dosagem , Masculino , Atividade Motora/fisiologia , Movimento/fisiologia , Ratos , Ratos Sprague-Dawley
8.
Neuron ; 92(3): 632-636, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-27810007

RESUMO

The greatest challenge in moving neuroscience research forward in the 21st century is recruiting, training, and retaining the brightest, rigorous, and most diverse scientists. The MBL research training courses Neurobiology and Neural Systems & Behavior, and the Summer Program in Neuroscience, Excellence, and Success provide a model for full immersion, discovery-based training while enhancing cultural, geographic, and racial diversity.


Assuntos
Academias e Institutos/organização & administração , Neurociências/educação , Humanos
9.
Pharmacol Biochem Behav ; 99(3): 451-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21549146

RESUMO

Use of drugs of abuse in combination is common among recreational users and addicts. The combination of a psychomotor stimulant with an opiate, known as a 'speedball,' reportedly produces greater effects than either drug alone and has been responsible for numerous deaths. Historically, the most popular speedball combination is that of cocaine and heroin. However, with the growing popularity of methamphetamine in recent years, there has been increased use of this drug in combination with other drugs of abuse, including opiates. Despite this, relatively little research has examined interactions between methamphetamine and opiates. In the current research, behavioral interactions between methamphetamine and the prototypical opiate, morphine, were examined across a variety of dose combinations in Sprague-Dawley rats. The combination of methamphetamine and morphine produced stimulation of behavior that was dramatically higher than either drug alone; however, the magnitude of the interaction was dependent on the dose of the drugs and the specific behaviors examined. The results demonstrate complex behavioral interactions between these drugs, but are consistent with the idea that this combination is used because it produces a greater effect than either drug alone.


Assuntos
Drogas Ilícitas/farmacologia , Metanfetamina/administração & dosagem , Morfina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley
10.
ILAR J ; 52(3): 366-78, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-23382150

RESUMO

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.


Assuntos
Antidepressivos , Ketamina , Analgésicos , Animais , Comportamento Aditivo , Humanos , Transtornos Relacionados ao Uso de Substâncias
11.
Psychopharmacology (Berl) ; 196(3): 497-509, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17994223

RESUMO

RATIONALE: N-Methyl-D: -aspartate (NMDA) receptors have an important role in different forms of behavioral and neural plasticity. Evidence suggests that these receptors may also be involved in plasticity arising from long-term treatment with different drugs of abuse, including tolerance, sensitization, and physical dependence. There is abundant evidence demonstrating that NMDA receptors are involved in tolerance to opiate-induced antinociception; however, the role of these receptors in sensitization to the locomotor effects of opiates is more controversial. OBJECTIVE: The ability of NMDA receptor antagonists to modify the development of sensitization to the locomotor stimulant effect of three different opiates was examined. In selected studies, the ability of the antagonists to modify tolerance to the antinociceptive effects of the opiates was also examined. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine. It was predicted that low, selective doses of the antagonists would inhibit the development of opiate tolerance and sensitization. RESULTS: Consistent with our predictions, the noncompetitive NMDA receptor antagonists MK-801 and memantine and the competitive NMDA receptor antagonist LY235959 inhibited the development of sensitization to the locomotor stimulant effect of morphine. Additionally, MK-801 inhibited the development of tolerance and sensitization to methadone and buprenorphine in a similar manner. CONCLUSIONS: The results, together with previous research, suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization.


Assuntos
Tolerância a Medicamentos/fisiologia , Entorpecentes/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Buprenorfina/administração & dosagem , Buprenorfina/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Isoquinolinas/farmacologia , Masculino , Memantina/farmacologia , Metadona/administração & dosagem , Metadona/farmacologia , Morfina/administração & dosagem , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Opioides , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
12.
Biol Psychiatry ; 63(2): 178-83, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17568566

RESUMO

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.


Assuntos
Analgésicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ketamina/farmacologia , Atividade Motora/efeitos dos fármacos , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
13.
Drug Alcohol Depend ; 84 Suppl 1: S17-28, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16777354

RESUMO

Impressive progress has been made in the understanding of biological contributions to drug abuse and addiction. An area that has only recently begun to receive attention is potential ethnic and racial differences in biological systems that contribute to, or protect from, problem drug use. This article reviews recent research on drug abuse and addiction in Hispanics in which biological questions have been addressed, including work on genes, gene products (proteins), physiology and pharmacotherapy. Taken together, work to date suggests that there are both similarities and differences between Hispanics and other ethnic groups in biological factors related to drug abuse and addiction. Although the results are intriguing, relatively few studies have been done, and those that have been done have often been inconclusive due to low numbers of Hispanic subjects. Moreover, studies have often failed to recognize the complexity and heterogeneity of Hispanic populations in the United States and around the world. After reviewing the current status of the field, recommendations are given for future research in both humans and relevant animal models that will lead to a better understanding of drug abuse and addiction in Hispanics.


Assuntos
Biologia/métodos , Biologia/tendências , Encéfalo/metabolismo , Hispano-Americanos/estatística & dados numéricos , Projetos de Pesquisa , Pesquisa/tendências , Transtornos Relacionados ao Uso de Substâncias/etnologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Aldeído Desidrogenase/metabolismo , Carcinógenos Ambientais/efeitos adversos , Dopamina/metabolismo , Meio Ambiente , Previsões , Expressão Gênica/genética , Humanos , N-Metilaspartato/metabolismo , Norepinefrina/metabolismo , Estado Nutricional , Prevalência , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , Fatores Socioeconômicos , Transtornos Relacionados ao Uso de Substâncias/genética
14.
Pharmacol Biochem Behav ; 79(4): 661-9, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15582674

RESUMO

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.


Assuntos
Fentanila/administração & dosagem , Morfina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Animais , Bombas de Infusão Implantáveis , Masculino , Atividade Motora/fisiologia , Entorpecentes/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley
15.
Neuroscientist ; 10(1): 26-30, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14987445

RESUMO

Despite significant efforts in recent years to increase diversity in science and academia, African Americans, Hispanics, and American Indian/Alaskan Natives remain severely underrepresented in these fields. To date, institutional social climate has received little attention as a target to improve the representation of these minority groups. In this article, we suggest that improvement in the social climate in both individual laboratories and larger institutions may lead to better recruitment and retention of minorities in science and academia. After documenting the magnitude of the underrepresentation problem, we offer a framework for a better understanding of climate, illustrate how members of majority and minority groups may perceive climate differently, and provide specific recommendations for improving the climate. The benefits of a diverse workforce in the sciences include a commitment to social justice, a broad diversity of perspectives leading to greater opportunities for scientific advancement, and a potentially enhanced focus on understanding and eliminating the health disparities among different racial and ethnic groups.


Assuntos
Pesquisa Biomédica , Grupos Minoritários/psicologia , Pesquisadores/psicologia , Atitude , Pesquisa Biomédica/estatística & dados numéricos , Humanos , Grupos Minoritários/estatística & dados numéricos , Pesquisadores/estatística & dados numéricos
16.
Pharmacol Biochem Behav ; 76(2): 361-72, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14592689

RESUMO

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.


Assuntos
Analgésicos Opioides/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores Opioides mu/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Fentanila/farmacologia , Masculino , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Neurotox Res ; 4(4): 373-91, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12829426

RESUMO

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.

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