Patricia Robledo

Associative Processes in Addiction and Reward The Role of Amygdala‐Ventral Striatal Subsystems

ABSTRACT: Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic‐cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal‐directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign‐tracking), conditioned reinforcement (whereby pavlovian stimuli control goal‐directed action), and also more general response‐invigorating processes (often called “activation,”“stress,” or “drive”) may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second‐order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug‐seeking response can be seen to operate both serially and concurrently. The power of our analytic techniques for understanding complex motivated behavior has been evident for some time. However, the crucial point is that we are now able to map these components with increasing certainty onto discrete amygdaloid, and other limbic cortical‐ventral striatal subsystems. The neural dissection of these mechanisms also serves an important theoretical purpose in helping to validate the various hypothetical constructs and further developing theory. Major challenges remain, not the least of which is an understanding of the operation of the ventral striatum together with its dopaminergic innervation and its interactions with the basolateral amygdala, hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal level.

Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiological data.

By selective chemical stimulation of the subthalamic nucleus (STh) with the gamma-aminobutyric acid (GABA) antagonist bicuculline, we have studied the effect of its projections to the target nuclei. Results show that bicuculline (0.39 mM) produced a mean activation of 358% in subthalamic neurons. Most of the cells recorded in the substantia nigra pars reticulata (SNpr), the entopenduncular nucleus (EP), and the globus pallidus (GP) were also significantly activated. In the substantia nigra pars compacta (SNpc), slight and opposite changes were produced: half of the cells were activated and half were inhibited. In the striatum, 3 types of responses were recorded: activation, inhibition, and biphasic effect. Inhibition of subthalamic neurons by local microinjection of muscimol (0.95 mM), produced reductions in the neuronal activity of cells in the SNpr, the EP, and the GP. These results suggest that the STh conveys an important and permanent excitatory influence onto its target nuclei. In another set of experiments, in order to investigate whether or not the STh utilizes glutamate for neurotransmission in the SNpr, we injected the glutamate receptor antagonist kynurenic acid (2.6 mM) into the SNpr, later followed by an injection of bicuculline in the STh. Kynurenic acid alone produced a mean inhibition of 30% in non-dopaminergic nigral cells, and antagonized the subsequent bicuculline-induced activating effect of the STh. These results further confirm recent data showing that the STh exerts an excitatory action on its efferent structures, and provide new evidence for glutamatergic transmission in subthalamic projections.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of CB1 cannabinoid receptor impairs cocaine self-administration.

Acute rewarding properties are essential for the establishment of cocaine addiction, and multiple neurochemical processes participate in this complex behavior. In the present study, we used the self-administration paradigm to evaluate the role of CB1 cannabinoid receptors in several aspects of cocaine reward, including acquisition, maintenance, and motivation to seek the drug. For this purpose, both CB1 receptor knockout mice and wild-type littermates were trained to intravenously self-administer cocaine under different schedules. Several cocaine training doses (0.32, 1, and 3.2 mg/kg/infusion) were used in the acquisition studies. Only 25% of CB1 knockout mice vs 75% of their wild-type littermates acquired a reliable operant responding to self-administer the most effective dose of cocaine (1 mg/kg/infusion), and the number of sessions required to attain this behavior was increased in knockout mice. Animals reaching the acquisition criteria were evaluated for the motivational strength of cocaine as a reinforcer under a progressive ratio schedule. The maximal effort to obtain a cocaine infusion was significantly reduced after the genetic ablation of CB1 receptors. A similar result was obtained after the pharmacological blockade of CB1 receptors with SR141716A in wild-type mice. Moreover, the cocaine dose–response curve was flattened in the knockout group, suggesting that the differences observed between genotypes were related to changes in the reinforcing efficacy of the training dose of cocaine. Self-administration for water and food was not altered in CB1 knockout mice in any of the reinforcement schedules used, which emphasizes the selective impairment of drug reinforcement in these knockout mice. Finally, cocaine effects on mesolimbic dopaminergic transmission were evaluated by in vivo microdialysis in these mice. Acute cocaine administration induced a similar enhancement in the extracellular levels of dopamine in the nucleus accumbens of both CB1 knockout and wild-type mice. This work clearly demonstrates that CB1 receptors play an important role in the consolidation of cocaine reinforcement, although are not required for its acute effects on mesolimbic dopaminergic transmission.

D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat

Previous work using systemic injections of dopamine receptor antagonists has established that dopamine D1 receptors may have a role in cocaine self-administration. The purpose of the present study was to test the hypothesis that these effects were mediated by dopamine D1 receptors in the region of the nucleus accumbens. Animals were trained to perform operant responses to self-administer cocaine via an IV catheter on a fixed-ratio 5 (FR 5) schedule of reinforcement. SCH23390, a selective D1 dopamine antagonist, significantly increased the self-administration of cocaine when injected into the nucleus accumbens. This increase in self-administration is thought to reflect decreases in the magnitude of the reinforcer, similar to the increase observed when the dose of cocaine is reduced. Similar doses of SCH23390 injected into the posterior caudate nucleus failed to alter cocaine self-administration. These data suggest that D1 receptors in the nucleus accumbens are important for the reinforcing properties of cocaine.

