Prefrontal synaptic markers of cocaine addiction-like behavior in rats.

Defining the drug-induced neuroadaptations specifically associated with the behavioral manifestation of addiction is a daunting task. To address this issue, we used a behavioral model that differentiates rats controlling their drug use (Non-Addict-like) from rats undergoing transition to addiction (Addict-like). Dysfunctions in prefrontal cortex (PFC) synaptic circuits are thought to be responsible for the loss of control over drug taking that characterizes addicted individuals. Here, we studied the synaptic alterations in prelimbic PFC (pPFC) circuits associated with transition to addiction. We discovered that some of the changes induced by cocaine self-administration (SA), such as the impairment of the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) was similarly abolished in Non-Addict- and Addict-like rats and thus unrelated to transition to addiction. In contrast, metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) was specifically suppressed in Addict-like rats, which also show a concomitant postsynaptic plasticity expressed as a change in the relative contribution of AMPAR and NMDAR to basal glutamate-mediated synaptic transmission. Addiction-associated synaptic alterations in the pPFC were not fully developed at early stages of cocaine SA, when addiction-like behaviors are still absent, suggesting that pathological behaviors appear once the pPFC is compromised. These data identify specific synaptic impairments in the pPFC associated with addiction and support the idea that alterations of synaptic plasticity are core markers of drug dependence.

Cocaine-induced sensitization is associated with altered dynamics of transcriptional responses of the dopamine transporter, tyrosine hydroxylase, and dopamine D2 receptors in C57Bl/6J mice.

RATIONALE: Behavioural sensitization is a long lasting phenomenon that has been proposed to be involved in drug addiction. Although the expression of cocaine-induced sensitization has been associated with the activity of the mesencephalic dopaminergic neurons, little is known about the transcriptional adaptations of these neurons to a new challenge with cocaine long after cessation of repeated exposure to the drug. OBJECTIVES: We studied the time course of the mRNA levels of three main regulatory elements of dopaminergic transmission after a challenge with cocaine (15 mg/kg) that followed 21 days of withdrawal from a cocaine pretreatment (20 mg/kg, ip, every 2 days for 21 days) in C57Bl/6J mice. MATERIALS AND METHODS: Mice were placed 45 min in activity chambers and were killed 45 min, 2 h or 24 h after the challenge injection. Dopamine transporter (DAT), D2 auto-receptor (D2) and tyrosine hydroxylase (TH) mRNA levels were assessed by in situ hybridization in the ventral tegmental area and the substantia nigra compacta. RESULTS: As compared to vehicle challenge, cocaine challenge in vehicle pretreated mice induced a rapid increase (+208%) in DAT mRNA (45 min) followed by a delayed decrease (-70%) (24 h), while TH and D2 mRNA were both increased (+45%) 24 h after the challenge. In cocaine pretreated mice, cocaine-induced short-term increase and long-term decrease in DAT mRNA levels were amplified (+328%) and reduced (-40%), respectively. CONCLUSIONS: Repeated exposure to cocaine alters the transcriptional response of DA neurons to a new cocaine challenge long after cessation of repeated exposure to the drug. They point to the DAT mRNA as a major responsive element to a new presentation of cocaine.

Gene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain.

Several findings suggest that glucocorticoid hormones influence the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor and the mineralocorticoid receptor. We have shown previously that mice carrying a mutation of the glucocorticoid receptor gene specifically in neural cells, glucocorticoid receptor knock-out in the brain, show a dramatic decrease in cocaine-induced self-administration and no behavioral sensitization to this drug, two experimental procedures considered relevant models of addiction. Here, we investigated in glucocorticoid receptor knock-out in the brain mice the consequences of this mutation at the level of the expression of neuropeptide, dopamine receptor and glutamate receptor subunit mRNAs. We quantified mRNA levels in the cortex, striatum and accumbens under basal conditions and following acute or repeated cocaine treatments. Our results show that, under basal conditions, neuropeptide (substance P, dynorphin) and dopamine receptor (D1, D2) mRNAs were decreased in glucocorticoid receptor knock-out in the brain mice in the dorsal striatum but not in the accumbens. However, cocaine-induced changes in the levels of these mRNAs were not modified in glucocorticoid receptor knock-out in the brain mice. In contrast, mutant mice showed altered response in mRNA levels of N-methyl-D-aspartate, GLUR5 and GLUR6 glutamate receptor subunits as well as of enkephalin following cocaine administration. These modifications may be associated to decrease of behavioral effects of cocaine observed in glucocorticoid receptor knock-out in the brain mice.

Relationships between individual sensitivity to CS- and cocaine-induced reinstatement in the rat.

