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Drug-Induced Adaptations in Catecholamine Systems: On the Inevitability of Sensitization
Drug-Induced Adaptations in Catecholamine Systems
987
2. Pontieri, F. E., Tanda, G . , and Di Chiara, G. (1995). Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc. Natl. Acud. Sci. U.S.A. 92, 12304-12308. 3 . Pontieri, F. E., Tanda, G., Orzi, F., and Di Chiara, G. (1996). Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255-257. 4. Bassareo, V., Tanda, G., Petromilli, P., Giua, C., and Di Chiara, G . (1996). Nonpsychostimulant drugs of abuse and anxiogenic drugs activate with differential selectivity dopamine transmission in the nucleus accumbens and in the medial prefrontal cortex of the rat. Psychopharamcology 124, 293-299. 5. Acquas, E., and Di Chiara, G. (1994). D, receptor blockade stereospecifically impairs the acquisition of drug-conditioned place-preference and place-aversion. Behav. Phartnacol. 5,555-569.
Terry E. Robinson and Aldo Badiani Department of Psychology (Biopsychology Program) The University of Michigan Ann Arbor Michigan 48 I09
Drug-Induced Adaptations in Catecholamine Systems: On the Inevitability of Sensitization It is well established that psychostimulant drugs produce many of their effects via actions on brain catecholamine (CA) systems. When these drugs are administered repeatedly, their effects often change, and these changes are thought to be due in part to drug-induced adaptations in CA systems. One form of drug-induced adaptation is manifest behaviorally as the phenomenon of sensitization (1). For example, the repeated intermittent administration of amphetamine (AMPH) o r cocaine (COC) results in a progressive increase in the ability of these drugs to produce locomotor hyperactivity, stereotyped behaviors, o r rotational behavior. Once induced, sensitization may persist for very long periods, perhaps even for years. The neural basis of behavioral sensitization is not known, but both presynaptic and postsynaptic adaptations have been described in CA systems (1, 2 ) . Presynaptic adaptations include (1) a persistent increase in the ability of AMPH or C O C to enhance the overflow of dopamine (DA) in the caudate and nucleus accumbens and (2) a persistent increase in the overflow of norepinephrine (NE) in the hippocampus of rats Aduuncer in Phormaculugy, Volume 42 Copyright Q 1998 by Academic Press. All rights uf reproduction 1054-3589198 $25.00
in
any form reserved
988
Terry
E. Robinson and Aldo
Badiani
sensitized with AMPH, both under resting conditions and after an AMPH challenge (3). An example of a postsynaptic adaptation is a sensitization-related increase in the responsiveness of DA D 1 receptors in the nucleus accumbens (2). Sensitization of DA systems has attracted much of the attention in this field, perhaps because of the well-known role of these neurons in mediating the rewarding effects of drugs of abuse and of natural rewards. The fact that drugs of abuse can produce long-lasting alterations in a neural system involved in reward suggests that “neural sensitization” may play a role in the process of addiction. Indeed, it is difficult to imagine that if repeated exposure to drugs renders DA systems persistently hypersensitive to activating stimuli, including drugs themselves, that such neuroadaptations would not alter the process of reward and, thus, in some way contribute to addiction. Consistent with this idea, there is experimental evidence that repeated exposure to psychostimulant drugs results not only in sensitization to their psychomotor activating effects, but also to their rewarding effects (1).Exactly how sensitization of CA systems might contribute to addiction has been the subject of much speculation and discussion, and Kent Berridge and I (T. E. R.) have suggested (1)that neural sensitization may lead to pathological “wanting” (because of excessive incentive salience attribution), dissociated from the ability of drugs to produce subjective pleasurable effects (“liking”). Whatever the mechanism(s) by which psychostimulants produce adaptations in CA systems and alter the behavioral effects of drugs, it is important to determine the conditions that lead to neural sensitization and promote its expression. Sensitization is often thought of as an inevitable consequence of the pharmacological actions of a drug on a sensitive neural substrate; that is, when a sensitive neural substrate is repeatedly exposed to a drug (or other ligand), the substrate adapts. The behavioral effects of drugs are, however, powerfully modulated by the circumstances surrounding drug administration. In the remainder of this essay, we will consider two examples of how the circumstances surrounding drug administration can alter the induction and expression of sensitization. These examples illustrate that sensitization is not an inevitable consequence of exposure to psychostimulant drugs. In the first example, drug administration is thought to induce neural sensitization, but the circumstances surrounding drug administration and readministration determine whether neural sensitization is expressed in behavior. In the second example, the circumstances surrounding drug administration may determine whether neural sensitization is induced a t all.
