PRTFDC1 Is a Genetic Modifier of HPRT-Deficiency in the Mouse

Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND

Review article: pharmacotherapy for alcohol dependence - the why, the what and the wherefore

BACKGROUND: The development of alcohol dependence is associated with significant morbidity and mortality. For the majority of affected people the most appropriate goal, in terms of drinking behaviour, is abstinence from alcohol. Psychosocial intervention is the mainstay of the treatment but adjuvant pharmacotherapy is also available and its use recommended. AIM: To provide an updated analysis of current and potential pharmacotherapeutic options for the management of alcohol dependence. In addition, factors predictive of therapeutic outcome, including compliance and pharmacogenetics, and the current barriers to treatment, including doctors' unwillingness to prescribe these agents, will be explored. METHODS: Relevant papers were selected for review following extensive, language- and date-unrestricted, electronic and manual searches of the literature. RESULTS: Acamprosate and naltrexone have a substantial evidence base for overall efficacy, safety and cost-effectiveness while the risks associated with the use of disulfiram are well-known and can be minimised with appropriate patient selection and supervision. Acamprosate can be used safely in patients with liver disease and in those with comorbid mental health issues and co-occurring drug-related problems. A number of other agents are being investigated for potential use for this indication including: baclofen, topiramate and metadoxine. CONCLUSION: Pharmacotherapy for alcohol dependence has been shown to be moderately efficacious with few safety concerns, but it is substantially underutilised. Concerted efforts must be made to remove the barriers to treatment in order to optimise the management of people with this condition

Mechanisms of Disulfiram-induced Cocaine Abstinence: Antabuse and Cocaine Relapse

Chemokines are chemoattractant proteins, secreted by a great many cell types, that function particularly to direct the migration of cells of the immune system. Chemokine receptors are G protein–coupled and have been implicated in a number of important disease states, including cancer, inflammatory disorders, and AIDS/HIV. Neuroinflammatory aspects of chronic pain are also chemokine-dependent, and given the many clinical difficulties that often arise in the treatment of chronic pain, novel therapeutics are urgently needed. Chemokine receptors would thus appear to be in ideal target for drug development, and indeed, animal models of neuropathic pain have allowed pharmacologists to identify a number of cell types and signaling pathways that are essential to the initiation and maintenance of chronic pain. In this regard, the chemokine receptor CCR2, activated by a chemokine known as monocyte chemoattractant protein 1, has been attributed to a number of specific regulatory and neural activation processes that contribute to chronic pain. But in order to target chemokine receptors such as CCR2 and thereby develop effective treatment, investigators must identify, from among many cell types and peripheral and central neural pathways, the relevant sites of CCR2 function

Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/-) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/-) and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors

<i>Dbh −/−</i> mice are hypersensitive to cocaine-induced locomotion.

<p>(A) Drug-naïve <i>Dbh +/−</i> (n = 9) and <i>Dbh −/−</i> mice (n = 8) were placed in automated locomotor activity chambers, injected with cocaine (15 mg/kg, i.p.) 30 minutes later, and locomotor activity was recorded for 2 hours. Shown are mean ± SEM ambulations (consecutive beam breaks). *** <i>p</i><0.0001, ** <i>p</i><0.01, * <i>p</i><0.05 compared with <i>Dbh −/−</i> mice at that time point. (B) On each of the next 5 days, mice were administered saline (3 injections of 10 ml/kg, each injection spaced 2 hours apart). Ninety minutes after the last saline injection, mice were placed in automated locomotor activity chambers, injected with cocaine (15 mg/kg, i.p.) 30 minutes later, and locomotor activity was recorded for 2 hours. Shown are mean ± SEM ambulations (consecutive beam breaks) for the 2 hours following cocaine administration. * p<0.05 between genotypes for that day.</p

Effects of chronic disulfiram or nepicastat administration on cocaine-induced locomotor activity in <i>Dbh +/−</i> mice during the development of sensitization.

<p>Each day for 5 consecutive days, <i>Dbh +/−</i> mice were administered saline (n = 9), disulfiram (3 injections of 100 mg/kg, i.p., each injection spaced 2 hours apart; n = 13), or nepicastat (3 injections of 50 mg/kg, i.p., each injection spaced 2 hours apart; n = 7). Ninety minutes after the last pretreatment, mice were placed in automated locomotor activity chambers, injected with cocaine (15 mg/kg, i.p.) 30 minutes later, and locomotor activity was recorded for 2 hours. (A) shows data with all disulfiram-treated mice in a single group. (B) shows data with disulfiram-treated mice divided into “no stereotypy” and “with stereotypy” groups. * p<0.01 compared to saline-treated group.</p

Drug administration paradigm.

<p>(A) Timeline for behavioral testing. (B) Timeline for injections and activity recording on each of the 5 cocaine sensitization days. P, pretreatment (saline, disulfiram, or nepicastat); A, mice placed in activity chambers; S, saline injection; C, cocaine injection; R, mice returned to their home cage. (C) Pretreatment and treatment groups for each genotype.</p