Rationale Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear. Objective The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT). Methods We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ‘HI’ and low impulsive ‘LI’, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner. Results Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats. Conclusions These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.

Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes.SIGNIFICANCE STATEMENTThis study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain.

It has long been suggested that some of the neuropharmacological, neurochemical and behavioural effects of ethanol are mediated by its first metabolite, acetaldehyde. In spite of the well documented psychoactivity of acetaldehyde, the precise role of this compound in alcohol abuse remains a matter of intense debate among scientists devoted to the study of alcoholism. Very frequently, the main drawback has been related to the presence of adequate levels of acetaldehyde or its derivatives inside the brain after ethanol ingestion. Since penetration into the central nervous system from blood of peripherically derived acetaldehyde is very low due to the high aldehyde dehydrogenase activity at the blood-brain barrier, several authors called into question the acetaldehyde implication in the toxicity and neurobehavioral effects of ethanol. The confirmation in several laboratories of the existence of enzymatic mechanisms of ethanol oxidation in the brain has revitalized the old theories supporting the acetaldehyde contribution to alcohol abuse and alcoholism. In this paper, we review current data on the brain metabolism of ethanol. We focused on the description of the enzymatic mechanisms involved in this metabolic process, reviewing the constitutive expression, catalytic activity and inhibition and inducibility of the enzymes involved in brain ethanol metabolism. We also analyze old and recent data on their regional distribution and cellular localization in the central nervous system, with special reference to the mesocorticolimbic system, a dopaminergic brain pathway that plays an important role in drug and ethanol reinforcement.