1. Modulation of Expression There are many reports that under some circumstances the expression of behavioral sensitization is context-specific (1). If animals are given repeated treatments with AMPH or COO in one environment and then later a challenge injection of the drug in a different (test) environment (“unpaired” animals), behavioral sensitization may not be expressed in the test environment (i. e., it is specific to the treatment context). Despite this powerful conditioned stimulus
Drug-Induced Adaptations in Catecholamine Systems
989
control over the expression of behavioral sensitization, there are two reasons to believe that even unpaired animals undergo neural sensitization (4). One, unpaired animals develop behavioral sensitization in the drug treatment environment. This suggests that the neuroadaptations responsible for behavioral sensitization are induced in these animals, even though they will not be expressed when later the animals are given a drug challenge in a unique test environment. Two, examples of neural sensitization have been described under conditions that preclude the influence of contextual stimuli on the expression of the drug response, for example, in striatal tissue slices in vitro and in anesthetized animals (1, 2 ) . These studies indicate that behavioral sensitization does not simply represent unconditional neurobiological adaptations produced by the actions of drugs on a neural substrate, because the major determinant of whether sensitization is expressed at any particular place or time is the context in which the drug is readministered. Exactly how contextual stimuli and other circumstances surrounding drug administration and readministration modulate the expression of sensitization is not known, although Anagnostaras and Robinson (4)discuss the pros and cons of three different models (an excitatory conditioning model, an inhibitory conditioning model, and an occasion-setting model).
II. Modulation of Induction Not only might the circumstances surrounding drug administration determine whether neural sensitization is expressed in behavior, but also whether neural sensitization is induced in the first place, or at least, the rate and extent of sensitization induced by a particular dose of a drug. Previous studies on context-specific sensitization do not address this issue because in none of these studies was the development of sensitization assessed, just the extent to which stimuli previously associated with drug administration influenced the subsequent expression of sensitization on a test day (5). The first study to report that an environmental manipulation alters the induction of sensitization was by Badiani et al. (5).In these experiments, rats received repeated i.p. injections of AMPH under one of two conditions. One group received drug treatments in the cage in which they lived (at “home”). Another group was transported from distinct cages in which they lived to test cages that were physically identical to the other groups home cages, where they then received the drug. For the latter group, therefore, drug treatments were given in a “novel” context. In these experiments, the rate and extent of psychomotor sensitization was greater when AMPH was given in the novel situation, relative to the home situation. More recently, we reported that the unsignaled intravenous infusion of 1.0 mg/kg of AMPH at home (using a remotely activated syringe pump) failed to induce behavioral sensitization (6). When the same treatment was signaled by placement in a physically identical but novel environment, animals did develop behavioral sensitization. These studies suggest, therefore, that the circumstances surrounding drug administration may determine whether a given dose of a drug is capable of inducing neural sensitization.
