Full-length reviewA circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants
Introduction
Behavioral sensitization to amphetamine-like psychostimulants is a consequence of repeated drug administration and is defined as an augmentation in the behavioral effect of a psychostimulant upon re-administration. Although initially observed in both experimental animals and humans in the 1930s 63, 322, the study of behavioral sensitization was revitalized in the 1970s 232, 255as a result of growing evidence that chronic psychostimulant abuse led to an increase in anxiety and paranoia that often could not be distinguished from paranoid schizophrenia 6, 68, 230. At this time it was also discovered that the expression of behavioral sensitization to psychostimulants is strengthened by the association of drug injections with environmental cues [286]. Thus, behavioral sensitization to psychostimulants could be attributed not only to a direct pharmacological action of the drug but also to learned associations with the drug experience.
The investigation into the neural underpinnings of behavioral sensitization in the 1970s was focused on dopamine, which had been identified as a neurotransmitter critical for both the reinforcing and behavioral stimulant effects of amphetamine-like psychostimulants 33, 236. Clarification that psychostimulants bind to the dopamine transporter 238, 241prompted further experimental scrutiny of the role of dopamine in the expression of behavioral sensitization that has continued into the 1990s 141, 244. Experimentation evolved in two general directions: (1) the study of the cellular and molecular mechanisms of drug effects on dopamine terminal fields, such as the nucleus accumbens, striatum and prefrontal cortex (PFC), and (2) the study of alterations in neurotransmission in the circuitry in which the dopamine projections are embedded following repeated psychostimulant injections. The former direction has yielded a conglomerate of data that has resisted simple interpretations, primarily because no single neuronal effect is likely to be responsible for the expression of behavioral sensitization. The latter line of investigation has included the study of neurotransmitters other than dopamine, but is fraught with interpretational difficulties since the role of circuitry in behavior is studied in vivo with experimental tools that encompass relatively large brain regions.
The present review endeavors to relieve some of the confusion currently associated with the mechanisms underlying the expression of behavioral sensitization to psychostimulants and to assist in charting future experimental directions. This will be attempted as follows.
- 1.
Review the literature and critically evaluate the extent to which the neural consequences of repeated psychostimulant administration are associated with the expression of behavioral sensitization.
- 2.
Employ the `motive' circuit shown in Fig. 1 as a template to organize the relevant biochemical and molecular findings into a neural model of the expression of behavioral sensitization.
Behavioral augmentation following repeated psychostimulant administration is one manifestation of sensitization in the nervous system. A fundamental conceptualization employed in studying the mechanisms of neural sensitization is that these phenomena can be examined in two distinct temporal domains, termed initiation and expression 130, 141, 244.
The initiation of behavioral sensitization to psychostimulants is operationally defined as the transient sequence of cellular and molecular events precipitated by psychostimulant administration that leads to the enduring changes in neural function responsible for behavioral augmentation. Expression is defined as the enduring neural alterations arising from the initiation process that directly mediate the augmented behavioral response. A variety of data show that these processes are not only temporally but also anatomically distinct. Initiation of behavioral sensitization to psychostimulants occurs in the ventral tegmental area (VTA; see [129]for a review), which is the locus of the dopamine cells in the ventral mesencephalon that give rise to the mesocorticolimbic pathway [71]. In contrast, the neuronal events associated with expression are distributed among the interconnected nuclei of the motive circuit (Fig. 1). Several recent reviews have outlined the neurotransmitter interactions and cellular events in the VTA that are associated with the initiation of behavioral sensitization (see 76, 129, 304). Therefore, the present review will not address the mechanisms underlying initiation and will instead focus on the changes in neurotransmission that contribute to the expression of behavioral sensitization.
