Individual differences in the neuropsychopathology of addiction.

Drug addiction or substance-use disorder is a chronically relapsing disorder that progresses through binge/intoxication, withdrawal/negative affect and preoccupation/anticipation stages. These stages represent diverse neurobiological mechanisms that are differentially involved in the transition from recreational to compulsive drug use and from positive to negative reinforcement. The progression from recreational to compulsive substance use is associated with downregulation of the brain reward systems and upregulation of the brain stress systems. Individual differences in the neurobiological systems that underlie the processing of reward, incentive salience, habits, stress, pain, and executive function may explain (i) the vulnerability to substance-use disorder; (ii) the diversity of emotional, motivational, and cognitive profiles of individuals with substance-use disorders; and (iii) heterogeneous responses to cognitive and pharmacological treatments. Characterization of the neuropsychological mechanisms that underlie individual differences in addiction-like behaviors is the key to understanding the mechanisms of addiction and development of personalized pharmacotherapy

Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats.

The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder

El sistema endógeno de serotonina no participa en la abstinencia opiácea, aunque su inhibición por estimulación del receptor 5-HT1A incrementa la eficacia antidisfórica de la clonidina en ratas

El objetivo del estudio fue discernir el papel del sistema endógeno de serotonina en la abstinencia opiácea, tanto en su vertiente somática como emocional, así como su posible interacción con los efectos de la clonidina. Con tal fin, se empleó un protocolo basado en la lesión casi total de los principales centros serotoninérgicos del mesencéfalo, y también se bloqueó la actividad serotoninérgica mediante 8-hidroxi-dipropilaminotetralina (8-OHDPAT), agonista 5-HT1A. Los resultados indicaron que el sistema serotoninérgico no se encuentra involucrado en el síndrome somático de abstinencia y que la clonidina mantuvo su eficacia en el síndrome somático tras la depleción de serotonina. Los resultados también mostraron que el sistema de serotonina tampoco se encuentra involucrado en el síndrome emocional en la rata, evaluado mediante la aversión condicionada tras naloxona. Sin embargo, la eficacia antiaversiva de la clonidina se vio incrementada casi 10 veces tras la depleción casi completa de serotonina cerebral. Además, la inhibición farmacológica del sistema serotonérgico con 8-OHDPAT indujo efectos similares a la depleción serotoninérgica respecto a la eficacia antiaversiva de la clonidina. Por tanto, el uso combinado de compuestos agonistas del receptor 5- HT1A y clonidina podría ser eficaz para el tratamiento del síndrome de abstinencia opiáceo.The aim of the study was to discern the role of the endogenous serotonin system in opiate withdrawal, in both somatic and emotional aspects, along with its possible interaction with clonidine effects. To this end, a protocol based on near complete lesion of main serotonergic brain centers was carried out, and serotonin neurotransmission was also blocked by 8-hydroxy-dipropylaminotetraline (8-OHDPAT), 5- HT1A receptor agonist. The findings revealed that the serotonin system is not involved in somatic abstinence, and clonidine efficacy was not affected after serotonin depletion. The findings also revealed that the serotonin system is not involved in the emotional aspect of opiate abstinence, as measured through conditioned place aversion in rats. However, antiaversive clonidine efficacy was enhanced near 10 times following serotonin depletion. Moreover, 8-OHDPAT treatment induced similar effects on antiaversive clonidine efficacy to those found after serotonin depletion. Hence, the combined use of 5-HT1A receptor agonists and clonidine could be of value for treatment of opiate withdrawal syndrome

CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats

RATIONALE: Previous work suggests a role for stress-related corticotropin-releasing factor (CRF) systems in cocaine dependence. However, the involvement of activation of CRF(1) receptors in rats self-administering cocaine with extended access is unknown. OBJECTIVE: The current study examined whether CRF(1) receptor antagonist administration alters cocaine self-administration in animals given extended access. MATERIALS AND METHODS: Wistar rats (n = 32) acquired cocaine self-administration (0.66 mg/kg per infusion) in 1 h sessions for up to 11 days. Rats then were assigned to receive either daily short (1 h, ShA) or long (6 h, LgA) access to cocaine self-administration (n = 7-9 per group). Following escalation of intake, animals received one of two selective CRF(1) antagonists: antalarmin (6.3-25 mg/kg, i.p.) or N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5a]pyrimidin-7-amine (MPZP; 3.6-27.5 mg/kg, s.c.). RESULTS: By day 11 of the escalation period, LgA rats increased their cocaine intake, reaching an intake level of 15.1 mg/kg, compared to 11.1 mg/kg in ShA rats, during the first hour of sessions. Antalarmin reduced cocaine self-administration at the highest dose selectively in the LgA group but not the ShA group. MPZP reduced cocaine intake both in LgA and ShA rats. However, MPZP did so at a lower dose in LgA rats than in ShA rats. Within the LgA group, MPZP decreased cocaine intake in the first 10 min (loading phase) as well as in the latter session intake (maintenance phase). CONCLUSION: The data suggest that hypersensitivity of the CRF system occurs with extended access to cocaine self-administration and that this altered CRF system may contribute to the increased motivation to self-administer cocaine that develops during psychostimulant dependence

SHORT COMMUNICATION Key role for enkephalinergic tone in cortico±striatal± thalamic function

Abstract Whereas the role of dopaminergic tone in the cortico-striatal-thalamic system is well-established, the role of endogenous opioids in the function of this system is less understood. We show that Borna disease virus infection of adult rats results in an increase in preproenkephalin transcripts in the striatum of Borna-infected rats, a region important for forming coordinated sequential motor actions and in developing programmes of thought and motivation. Stereotypic behaviours and dyskinesias, the clinical hallmarks of infection in adult Lewis rats (BD rats), are accompanied by a disrupted pattern of immediate early gene c-fos activation in the motor thalamus, with signi®cance for the breakdown in coordinated sequential motor actions. We also ®nd increased preproenkephalin in infected cultured neuroblastoma and rat foetal glial cells. The expression pattern of enkephalin mRNA in vivo and in vitro suggest that increased enkephalin function is one of the neuropharmacological means by which Borna disease virus causes motor disease of animals and possibly cognitive and affective disease in man, and further suggest that enkephalins play a critical role in the maintenance of a balanced tone of activity in the cortico-basal ganglia-thalamo-cortical loops

Neurotrophic factor expression after CNS viral injury produces enhanced sensitivity to psychostimulants : potential mechanism for addiction vulnerability

Hypothesized risk factors for psychostimulant, amphetamine, and cocaine abuse include dopamine (DA) receptor polymorphisms, HIV infection, schizophrenia, drug-induced paranoias, and movement disorders; however, the molecular, cellular, and biochemical mechanisms that predispose to drug sensitivity or drive the development of addiction are incompletely understood. Using the Borna disease rat, an animal model of viralinduced encephalopathy wherein sensitivity to the locomotor and stereotypic behavioral effects of D-amphetamine and cocaine is enhanced (Solbrig et al., 1994, 1998), we identify a specific neurotrophin expression pattern triggered by striatal viral injury that increases tyrosine hydroxylase activity, an early step in DA synthesis, to produce a phenotype of enhanced amphetamine sensitivity. The reactive neurotrophin pattern provides a molecular framework for understanding how CNS viral injury, as well as other CNS adaptations producing similar growth factor activation profiles, may influence psychostimulant sensitivity