990
Terry E. Robinson and Aldo Badiani
As in the case of contextual control over the expression of neural sensitization, it is not known how environmental and psychological factors gain access to the neural substrate that is sensitized by psychostimulant drugs. Indeed, it is not even known what the critical variables are. We have speculated that exposure to a relatively novel environment may promote sensitization either because of some action as a stressor or because it facilitates associative learning, but these hypotheses remain to be tested ( 5 ) . Whatever the mechanism, to fully understand the phenomenon of sensitization (and other drug-induced neuroadaptations), it will be important to determine how seemingly simple manipulations of the circumstances surrounding drug administration can have such profound effects on the ability of drugs to change the nervous system. In humans, the experience associated with the administration of drugs of abuse varies enormously. This variation exists because a given drug effect is not a simple consequence of the pharmacological actions of a drug, but is due to complex interactions among pharmacological, environmental, and psychological factors, for example, whether drugs are taken in a drug-associated environment, what expectations the person brings to the situation, and so on. It is suggested here that similar complex interactions also determine the probability that psychostimulant drugs will produce adaptations in neural systems involved in psychomotor activation and reward, and in this way may contribute to susceptibility to sensitization and addiction. The two examples discussed, of how the circumstances surrounding drug administration can modulate the expression or induction of psychostimulant sensitization, may provide, therefore, a powerful animal model to study the nature of the environmental and psychological factors that influence the ability of drugs to change the nervous system, as well as a way to begin to explore the neurobiological mechanisms by which they act.
References 1. Robinson, T. E., and Berridge, K. C. (1993). The neural basis of drug craving: An incentivesensitization theory of addiction. Brain Res. Rev. 18, 247-291. 2. White, F. J., and Wolf, M. E. (1991). Psychomotor stimulants. In The Biological Bases of Drug Tolerance and Dependence. (J. Pratt, ed.), pp. 153-197. Academic Press, New York. 3. Camp, D. M., DeJonghe, D. K., and Robinson, T. E. (1997). Time-dependent effects of repeated amphetamine treatment on norepinephrine in the hypothalamus and hippocampus assessed with in vivo microdialysis. Neuropsychopharmacol (in press). 4. Anagnostaras, S. G., and Robinson, T. E. (1996).Sensitization to the psychomotor stimulant effects of amphetamine: Modulation by associative learning. Behav. Neurosci. 110, 13971414. 5. Badiani, A., Anagnostaras, S. G., and Robinson, T. E. (1995).The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment. Psychopharmacology 117, 443-452. 6. Crombag, H. S., Badiani, A., and Robinson, T. E. (1996). Signalled versus unsignalled intravenous amphetamine: Large differences in the acute psychomotor response and sensitization. Brain Res. 722, 227-231.
987
2. Pontieri, F. E., Tanda, G . , and Di Chiara, G. (1995). Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc. Natl. Acud. Sci. U.S.A. 92, 12304-12308. 3 . Pontieri, F. E., Tanda, G., Orzi, F., and Di Chiara, G. (1996). Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255-257. 4. Bassareo, V., Tanda, G., Petromilli, P., Giua, C., and Di Chiara, G . (1996). Nonpsychostimulant drugs of abuse and anxiogenic drugs activate with differential selectivity dopamine transmission in the nucleus accumbens and in the medial prefrontal cortex of the rat. Psychopharamcology 124, 293-299. 5. Acquas, E., and Di Chiara, G. (1994). D, receptor blockade stereospecifically impairs the acquisition of drug-conditioned place-preference and place-aversion. Behav. Phartnacol. 5,555-569.
