occur with the transition from occasional drug use to pathological abuse and addiction are only partially un-La Jolla, California 92037derstood as yet. To reach a more complete understanding, these events will have to be integrated with the animal models of the different elements of the addiction Human addictions are chronically relapsing disorders process, including models of the transition from simple characterized by compulsive drug taking, an inability drug taking to compulsive use at the molecular, cellular, to limit the intake of drugs, and the emergence of a and behavioral levels. In this review, we will focus in withdrawal syndrome during cessation of drug taking particular on the factors that drive drug-seeking behav-(dependence). The development of an addiction impacts ior at different stages of the addiction cycle (Koob and on several separate neurobiological processes, and Le Moal, 1997), and we will place particular emphasis these effects are both drug-and drug use-dependent.on trying to identify what is currently known and what In animal models of addiction, changes in specific neuremains to be elucidated. rotransmitter systems within a highly limited band of structures, including specific parts of the nucleus accumbens and amygdala, may underlie drug reward and Neurobiological Substrates for the Acute the motivational effects associated with dependence.Reinforcing Effects of Drugs of Abuse Changes in the signals mediated by several neurotrans-Animals and humans will readily self-administer the mitters, including dopamine, opioid peptides, and cortisame classes of drugs, and such self-administration cotropin-releasing factor (CRF), and in the regulation of defines these drugs as positive reinforcers (Headlee et selected transcription factors within the neurons of this al., 1955). The powerful reinforcing properties of such reward circuit, may underlie the vulnerability to relapse drugs are revealed by the efforts experimental animals that characterizes addiction in humans.

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Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharinsweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.

The conditioning of cocaine's subjective actions with environmental stimuli may be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of learning factors in persistent addictive behavior as well as the neurobiological basis of this phenomenon, rats were trained to associate discriminative stimuli (S D ) with the availability of i.v. cocaine vs. nonrewarding saline solution, and then placed on extinction conditions during which the i.v. solutions and S D s were withheld. The effects of reexposure to the S D on the recovery of responding at the previously cocaine-paired lever and on Fos protein expression then were determined in two groups. One group was tested immediately after extinction, whereas rats in the second group were confined to their home cages for an additional 4 months before testing. In both groups, the cocaine S D , but not the non-reward S D , elicited strong recovery of responding and increased Fos immunoreactivity in the basolateral amygdala and medial prefrontal cortex (areas Cg1͞Cg3). The response reinstatement and Fos expression induced by the cocaine S D were both reversed by selective dopamine D1 receptor antagonists. The undiminished efficacy of the cocaine S D to elicit drug-seeking behavior after 4 months of abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. Moreover, the results implicate D 1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala as substrates for cocaine-seeking behavior elicited by cocaine-predictive environmental stimuli. T he conditioning of cocaine's pharmacological actions with discrete environmental stimuli has been implicated as a major factor in the abuse potential of this drug (1). Both retrospective (2) and controlled laboratory studies (3)(4)(5) show that such stimuli can evoke drug desire that may lead to the resumption of drug use in abstinent individuals. Drug-related stimuli may also elicit automatic responses that lead to drug-seeking behavior and relapse without the intervention of distinct feelings of craving (6, 7). Learned responses to drug-related stimuli, therefore, represent a possibly critical element contributing to the chronic relapsing nature of cocaine and other drug addiction (8, 9).Consistent with a role of learning factors in the initiation of drug-seeking behavior, cocaine-related stimuli can elicit strong recovery of responding at a lever previously associated with i.v. cocaine infusions in animal models of relapse (10, 11). However, little information is available about the perseverance of the motivating actions of such stimuli over prolonged periods of abstinence and the neurobiological substrates mediating these effects. In humans, relapse risk is typically greatest during the first 6 months of abstinence but may persist for substantially longer periods of time (1,8,12). Bette...

Mammalian target of rapamycin (mTOR) is a key regulator of translational capacity. The mTOR inhibitor rapamycin can prevent forms of protein synthesis-dependent synaptic plasticity such as long-term facilitation in Aplysia and late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of rodents. In the latter model, two issues remain to be addressed: defining the L-LTP phase sensitive to rapamycin and identifying the site of rapamycinsensitive protein synthesis. Here, we show that L-LTP is sensitive to application of rapamycin only during the induction paradigm, whereas rapamycin application after the establishment of L-LTP was ineffective. Second, we observed that Thr-389-phosphorylated p70 S6 kinase (p70 S6K ), the main active phosphoform of the mTOR effector p70 S6K , was induced in an N-methyl-D-aspartateand phosphatidylinositol 3-kinase-dependent manner throughout the dendrites but not in the cell bodies of CA1 neurons in hippocampal slices after L-LTP induction. A similar dendrite-wide activation of p70 S6K was induced in primary hippocampal neurons by depolarization with KCL or glutamate. In primary hippocampal neurons, the sites of dendritic activation of p70 S6K appeared as discrete compartments along dendritic shafts like the hotspots for fast dendritic translation. Conversely, only a subset of dendritic spines also displayed activated p70 S6K . Taken together, the present data suggest that the N-methyl-D-aspartate-, phosphatidylinositol 3-kinase-dependent dendritic activation of the mTOR-p70 S6K pathway is necessary for the induction phase of protein synthesisdependent synaptic plasticity. Newly synthesized proteins in dendritic shafts could be targeted selectively to activity-tagged synapses. Thus, coordinated activation of dendrite-wide translation and synaptic-specific activation is likely to be necessary for long-term synaptic plasticity. F orms of long-term synaptic plasticity that require protein synthesis are believed to be cellular counterparts of longterm memory storage, whereas forms of synaptic plasticity that do not require protein synthesis are believed to be counterparts of short-term memory (1). In particular, dendritic protein synthesis is believed to play a crucial role in long-term synaptic plasticity and memory (1-4). Mammalian target of rapamycin (mTOR) regulates the translation initiation complex in a rapamycin-sensitive manner. It does so primarily through its downstream targets, the kinase p70 S6 kinase (p70 S6K ) and the elongation factor binding protein 4E-BP1. p70 S6K is a major regulator of translation under the control of multiple signal transduction pathways including phosphatidylinositol 3-kinase (PI3K) (5). It increases translational capacity by promoting the expression of several members of the translational machinery whose mRNAs display oligopyrimidine tracts at their 5Ј ends (6). 4E-BP1 is an inhibitor of the cap binding protein eukaryotic initiation factor 4E. 4E-BP1 phosphorylation by mTOR leads to increased translation of capped mRNAs (7). The major d...