A primary concern in accurately interpreting the literature with regard to the neural underpinnings of behavioral sensitization is the time at which the experimental measurements are obtained after discontinuing the psychostimulant treatment regimen. Fig. 2 illustrates a general pattern of drug taking for the induction of behavioral sensitization in a psychostimulant addict and in an animal model. Although sensitization is an enduring behavioral transformation, much of our understanding of the neural alterations precipitated by repeated psychostimulant administration is derived from measurements obtained during the first 1–72 h after the last drug injection. Measurements made during this period are appropriate for comprehending the neural basis of behavioral events accompanying the psychostimulant withdrawal syndrome, such as drug craving and anhedonia 81, 178. However, the biochemical alterations in the brain mediating these behavioral conditions will dissipate in parallel with the withdrawal syndrome over the first week after discontinuing drug administration and, therefore, do not constitute the biochemical basis of long-term behavioral sensitization. Furthermore, the biochemical alterations associated with early drug withdrawal may mask some of the changes underlying behavioral sensitization [133]. For these reasons, it is most appropriate to measure changes in neural function following a drug challenge administered a week or more after discontinuing the repeated drug administration regimen (see Fig. 2). In composing this review, the literature was evaluated according to the time during withdrawal that measurements were made, and greater emphasis was given to data obtained at later withdrawal times.
The neuronal circuit illustrated in Fig. 1 is termed the motive circuit and has a consequential role in translating biologically relevant stimuli into adaptive behavioral responses (see [131]for a review). Studies conducted over the last decade demonstrate that the interconnected nuclei of the motive circuit act in concert to permit or obstruct the expression of behavioral responses to environmental and pharmacological stimuli 139, 162, 190, 191, 281(see Table 1). The motive circuit is conceptualized as a gain control mechanism that determines both the threshold and intensity of behavioral responses to a given stimulus. A primary hypothesis of this review is that repeated psychostimulant administration produces long-term changes in neurotransmission that are distributed throughout the motive circuit. Behavioral sensitization occurs because these distributed changes in neurotransmission alter the gain of the motive circuit such that a greater behavioral response is elicited by a given pharmacological stimulus.
The nuclei of the motive circuit are topographically interconnected in a manner that permits the relatively discrete flow of information from limbic nuclei to both pyramidal and extrapyramidal motor systems 105, 213, 315. Fig. 1A illustrates the topography of the interconnections within the motive circuit that provides the anatomical framework for information to progress from limbic nuclei to motor systems. For example, the amygdala preferentially innervates the VTA, the shell of the nucleus accumbens and the ventromedial compartment of the ventral pallidum (VP) 105, 315. These three subnuclei are reciprocally interconnected with each other, but not with motor systems 43, 100, 106, 149, 325. In order to access the nuclei directly regulating motor activity, the VTA projects to the core of the nucleus accumbens and the dorsolateral compartment of the VP 71, 149, which are interconnected with extrapyramidal motor systems via the substantia nigra, medial subthalamic nucleus and pedunculopontine motor region 97, 105, 131, 192. In addition, the ventromedial compartment of the VP projects to the mediodorsal thalamus (MD) which innervates the dorsal PFC 45, 159. The dorsal, prelimbic compartment of the PFC preferentially projects to the core of the nucleus accumbens, as well as to the substantia nigra 17, 259. Thus, this thalamic component of the motive circuit permits information to access extrapyramidal systems via interconnections with the PFC 45, 326.
A growing number of studies using a variety of experimental techniques indicate that the nuclei comprising the motive circuit play a critical role in translating environmental or pharmacological stimuli into behavioral responses. Lesions of the nucleus accumbens, amygdala, MD or VP inhibit the maintenance of conditioned responding for food or psychostimulant administration 30, 70, 119, 183, 205, 274. Numerous experiments also reveal that the microinjection of transmitter analogues into nuclei of the motive circuit can inhibit or promote the execution of behavioral responses to environmental or pharmacological stimuli (see [131]for a review). In addition, behavioral responding to biologically relevant stimuli is associated with changes in extracellular neurotransmitter levels and electrophysiological activity in nuclei of the motive circuit 8, 107, 177, 189, 217, 251, 301. This convergence of evidence from a variety of methodological approaches is summarized in Table 1 and testifies to the important role played by the motive circuit in the initiation and maintenance of behavioral responses to both natural stimuli and drugs of abuse.
