Cortico-Basal Ganglia Reward Network: Microcircuitry

Schizophrenia is associated with frontostriatal network impairments underlying clinical and cognitive symptoms. We previously found disruptions in anatomical pathways, including the tract connecting the left nucleus accumbens and left dorsolateral prefrontal cortex (DLPFC). Similar deficits are observed in unaffected siblings of schizophrenia patients, indicating that these deficits are linked to a genetic vulnerability for the disorder. Frontostriatal tract disruptions may arise during adolescence, preceding the clinical manifestation of the disorder. However, to date, no studies have been performed to investigate frontostriatal tract connections in adolescents who are at increased familial risk for schizophrenia. In this study, we investigate the impact of familial risk on frontostriatal tract connections using diffusion tensor imaging in 27 adolescent offspring of schizophrenia patients and 32 matched control adolescents, aged 10-18 years. Mean fractional anisotropy (FA) was calculated for the tracts connecting the striatum (caudate nucleus, putamen, nucleus accumbens) and frontal cortex regions (DLPFC, medial orbital frontal cortex, inferior frontal gyrus). As expected, based on siblings data, we found an impact of familial risk on frontostriatal development: schizophrenia offspring showed increased FA in the tracts connecting nucleus accumbens and DLPFC as compared with control adolescents. Moreover, while FA increased across age in control adolescents, it did not in schizophrenia offspring. We did not find differences in FA in other frontostriatal tracts. These results indicate altered development of white matter in subjects who are at familial risk for schizophrenia and may precede frontostriatal white matter alterations in adult schizophrenia patients and siblings.

Section: Discussionmentioning

confidence: 99%

Changes in White Matter Organization in Adolescent Offspring of Schizophrenia Patients

Leeuw

Bohlken

Mandl

et al. 2016

“…Goal-directed behaviors, such as the spinning of a wheel to retrieve a reward, involve excitatory projections from the prefrontal cortex, the subiculum and the basolateral amygdala to the NAcc (Sesack and Grace, 2010), while simple 'liking' of a rewarding stimulus, such as a solution that contains midazolam, can be controlled by a small 'hedonic hotspot' within the medial region of the NAcc shell (Pecina and Berridge, 2005). Indeed, there is strong evidence showing that the neuronal circuitry underlying different components of reward, such as 'liking' (ie, experience of simple pleasure through the administration of an appetitive stimulus), 'wanting' (ie, incentive salience that leads to motivated behavior) and learning (ie, the acquisition of the associations between reward-predictive cues and the natural reward) is distinct (Berridge et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of GABAA Receptor Subtypes in Benzodiazepine-Induced Enhancement of Brain-Stimulation Reward

Reynolds

Engin

Tantillo

et al. 2012

Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABA A receptor subtypes. To elucidate the a subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the a1, a2, or a3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and a1-pointmutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in a2-and a3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. a2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in a2-point-mutant animals. Zolpidem, an a1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate a2 and a3 subunit containing GABA A receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability.

“…The ventral tegmental area (VTA) sends dopaminergic projections to the OFC (Berger et al, 1991;Dunnett and Robbins, 1992;Frankle et al, 2006;Geisler et al, 2007;Sesack and Grace, 2010). Furthermore, dopaminergic neurotransmission in the frontal cortices critically regulates higher-order cognitive function, including reward-related processing by the OFC that likely facilitates cocaine-seeking behavior (Cetin et al, 2004;Dalley et al, 2004;Kheramin et al, 2004;Ragozzino et al, 1999;Ward et al, 2009;Winter et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Lasseter

Xie

Arguello

et al. 2013

Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra-and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.