RATIONALE: Maintaining abstinence is highly challenging for cocaine ex-users. Exposure to drug conditioned stimuli (CS) and to low doses of cocaine can provoke craving in humans and reinstate self-administration (SA) behavior in animal models. Whether drug- and CS-induced reinstatement depend on the same biological substrates remains controversial. OBJECTIVES: We investigated the relationships between cocaine- and CS-induced SA reinstatement within the same individuals as a function of the duration of the withdrawal period after cessation of extended cocaine SA. METHODS: Sprague-Dawley rats were trained for cocaine intravenous SA (0.8 mg/kg per infusion) during 74 sessions (2 h daily exposure to cocaine) and submitted to withdrawal. Five and 30 days after the end of SA, cocaine- and CS-induced reinstatement were tested. RESULTS: Both after a short and a long withdrawal, CS- and cocaine-induced reinstatement were not related. Furthermore, cocaine-induced reinstatement measured after a short and a long withdrawal was positively related while CS-induced reinstatement was not. The sensitivity of an individual to cocaine-induced reinstatement is not related to its sensitivity to CS-induced reinstatement. Furthermore, vulnerability to cocaine-induced reinstatement is determined quickly after SA cessation and is a long lasting state, whilst vulnerability to CS-induced reinstatement develops quickly or slowly depending on the individual. CONCLUSIONS: These results support the view that cocaine and CS induce reinstatement through different mechanisms. They imply that reinstatement in drug abuse is a heterogeneous condition with some individuals being more sensitive to one factor than to the other. Research for effective anti-relapse therapies should take these elements into account.

Study of the addictive potential of modafinil in naive and cocaine-experienced rats.

RATIONALE: Modafinil is a drug that promotes wakefulness and, as such, is used to treat hypersomnia and narcolepsy. Preclinical and clinical studies suggest that modafinil could possess weak reinforcing effects in drug-experienced subjects. However, its abuse potential in drug-naive healthy individuals is still totally uninvestigated, despite the fact that availability of modafinil has recently increased. OBJECTIVES: The purpose of our study was to investigate the potential addictive properties of modafinil by testing its reinforcing effects in naive rats. The interactions of modafinil with the reinforcing effects of cocaine were also tested. METHODS: First, using i.v. self-administration and place conditioning tests, we studied the reinforcing and rewarding effects of a large range of doses of modafinil in naive rats. Second, we tested the influence of modafinil on reinforcing and incentive effects of cocaine in rats trained for cocaine self-administration. The effects of modafinil were compared with those of amphetamine and haloperidol. RESULTS: Modafinil did not produce reinforcing or rewarding effects and did not modify the effects of cocaine. CONCLUSIONS: Our results suggest that modafinil does not possess an addictive potential in naive individuals. Furthermore, it would be behaviorally distinct from classical central nervous system stimulants which are known to alter cocaine-induced effects. However, as shown previously in nonhuman primates and in humans, modafinil could possibly have reinforcing effects in cocaine-experienced individuals.

SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats.

RATIONALE: The endogenous cannabinoid system is thought to play a role in reinforcement processes. OBJECTIVES: We tested the effects of five doses of the cannabinoid receptor 1 (CB1) antagonist SR141716 [0, 0.3, 1, 3 and 10 mg/kg intraperitoneal (IP)] on intracranial self-stimulation at the level of the median forebrain bundle (MFB). Self-stimulation was assessed 30 min and 210 min after SR141716 administration. We compared the effect of SR141716 with the effect of a decrease in the magnitude of stimulation (-100 microA) and the effects of a cocaine injection (1, 5 and 10 mg/kg IP). METHODS: a protocol of rate-frequency curve for self-stimulation was applied. Two rate-frequency curves were established daily, 3 h apart. The frequency required to produce half-maximal performance (M50) and the maximal performance (RMax) were used as the parameters to characterize the rate-frequency functions. RESULTS: SR141716 decreased the sensitivity to the electrical brain stimulation. SR141716 induced a shift to the right of the rate-frequency curve. This effect depended on the dose administered and the time after injection. Thirty minutes after the injection, 1, 3 and 10 mg/kg SR141716 induced a significant decrease in sensitivity to electrical stimulation, as shown by an elevation in the M50 value. RMax showed a tendency to decrease with increasing doses. At 210 min after administration, 3 and 10 mg/kg SR141716 maintained their decreasing effect on the sensitivity to the stimulation as shown by the significant increase of the M50, however, the maximal response was restored to the basal value. A decrease in self-stimulation intensity produced an effect comparable to the one observed 30 min after either 3 or 10 mg/kg SR141716, while cocaine (5 and 10 mg/kg) produced the opposite effect. Neither condition affected the rate-frequency curve measured 3 h later. CONCLUSIONS: In accordance with recent observations, these experiments suggest that the endogenous cannabinoid system facilitates the perception or the effects of positive reinforcers. They also suggest that this neurochemical system could be a target of interest for treating psychopathologies implicating the reinforcing system.