We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.

Methamphetamine (meth) addicts often exhibit enduring cognitive and neural deficits that likely contribute to persistent drug seeking and the high rates of relapse. These deficits may be related to changes in the prefrontal cortex (PFC) and its glutamatergic projections to the nucleus accumbens (NAc). Here, we performed in vivo microdialysis in the PFC and NAc in rats following either meth self-administration or yoked-saline control histories to assess baseline glutamate (GLU) levels, or reinstatement-evoked GLU and dopamine (DA) efflux in both regions simultaneously under cue-induced, meth-primed, or combined cues þ meth reinstatement conditions. Our results show that meth self-administration (1) reduced basal GLU levels in both the dmPFC and NAc, (2) concurrently increased dmPFC and NAc GLU efflux during reinstatement, and (3) increased DA efflux in the dmPFC, but not in the NAc, under all reinstatement conditions when compared with yoked-saline controls. These data demonstrate for the first time that a history of psychostimulant self-administration alters GLU homeostasis not only in the NAc, but also in the dmPFC, its primary GLU projection source. Furthermore, combined cues þ meth-primed reinstatement conditions produced the most pronounced increases in mPFC and NAc extracellular GLU, suggesting that the cue and meth prime conditions are additive in promoting reinstatement. Finally, increased efflux of DA in the dmPFC, but not in the NAc, across reinstatement conditions suggests that DA release in the dmPFC may be an important mediator of drug seeking initiated by multiple relapse triggers. Neuropsychopharmacology (2014) 39, 811-822; doi:10.1038/npp.2013; published online 9 October 2013 Keywords: dopamine; glutamate; methamphetamine self-administration; nucleus accumbens; prefrontal cortex; reinstatement INTRODUCTIONThe development of drug addiction is believed to derive in large part from maladaptive neurobiological responses to drugs of abuse within the corticostriatal glutamate (GLU) and mesostriatal dopamine (DA) systems of the brain (Berridge and Robinson, 1998;Wise, 2004;Kalivas et al, 2005). Although these circuits normally optimize behavior in response to a changing environment and establish welllearned behaviors, their dysregulation due to repeated drug abuse likely underlies the switch to habitual drug-taking behaviors, which operate outside of normal cortical regulation (Goldstein et al, 2009;George and Koob, 2010).Methamphetamine (meth) addicts often exhibit pronounced deficits in cortical regulation of subcortical drive (Baicy and London, 2007;Salo et al, 2009). The impact of meth on this circuitry may be more profound than other addictive drugs, due in part to its long half-life, high-lipid solubility, fast uptake and accumulation, and distinctive pharmacological effects on both DA and GLU functions (Bowyer et al, 2008;Fowler et al, 2008;Stephans and Yamamoto, 1994). Thus, meth abuse may alter DA receptive pyramidal neurons in the PFC, in turn affecting downstream signaling in the nucleus accum...

Stress triggers psychiatric conditions including depressive and anxiety disorders. The mechanisms by which stress produces persistent changes in behavior are not fully understood. Here we show in rats that stress (footshock) activates the transcription factor cAMP response element binding protein (CREB) within the nucleus accumbens shell (NAS), a brain area involved in encoding reward and aversion. To examine the behavioral significance of altered CREB function in the NAS, we used viral vectors to elevate or disrupt CREB in this region. Elevated CREB produced increases in intracranial self-stimulation thresholds, a depressive-like sign reflecting anhedonia (decreased sensitivity to reward), whereas disruption of CREB function by expression of a dominant-negative CREB had the opposite effect. To determine whether neuroadaptations that produce anhedonia subsequently affect vulnerability to stress-induced behavioral adaptations, we subjected rats with altered CREB function in the NAS to fear conditioning. Although neither elevation nor disruption of CREB function altered the development of conditioned fear, elevation of CREB impaired extinction of conditioned fear. To mimic downstream effects of CREB activation on expression of the opioid peptide dynorphin, we microinjected the -opioid receptor (KOR) agonist U50,488 directly into the NAS. KOR stimulation produced anhedonia but had no effect on expression or extinction of conditioned fear. These findings demonstrate that activation of CREB in the NAS produces multiple behavioral signs (anhedonia, impaired extinction) characteristic of experience-dependent psychiatric conditions such as posttraumatic stress disorder. Although CREB activation is a common trigger, expression of these individual signs appears to involve divergent downstream mechanisms.

Background Chronic methamphetamine abusers exhibit deficits in tasks requiring intact prefrontal cortex (PFC) function, and PFC dysfunction has been implicated in the loss of control over drug use. The current study used a combination of behavioral and electrophysiological assessments in rats with a history of long access methamphetamine self-administration to determine methamphetamine-induced changes in PFC-dependent attentional set-shifting performance, drug-seeking, and PFC neuronal activity. Methods Male Long-Evans rats self-administered methamphetamine (0.02 mg/infusion, i.v.) or received yoked saline infusions for 6 hours/day for 14 days. Cognitive flexibility was assessed using an attentional set-shifting task prior to 2 weeks of self-administration and one day after self-administration. Animals then underwent 11 days of abstinence, followed by three subsequent tests for context-induced drug-seeking. Finally, animals were anesthetized and single-unit in vivo extracellular recordings were performed in the dorsomedial PFC. Results Methamphetamine-experienced rats showed escalated drug intake and context-induced drug-seeking following abstinence. During the extra-dimensional set-shift component, meth-experienced rats showed selective impairments that were identical to deficits produced by excitotoxic lesions of the PFC. Rats with a history of chronic methamphetamine intake also exhibited higher basal firing frequency and a significantly greater proportion of burst-firing cells in the PFC as compared to yoked-saline controls. Conclusions PFC-specific alterations in neuronal function may play a key role in methamphetamine-induced attentional deficits and drug-seeking. These data support the possibility that targeting PFC pathology may improve treatment outcome in methamphetamine addiction.