The endogenous opioid system: A common substrate in drug addiction

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.

Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene

It has been shown previously that the endogenous opioid system may be involved in the behavioral effects of nicotine. In the present study, the participation of endogenous enkephalins on nicotine responses has been investigated by using preproenkephalin knock-out mice. Acute nicotine-induced hypolocomotion remained unaffected in these mice. In contrast, antinociception elicited in the tail-immersion and hot-plate tests by acute nicotine administration was reduced in mutant animals. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine induced a conditioned place preference in wild-type animals, but this effect was absent in knock-out mice. Accordingly, in vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels in the nucleus accumbens induced by nicotine was also reduced in preproenkephalin-deficient mice. Finally, the somatic expression of the nicotine withdrawal syndrome precipitated in nicotine-dependent mice by mecamylamine was significantly attenuated in mutant animals. In summary, the present results indicate that endogenous opioid peptides derived from preproenkephalin are involved in the antinociceptive and rewarding properties of nicotine and participate in the expression of physical nicotine dependence.

Two discrete nucleus accumbens projection areas differentially mediate cocaine self-administration in the rat.

The region of the nucleus accumbens and its connections have been implicated in the reinforcing actions of cocaine as measured by intravenous self-administration. Our previous work has demonstrated that ibotenic acid lesions of one of the output regions of the nucleus accumbens, the sublenticular region of the extended amygdala (SEA), resulted in significant decreases in the highest ratio obtained in rats self-administering cocaine. In the present study, the importance of another nucleus accumbens output, the subcommissural ventral pallidum (SVP), in mediating the self-administration of cocaine in the rat was explored. Animals were trained to self administer cocaine (0.75 mg/kg/inj) via an intravenous catheter on a FR5 schedule of reinforcement. Subsequently, subjects were either given bilateral intracerebral injections (0.5 microliter per side) of ibotenic acid (10 micrograms/microliter lesion group) or vehicle (sham group) into the SVP or into the SEA. Four days postlesion, cocaine self-administration on a FR5 schedule was resumed for 3 days. Next, a dose effect function was determined in one 3-h session. Finally, a progressive ratio probe in which the ratio requirement was increased after each reinforcement was tested. Lesions of both the SVP and the SEA produced significant changes in responding for intravenous cocaine on a FR5 schedule of reinforcement as compared to sham lesioned controls, although the effect was found to be greater for the rats bearing lesions of the SEA. While the lesions produced decreases in responding for cocaine at all doses tested in the dose-effect function, the rate of responding was still inversely proportional to the dose in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of excitotoxic lesions of the central amygdaloid nucleus on the potentiation of reward-related stimuli by intra-accumbens amphetamine.

The present study examined the effects of lesions of the central nucleus of the amygdala (CeA) on the acquisition of a new response with conditioned reinforcement (CR) and its potentiation by intra-accumbens infusions of d-amphetamine (1, 3, 10, and 20 microg/microl). Rats were trained to associate a light-plus-noise compound stimulus with the availability of a sucrose solution before receiving both bilateral ibotenic acid lesions of the CeA and cannulas implanted above the nucleus accumbens. Lesions of the central nucleus did not impair the performance of positively reinforced discriminated approach, nor did they impair the acquisition of a new response with conditioned reinforcement. However, the potentiation of responding with CR following intra-accumbens amphetamine was blocked in lesioned animals. These results are discussed in terms of the possible interactions between associative mechanisms in the amygdala and the mesolimbic dopamine projection.

Neurobiological mechanisms involved in nicotine dependence and reward: Participation of the endogenous opioid system

Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine-rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An up-regulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the down-regulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain sub-populations of smokers.

Advances in the field of cannabinoid–opioid cross‐talk

A remarkable amount of literature has been generated demonstrating the functional similarities between the endogenous opioid and cannabinoid systems. Anatomical, biochemical and molecular data support the existence of reciprocal interactions between these two systems related to several pharmacological responses including reward, cognitive effects, and the development of tolerance and dependence. However, the assessment of the bidirectionality of these effects has been difficult due to their variety and complexity. Reciprocal interactions have been well established for the development of physical dependence. Cross‐tolerance and cross‐sensitization, although not always bidirectional, are also supported by a number of evidence, while less data have been gathered regarding the relationship of these systems in cognition and emotion. Nevertheless, the most recent advances in cannabinoid–opioid cross‐modulation have been made in the area of drug craving and relapse processes. The present review is focused on the latest developments in the cannabinoid–opioid cross‐modulation of their behavioural effects and the possible neurobiological substrates involved.