Terry E. Robinson and Aldo Badiani Department of Psychology (Biopsychology Program) The University of Michigan Ann Arbor Michigan 48 I09
Drug-Induced Adaptations in Catecholamine Systems: On the Inevitability of Sensitization It is well established that psychostimulant drugs produce many of their effects via actions on brain catecholamine (CA) systems. When these drugs are administered repeatedly, their effects often change, and these changes are thought to be due in part to drug-induced adaptations in CA systems. One form of drug-induced adaptation is manifest behaviorally as the phenomenon of sensitization (1). For example, the repeated intermittent administration of amphetamine (AMPH) o r cocaine (COC) results in a progressive increase in the ability of these drugs to produce locomotor hyperactivity, stereotyped behaviors, o r rotational behavior. Once induced, sensitization may persist for very long periods, perhaps even for years. The neural basis of behavioral sensitization is not known, but both presynaptic and postsynaptic adaptations have been described in CA systems (1, 2 ) . Presynaptic adaptations include (1) a persistent increase in the ability of AMPH or C O C to enhance the overflow of dopamine (DA) in the caudate and nucleus accumbens and (2) a persistent increase in the overflow of norepinephrine (NE) in the hippocampus of rats Aduuncer in Phormaculugy, Volume 42 Copyright Q 1998 by Academic Press. All rights uf reproduction 1054-3589198 $25.00
in
any form reserved
988
Terry
E. Robinson and Aldo
Badiani
sensitized with AMPH, both under resting conditions and after an AMPH challenge (3). An example of a postsynaptic adaptation is a sensitization-related increase in the responsiveness of DA D 1 receptors in the nucleus accumbens (2). Sensitization of DA systems has attracted much of the attention in this field, perhaps because of the well-known role of these neurons in mediating the rewarding effects of drugs of abuse and of natural rewards. The fact that drugs of abuse can produce long-lasting alterations in a neural system involved in reward suggests that “neural sensitization” may play a role in the process of addiction. Indeed, it is difficult to imagine that if repeated exposure to drugs renders DA systems persistently hypersensitive to activating stimuli, including drugs themselves, that such neuroadaptations would not alter the process of reward and, thus, in some way contribute to addiction. Consistent with this idea, there is experimental evidence that repeated exposure to psychostimulant drugs results not only in sensitization to their psychomotor activating effects, but also to their rewarding effects (1).Exactly how sensitization of CA systems might contribute to addiction has been the subject of much speculation and discussion, and Kent Berridge and I (T. E. R.) have suggested (1)that neural sensitization may lead to pathological “wanting” (because of excessive incentive salience attribution), dissociated from the ability of drugs to produce subjective pleasurable effects (“liking”). Whatever the mechanism(s) by which psychostimulants produce adaptations in CA systems and alter the behavioral effects of drugs, it is important to determine the conditions that lead to neural sensitization and promote its expression. Sensitization is often thought of as an inevitable consequence of the pharmacological actions of a drug on a sensitive neural substrate; that is, when a sensitive neural substrate is repeatedly exposed to a drug (or other ligand), the substrate adapts. The behavioral effects of drugs are, however, powerfully modulated by the circumstances surrounding drug administration. In the remainder of this essay, we will consider two examples of how the circumstances surrounding drug administration can alter the induction and expression of sensitization. These examples illustrate that sensitization is not an inevitable consequence of exposure to psychostimulant drugs. In the first example, drug administration is thought to induce neural sensitization, but the circumstances surrounding drug administration and readministration determine whether neural sensitization is expressed in behavior. In the second example, the circumstances surrounding drug administration may determine whether neural sensitization is induced a t all.
1. Modulation of Expression There are many reports that under some circumstances the expression of behavioral sensitization is context-specific (1). If animals are given repeated treatments with AMPH or COO in one environment and then later a challenge injection of the drug in a different (test) environment (“unpaired” animals), behavioral sensitization may not be expressed in the test environment (i. e., it is specific to the treatment context). Despite this powerful conditioned stimulus
Drug-Induced Adaptations in Catecholamine Systems
989
control over the expression of behavioral sensitization, there are two reasons to believe that even unpaired animals undergo neural sensitization (4). One, unpaired animals develop behavioral sensitization in the drug treatment environment. This suggests that the neuroadaptations responsible for behavioral sensitization are induced in these animals, even though they will not be expressed when later the animals are given a drug challenge in a unique test environment. Two, examples of neural sensitization have been described under conditions that preclude the influence of contextual stimuli on the expression of the drug response, for example, in striatal tissue slices in vitro and in anesthetized animals (1, 2 ) . These studies indicate that behavioral sensitization does not simply represent unconditional neurobiological adaptations produced by the actions of drugs on a neural substrate, because the major determinant of whether sensitization is expressed at any particular place or time is the context in which the drug is readministered. Exactly how contextual stimuli and other circumstances surrounding drug administration and readministration modulate the expression of sensitization is not known, although Anagnostaras and Robinson (4)discuss the pros and cons of three different models (an excitatory conditioning model, an inhibitory conditioning model, and an occasion-setting model).
