Accordingly, compulsive drug use would result from poorly developed (prefrontal) reflective

processes dependent on executive functioning, taken over by a fast motivational (amygdalar) impulse process (Bechara 2005; Wiers et al. 2007). This model integrates behavioral, emotional, and cognitive processes and thereby expanded the traditional concepts that relied on positive and negative reinforcement for compulsive drug use and relapse. In addition to the I-RISA model, the Habitual Behavioral Model emphasizes the importance of a switch from goal-directed behavior Inhibitors,research,lifescience,medical to habitual behavior during the development of drug dependence. Habitual behavior would be less sensitive to outcome values and would lead to loss of voluntary control and the development of compulsive behavior, such as compulsive drug use.

The switch to habitual behavior would represent a progression from prefrontal cortical to striatal control Inhibitors,research,lifescience,medical and a switch from ventral to more dorsal striatal regions (Wood and Neal 2007; Everitt et al. 2008). Whether changes in neuropsychological functioning should be viewed as a vulnerability trait or a response to chronic drug abuse still needs to be elucidated. Several studies have provided evidence Inhibitors,research,lifescience,medical for the involvement of predisposing VE-821 research buy genetic and environmental factors (Morgan et

al. 2002a; Bevilacqua and Goldman 2009), while others Inhibitors,research,lifescience,medical have described similar neurobiological changes as a response to chronic drug use (Nader et al. 2002; Volkow et al. 2004), or have assumed that both processes are present and mutually enhancing (Nader et al. 2006). While early hypotheses were stated from a behaviorist and psychological point of view (Hull 1943), subsequent theories were increasingly based on neurobiological animal research. With time, studies focused on integrating results from animal and human studies, and neuroanatomical substrates and dysregulated Inhibitors,research,lifescience,medical neurotransmitter systems were hypothesized to underlie the motivation to administer drugs, while recognizing the important role of genetic along with social factors Idoxuridine as contributors in the pathophysiology of drug use and addiction. Importantly, recent models of addiction have increasingly incorporated neuropsychological aspects of drug dependence, aided by the rapid expansion of the field of functional neuroimaging (for a review on substrates and neurocircuitries considered important in drug dependence, see the recent reviews of Goldstein et al. 2009a; Koob and Volkow 2010). However, results of these imaging studies usually do not allow causal inferences to be made, which should also be kept in mind when reading this review.

Additionally, the mother was of African origin, which further increases her risk of gestational diabetes. Therefore, Procaspase activation olanzapine seems a plausible cause of this baby’s hypoglycaemia, either through direct action on the infant’s basal insulin levels, or via undiagnosed maternal gestational diabetes. Olanzapine has an in vivo placental passage ratio of 72.2% [Newport et al. 2007], and several case reports on its use have described uneventful pregnancies and healthy Inhibitors,research,lifescience,medical infants. The

largest study to date found that olanzapine did not increase the risk of major congenital malformations, but was associated with a higher maternal BMI, maternal gestational diabetes and low birth weight [Reis and Kallen, 2008]. Another prospective study also reported a Inhibitors,research,lifescience,medical tendency towards low birth weight and neonatal intensive care admission [McKenna et al. 2005]. In contrast, others have linked maternal olanzapine with a higher incidence of large for gestational age (LGA) infants and higher mean birth weight [Babu et al. 2010; Inhibitors,research,lifescience,medical MacRitchie et al. 2006; Newham et al. 2008]. Predisposing factors for LGA infants include maternal obesity, type 1 diabetes mellitus, gestational diabetes mellitus and maternal weight gain, all conditions that

have been shown to be exacerbated or precipitated by some antipsychotics, including olanzapine. However, a large recent linkage study has found that women taking antipsychotic medication during pregnancy have an increased risk of gestational diabetes and a higher incidence of SGA infants [Boden et al. 2012]; olanzapine and clozapine therapy

were not associated with a higher incidence Inhibitors,research,lifescience,medical of gestational diabetes compared with other antipsychotics. Also of note was that the high incidence of SGA infants born Inhibitors,research,lifescience,medical to women on antipsychotics was explained by confounders such as smoking, which is a possible cause in this case. The mechanism for an olanzapine-induced metabolic syndrome is not well understood. However, the insulin Unoprostone resistance induced by olanzapine treatment is rapid, occurring within days, separately from weight gain [Ebenbichler et al. 2003]. Potential causative mechanisms may involve free fatty acids, leptin and tumour necrosis factor α [Kahn and Flier, 2000]. Studies have also shown that weight gain is due to the accumulation of white adipose tissue, and that low-grade adipose inflammation may play a role in this [Victoriano et al. 2010]. Conclusion Olanzapine exposure during pregnancy was associated with neonatal hyperinsulinaemia in the absence of proven gestational diabetes. Given the mechanisms discussed above, olanzapine is a potential causative agent either acting directly on the infant’s own glucose metabolism or indirectly via the mother.