Involvement of the dorsal striatum in cue-controlled cocaine seeking.
ABSTRACT Through association with the interoceptive effects of drugs of abuse, neutral environmental stimuli can gain motivational properties themselves, becoming conditioned reinforcers that can evoke craving and relapse to drug seeking. Nucleus accumbens dopamine (DA) neurotransmission plays an important role in the reinforcing effect of cocaine itself, but, unlike nucleus accumbens glutamate, it seems not to mediate the conditioned reinforcing properties of cocaine-paired stimuli. Dorsal striatal DA transmission, in contrast, has been shown to be enhanced during cocaine seeking under a second-order schedule of reinforcement, which depends on the conditioned reinforcing properties of cocaine-associated stimuli. Therefore, the aim of the present study was to evaluate the role of DA and glutamate transmission in the dorsal striatum in cue-controlled cocaine seeking. Infusion of the DA receptor antagonist alpha-flupenthixol into the dorsal striatum decreased cocaine seeking under a second-order schedule of reinforcement. In addition, intradorsal striatal infusion of the AMPA/kainate (KA) receptor antagonist LY293558 (3SR, 4aRS, 6RS, 8aRS-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid), but not the NMDA receptor antagonist AP-5, also decreased cue-controlled cocaine seeking. These data show that stimulation of DA and AMPA/KA receptors in the dorsal striatum is critical for well established drug seeking that depends on the reinforcing effects of cocaine-associated stimuli. In addition, given the importance of the dorsal striatum in stimulus-response habit learning, these data suggest that the habitual or compulsive quality of persistent drug seeking depends on dorsal striatal mechanisms.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Drug addiction is characterized by uncontrolled drug consumption and high rates of relapse to drug taking during periods of attempted abstinence. Addiction is now largely considered a disorder of experience-dependent neuroplasticity, driven by remodeling of synapses in reward and motivation relevant brain circuits in response to a history of prolonged drug intake. Alterations in gene expression play a central role in addiction-relevant neuroplasticity, but the mechanisms by which additive drugs remodel brain motivation circuits remains unclear. MicroRNAs (miRNAs) are a class of noncoding RNA that can regulate the expression of large numbers of protein-coding mRNA transcripts by binding to the 3' untranslated region (3' UTR) of target transcripts and blocking their translation into the encoded protein or triggering their destabilization and degradation. Emerging evidence has implicated miRNAs in regulating addiction-relevant neuroplasticity in the brain, and in controlling the motivational properties of cocaine and other drugs of abuse. Here, the role for miRNAs in regulating basic aspects of neuronal function is reviewed. The involvement of miRNAs in controlling the motivational properties of addictive drugs is also summarized. Finally, mechanisms by which miRNAs exert their actions on drug intake, when known, are considered.Dialogues in clinical neuroscience 09/2014; 16(3):335-44.
- [Show abstract] [Hide abstract]
ABSTRACT: Use of psychostimulants such as methylphenidate (Ritalin) in medical treatments and as cognitive enhancers in the healthy is increasing. Methylphenidate produces some addiction-related gene regulation in animal models. Recent findings show that combining selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine with methylphenidate potentiates methylphenidate-induced gene regulation. We investigated the endurance of such abnormal gene regulation by assessing an established marker for altered gene regulation after drug treatments – blunting (repression) of immediate-early gene (IEG) inducibility – 14 days after repeated methylphenidate + fluoxetine treatment in adolescent rats. Thus, we measured the effects of a 6-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or their combination on the inducibility (by cocaine) of neuroplasticity-related IEGs (Zif268, Homer1a) in the striatum, by in situ hybridization histochemistry. Repeated methylphenidate treatment alone produced modest gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine given in conjunction with methylphenidate produced pronounced potentiation of methylphenidate-induced blunting for both genes. This potentiation was seen in many functional domains of the striatum, but was most robust in the lateral, sensorimotor striatum. These enduring molecular changes were associated with potentiated induction of behavioral stereotypies in an open-field test. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs such as fluoxetine may increase the addiction liability of methylphenidate.Basal Ganglia. 12/2014; 4:109-116.
- [Show abstract] [Hide abstract]
ABSTRACT: Chronic alcohol self-administration leads to alcohol-seeking behavior that is habitual and insensitive to changes in the value of the earned alcohol. Such behavior has been shown to rely on the dorsolateral region of the striatum in rats but the specific pharmacological control of output from this region is not yet understood. In the following experiments rats were trained to self-administer unsweetened 10% (v/v) ethanol in daily sessions for 8 weeks prior to testing for sensitivity to outcome devaluation. We examined the role of glutamatergic AMPA-receptor activation by testing the effects of the antagonist NBQX (0.3 and 1.0 μg/μl) infused specifically into the dorsolateral striatum (DLS) before devaluation testing. In a separate group of rats we examined the role of dopaminergic D2-receptor activation using the D2-receptor antagonist raclopride (0.2 and 1.0 μg/μl) infused into the DLS before devaluation testing. Following control (saline) infusions rats' lever-press performance was insensitive to devaluation of ethanol thus showing evidence of habitual responding. NBQX and racolpride each restored goal-directed control of responding at doses that did not impair overall lever-press rates. These data demonstrate that expression of habitual alcohol seeking relies on glutamatergic inputs to the DLS and D2 receptors within the DLS.Frontiers in Behavioral Neuroscience 09/2014; 8:301. · 4.16 Impact Factor