II. Modulation of Induction Not only might the circumstances surrounding drug administration determine whether neural sensitization is expressed in behavior, but also whether neural sensitization is induced in the first place, or at least, the rate and extent of sensitization induced by a particular dose of a drug. Previous studies on context-specific sensitization do not address this issue because in none of these studies was the development of sensitization assessed, just the extent to which stimuli previously associated with drug administration influenced the subsequent expression of sensitization on a test day (5). The first study to report that an environmental manipulation alters the induction of sensitization was by Badiani et al. (5).In these experiments, rats received repeated i.p. injections of AMPH under one of two conditions. One group received drug treatments in the cage in which they lived (at “home”). Another group was transported from distinct cages in which they lived to test cages that were physically identical to the other groups home cages, where they then received the drug. For the latter group, therefore, drug treatments were given in a “novel” context. In these experiments, the rate and extent of psychomotor sensitization was greater when AMPH was given in the novel situation, relative to the home situation. More recently, we reported that the unsignaled intravenous infusion of 1.0 mg/kg of AMPH at home (using a remotely activated syringe pump) failed to induce behavioral sensitization (6). When the same treatment was signaled by placement in a physically identical but novel environment, animals did develop behavioral sensitization. These studies suggest, therefore, that the circumstances surrounding drug administration may determine whether a given dose of a drug is capable of inducing neural sensitization.
990
Terry E. Robinson and Aldo Badiani
As in the case of contextual control over the expression of neural sensitization, it is not known how environmental and psychological factors gain access to the neural substrate that is sensitized by psychostimulant drugs. Indeed, it is not even known what the critical variables are. We have speculated that exposure to a relatively novel environment may promote sensitization either because of some action as a stressor or because it facilitates associative learning, but these hypotheses remain to be tested ( 5 ) . Whatever the mechanism, to fully understand the phenomenon of sensitization (and other drug-induced neuroadaptations), it will be important to determine how seemingly simple manipulations of the circumstances surrounding drug administration can have such profound effects on the ability of drugs to change the nervous system. In humans, the experience associated with the administration of drugs of abuse varies enormously. This variation exists because a given drug effect is not a simple consequence of the pharmacological actions of a drug, but is due to complex interactions among pharmacological, environmental, and psychological factors, for example, whether drugs are taken in a drug-associated environment, what expectations the person brings to the situation, and so on. It is suggested here that similar complex interactions also determine the probability that psychostimulant drugs will produce adaptations in neural systems involved in psychomotor activation and reward, and in this way may contribute to susceptibility to sensitization and addiction. The two examples discussed, of how the circumstances surrounding drug administration can modulate the expression or induction of psychostimulant sensitization, may provide, therefore, a powerful animal model to study the nature of the environmental and psychological factors that influence the ability of drugs to change the nervous system, as well as a way to begin to explore the neurobiological mechanisms by which they act.
References 1. Robinson, T. E., and Berridge, K. C. (1993). The neural basis of drug craving: An incentivesensitization theory of addiction. Brain Res. Rev. 18, 247-291. 2. White, F. J., and Wolf, M. E. (1991). Psychomotor stimulants. In The Biological Bases of Drug Tolerance and Dependence. (J. Pratt, ed.), pp. 153-197. Academic Press, New York. 3. Camp, D. M., DeJonghe, D. K., and Robinson, T. E. (1997). Time-dependent effects of repeated amphetamine treatment on norepinephrine in the hypothalamus and hippocampus assessed with in vivo microdialysis. Neuropsychopharmacol (in press). 4. Anagnostaras, S. G., and Robinson, T. E. (1996).Sensitization to the psychomotor stimulant effects of amphetamine: Modulation by associative learning. Behav. Neurosci. 110, 13971414. 5. Badiani, A., Anagnostaras, S. G., and Robinson, T. E. (1995).The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment. Psychopharmacology 117, 443-452. 6. Crombag, H. S., Badiani, A., and Robinson, T. E. (1996). Signalled versus unsignalled intravenous amphetamine: Large differences in the acute psychomotor response and sensitization. Brain Res. 722, 227-231.