Much of the study of the neural basis of sensitization has involved evaluating changes in neurotransmission in the nuclei comprising the motive circuit. Fig. 1B summarizes the neurotransmitters associated with the projections of the motive circuit. Dopamine emanates solely from the VTA and innervates all nuclei in the motive circuit 71, 280. Excitatory amino acid transmitters arise from the thalamus and limbic structures, such as the amygdala, hippocampus and PFC, and widely innervate the motive circuit 42, 73, 194, 289. There are reciprocal γ-aminobutyric acid (GABA) projections between the nucleus accumbens and VP. In addition, the VP is a source of GABAergic innervation to the VTA and MD 43, 45, 99, 139, 327. The neurochemical alterations observed in the nuclei of the motive circuit that are associated with the long-term expression of behavioral sensitization to psychostimulants are reviewed in the following sections.
Section snippets
Nucleus accumbens: presynaptic dopamine transmission
The effects of amphetamine-like drugs in the central nervous system are linked to the ability of these drugs to bind to monoamine transporters. However, it is primarily an action at the dopamine transporter that mediates both the motor stimulant 46, 56, 146, 238and reinforcing effects 153, 313of this drug class. Psychostimulant-induced elevation of dopamine transmission in the nucleus accumbens has been particularly well characterized. Therefore, it is not surprising that the majority of the
Nucleus accumbens: postsynaptic dopamine transmission
Changes in dopamine transmission in the nucleus accumbens that are associated with behavioral sensitization are not confined to presynaptic terminals. As outlined below, several enduring changes in dopamine receptor transduction subsequent to repeated psychostimulant injection have been identified.
Nucleus accumbens: excitatory amino acids (EAAs)
In addition to dopaminergic inputs, there is a substantial, topographically organized EAA innervation of the nucleus accumbens arising from the hippocampus, basolateral amygdala, PFC and periventricular thalamus (see Fig. 1A) 17, 18, 26, 221, 315, 316. Dopamine and the EAAs interact within the nucleus accumbens to delimit the information that is transmitted from the nucleus accumbens to the VP and VTA/substantia nigra [191]. Anatomical studies demonstrate that EAA afferents from the
Nucleus accumbens: serotonin transmission
Amphetamine-like psychostimulants also bind to serotonin transporters 238, 240, and there is evidence that that the raphe-accumbens serotonergic system may play a role in the expression of behavioral sensitization. The behavioral response to the systemic administration of serotonin agonists is augmented among rats pretreated with cocaine [54]. In addition, the ability of cocaine or the 5-HT1A agonist, 8-OHDPAT, to reduce the firing frequency of dorsal raphe neurons is enhanced in animals
Ventral tegmental area
In addition to being a likely locus of drug action for the initiation of behavioral sensitization to psychostimulants (see Section 1.1), recent studies have identified changes in the VTA that may contribute to the expression of sensitization. Fig. 6 illustrates the local circuitry in the VTA that is affected by repeated cocaine administration. D1 dopamine receptors are located on the terminals of both GABA and EAA afferents to the VTA 4, 174, and the release of glutamate and GABA in this
A circuitry model of the expression of behavioral sensitization
The data outlined above describe a number of pre- and postsynaptic alterations in neurotransmission that are associated with the expression of behavioral sensitization to psychostimulants (see Fig. 1C). These changes are distributed among the nuclei of the motive circuit and, via the interconnections within the motive circuit, the individual changes in neurotransmission act in concert to mediate the expression of behavioral sensitization. It is proposed that the alterations in neurotransmitter
Environment-specific sensitization and drug relapse
There is substantial evidence for classical conditioning of the behavioral stimulant effects of psychostimulants to environmental stimuli [276]. The expression of behavioral sensitization is greater when the repeated drug injections are made in the same environmental context as the subsequent psychostimulant test injection 10, 27, 78, 111, 217, 231, 234, 276, 286, 300. Thus, psychostimulant sensitization consists of two components: (1) non-associative neural adaptations that are independent of
Concluding statements
Over the last 20 years, a number of changes in neurotransmission have been linked with the expression of behavioral sensitization to psychostimulants. However, it has proven difficult to combine these changes into a coherent model because, when viewed individually, the changes in neuronal function associated with behavioral sensitization can often seem contradictory. By envisioning these separate neuronal alterations in the context of an integrated neural circuit, the changes induced by
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