This review discusses the evidence for the hypothesis that the development of drug addiction can be understood in terms of interactions between Pavlovian and instrumental learning and memory mechanisms in the brain that underlie the seeking and taking of drugs. It is argued that these behaviours initially are goal-directed, but increasingly become elicited as stimulus–response habits by drug-associated conditioned stimuli that are established by Pavlovian conditioning. It is further argued that compulsive drug use emerges as the result of a loss of prefrontal cortical inhibitory control over drug seeking habits. Data are reviewed that indicate these transitions from use to abuse to addiction depend upon shifts from ventral to dorsal striatal control over behaviour, mediated in part by serial connectivity between the striatum and midbrain dopamine systems. Only some individuals lose control over their drug use, and the importance of behavioural impulsivity as a vulnerability trait predicting stimulant abuse and addiction in animals and humans, together with consideration of an emerging neuroendophenotype for addiction are discussed. Finally, the potential for developing treatments for addiction is considered in light of the neuropsychological advances that are reviewed, including the possibility of targeting drug memory reconsolidation and extinction to reduce Pavlovian influences on drug seeking as a means of promoting abstinence and preventing relapse.

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Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories--indications for novel treatments of addiction.

The role of serotonin in drug use and addiction.

Efficacy of antidepressants in substance use disorders with and without comorbid depression A systematic review and meta-analysis

The purpose of the present manuscript is to review the current status of the role of serotonin (5-hydroxytryptamine; 5-HT) systems in the stimulus and reinforcing properties of cocaine in non-humans and the subjective effects of cocaine in humans. Review of the current literature suggests that general enhancement (via precursor administration) or depletion of brain 5-HT content (via neurotoxin administration or tryptophan depletion) impact the reinforcing effects of cocaine in non-humans and its subjective effects in humans. Selective 5-HT reuptake inhibitors (SSRIs) enhance the discriminability of cocaine and decrease cocaine self-administration in animals, although data to the contrary also exist. Studies in humans suggest that SSRIs attenuate the subjective effects of cocaine in humans. Although few drugs with selectivity for 5-HT2 receptors have been studied systematically, a 5-HT2 agonist and several antagonists show some efficacy in enhancing and reducing, respectively, the reinforcing effects of cocaine in non-humans. Limited data from humans suggest that a 5-HT2 antagonist may also decrease the subjective effects of cocaine; thus, 5-HT2 compounds deserve further attention. The majority of studies evaluating the 5-HT3 antagonists have reported negative results across all paradigms. In summary, while the functional significance of 5-HT receptors has not been fully elucidated, these data suggest that changes in serotonergic activity can modulate the effects of cocaine in both animals and humans under a variety of experimental conditions. One commonality among the studies with positive findings is that cocaine effects are only partially modified by 5-HT agents regardless of the direction of change.

Serotonergic mechanisms involved in the discriminative stimulus, reinforcing and subjective effects of cocaine

OBJECTIVE The aim of this study was to test the hypothesis that, because of abnormalities in serotonergic neurotransmission that may underlie craving and impulsive behavior, fluoxetine treatment differentially affects drinking among type B alcoholics, who are characterized by high levels of both premorbid vulnerability and alcohol-related problems METHODS Using a k-means clustering procedure, alcohol-dependent subjects from a placebo-controlled trial of fluoxetine were grouped into low-risk/severity (type A: n = 60) and high-risk/ severity (type B: n = 35) groups Multivariate analysis of covariance (with pretreatment measures as covariates) evaluated the effects of Alcoholic Subtype, Medication Group, Treatment Completion, and their interactions on measures of drinking, both during the 12-week treatment period and a 6-month follow-up period RESULTS Although there were no main effects of Alcoholic Subtype or Medication Group, subjects who completed the treatment trial showed significantly better drinking-related outcomes There was also an interaction of Alcoholic Subtype by Medication Group during treatment Among type B subjects, fluoxetine treatment resulted in poorer drinking-related outcomes than placebo treatment Among type A subjects, there was no effect of Medication Group This interactive effect did not persist during the 6-month follow-up period CONCLUSIONS Alcoholic subtypes identified by cluster analysis seem to be differentially responsive to the effects of fluoxetine treatment on drinking-related outcomes Serotonergic abnormalities previously identified among a subgroup of alcoholics who are also characterized by impulsivity and severity of alcohol dependence may help to explain the differential medication effect Based on these findings, it is recommended that, in the absence of a comorbid mood or anxiety disorder, fluoxetine not be used to maintain abstinence or reduce drinking in high-risk/severity alcoholics

Fluoxetine Treatment Seems to Reduce the Beneficial Effects of Cognitive-Behavioral Therapy in Type B Alcoholics

Three methods of analysis were used to determine the effects of the combination of counseling with fluoxetine (20, 40, or 60 mg) and "active" placebo (diphenhydramine, 12.5 mg) randomly assigned. Forty-five cocaine-only dependent subjects were treated as outpatients with "interpersonal" counseling, medication, and drug use monitoring three times per week for up to 12 weeks. Treatment effects were analyzed: first, by comparing the three original assignments and placebo; second, by comparing the placebo group to fluoxetine subjects with detectable fluoxetine/norfluoxetine blood levels and those with no detectable medication blood level; third, by examining relapse prevention versus use cessation through stratifying the subjects into four groups according to fluoxetine or placebo assignment and initial urine cocaine positivity or negativity. All three analyses showed improvement on some measures over time regardless of group assignment. The 60-mg fluoxetine group showed least effectiveness, the group with detectable blood levels had less cravings, and the fluoxetine subjects who were abstinent at the start of treatment were somewhat less likely to avoid relapse than those on placebo.

C A Haertzen

Papers

Effects of combined fluoxetine and counseling in the outpatient treatment of cocaine abusers