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.
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- "The lateral (sensorimotor) striatum, on the other hand, is critical for 'automatic' and habitual behavior (Yin and Knowlton, 2006). Psychostimulant-induced changes in gene regulation (and resulting structural plasticity; Jedynak et al., 2007) in lateral striatal circuits are implicated in habitual and compulsive aspects of drug addiction (Berke and Hyman, 2000; Everitt et al., 2001; Everitt and Robbins, 2013) as well as in relapse to drug taking after abstinence (Vanderschuren et al., 2005; Fuchs et al., 2006; See et al., 2007). Although overlapping, the regional distribution of methylphenidate plus fluoxetine-induced changes in enkephalin expression was not identical to that of dynorphin expression (not correlated). "
ABSTRACT: Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs that use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate+fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling.Neuropharmacology 09/2014; 89. DOI:10.1016/j.neuropharm.2014.08.024 · 5.11 Impact Factor
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- "Similar results have bee reported with more discrete alcohol cues in humans (Hogarth et al., 2013). Discrete cues can also trigger and maintain responding for alcohol and other rewards (Lê and Shaham, 2002; Loeber et al., 2006; Corbit and Janak, 2007a) and many of these stimulus effects rely on the DLS (Vanderschuren et al., 2005; Volkow et al., 2006; Corbit and Janak, 2007b). Thus it is possible that the effects of either NBQX or raclopride relate to an ability to suppress the influence of environmental stimuli, such as the training context, which over the course of training had become paired with alcohol, and thus a remove context-mediated bias towards habitual performance. "
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. DOI:10.3389/fnbeh.2014.00301 · 3.27 Impact Factor
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- "Identifying the adaptive significance of trait variation is a primary challenge for evolutionary biology, and few traits have attracted as much speculation as the wide gap in cognitive skills (as reflected in complex language, tool use, etc.) between Homo sapiens and all other extant taxa (Faure et al., 2005; Poldrack et al., 2005; Ramnani, 2006; Passingham, 2008; Doyon et al., 2009; D'Angelo and Casali, 2012). Notwithstanding increasing evidence of high-level cognition in non-humans (Doya, 2000; Mithen, 2005; Poldrack et al., 2005; Vanderschuren and Di Ciano, 2005; Graybiel, 2008; MacNeilage, 2008; Passingham, 2008; Doyon et al., 2009), no other taxon exhibits the same cognitive capacities as our own species. The fossil record reveals a rapid increase in brain size and complexity (plausibly reflecting an increase in cognitive ability) approximately 2.4 million years ago, soon after humans evolved another distinctive feature–bipedal locomotion (Alexander et al., 1986; Faure et al., 2005; Lewin, 2009; Ashby et al., 2010). "
ABSTRACT: The ability to delegate control over repetitive tasks from higher to lower neural centers may be a fundamental innovation in human cognition. Plausibly, the massive neurocomputational challenges associated with the mastery of balance during the evolution of bipedality in proto-humans provided a strong selective advantage to individuals with brains capable of efficiently transferring tasks in this way. Thus, the shift from quadrupedal to bipedal locomotion may have driven the rapid evolution of distinctive features of human neuronal functioning. We review recent studies of functional neuroanatomy that bear upon this hypothesis, and identify ways to test our ideas.Frontiers in Neuroscience 04/2014; 8(8):90. DOI:10.3389/fnins.2014.00090 · 3.66 Impact Factor