Prefrontal Norepinephrine Determines Attribution of “High” Motivational Salience

Intense motivational salience attribution is considered to have a major role in the development of different psychopathologies. Numerous brain areas are involved in “normal” motivational salience attribution processes; however, it is not clear whether common or different neural mechanisms also underlie intense motivational salience attribution. To elucidate this a brain area and a neural system had to be envisaged that were involved only in motivational salience attribution to highly salient stimuli. Using intracerebral microdialysis, we found that natural stimuli induced an increase in norepinephrine release in the medial prefrontal cortex of mice proportional to their salience, and that selective prefrontal norepinephrine depletion abolished the increase of norepinephrine release in the medial prefrontal cortex induced by exposure to appetitive (palatable food) or aversive (light) stimuli independently of salience. However, selective norepinephrine depletion in the medial prefrontal cortex impaired the place conditioning induced exclusively by highly salient stimuli, thus indicating that prefrontal noradrenergic transmission determines approach or avoidance responses to both reward- and aversion-related natural stimuli only when the salience of the unconditioned natural stimulus is high enough to induce sustained norepinephrine outflow. This affirms that prefrontal noradrenergic transmission determines motivational salience attribution selectively when intense motivational salience is processed, as in conditions that characterize psychopathological outcomes

Olfactory priming reinstates extinguished chocolate-induced conditioned place preference

A major problem in the dietary treatment of disorders associated with excessive eating, such as obesity, is the high rate of relapse into maladaptive eating habits after withdrawal from Consumption of palatable, energy-dense food. As olfaction has a major role in appetite and eating behavior, in this Study We used a reinstatement model based on conditioned place preference to investigate the ability of olfactory priming to reinstate extinguished chocolate-induced conditioned place preference in sated mice. We found that olfactory priming, which was ineffective in inducing conditioned place preference in the control group, reactivated place preference following the extinction procedure in the experimental group. These results extend previous reports of the reinstatement of food seeking induced by pellet priming and, for the first time, show the possibility of using olfactory priming in ail animal model of relapse. In light of the major role of olfactory inputs in appetite and of cues in relapse, the present results indicate that smell is an important factor to consider in the treatment of eating disorders. (C) 2009 Elsevier Ltd. All rights reserved

5-Hydroxytryptophan rescues serotonin response to stress in prefrontal cortex of hyperphenylalaninaemic mice

Adult early treated hyperphenylalaninaemic patients can show specific deficits of prefrontal cortical functions. The development of additional therapeutic strategies for these patients requires the understanding of the mechanisms involved in phenylalanine-dependent impairment of fronto-cortical functions. We tested the hypothesis of phenylalanine interference with aminergic neurotransmission in the prefrontal cortex by evaluating, in vivo, amine release in adult Pah(enu2) mice, the genetic model of phenylketonuria. Mice of healthy background responded to a psychogenic stressor with the classic time-dependent increase of norepinephrine, dopamine and serotonin release from prefrontal cortical terminals. Neither the dopaminergic nor the serotoninergic responses were observable in the Pah(enu2) mice. Temporary reduction of circulating phenylalanine, by phenylalanine-free diet without amino-acid supplement, promoted recovery of the serotonin response only, demonstrating direct interference with serotonin synthesis in the mature brain. Evaluation of different steps of serotonin synthesis in the prefrontal cortex of hyperphenylalaninaemic mice demonstrated inhibition of cortical tryptophan hydroxylase activity. Finally, systemic administration of 5-hydroxytryptophan, the product of tryptophan hydroxylase activity, allowed frontal cortical serotonin response to stress in hyperphenylalaninaemic mice. Collectively, these results demonstrate that hyperphenylalaninaemia interferes with the ability of the mature prefrontal cortex to respond to psychological challenges, point to serotonin synthesis as the target of phenylalanine interference, and support the use of 5-hydroxytryptophan in lifelong treatment of hyperphenylalaninaemic subjects

Chocolate consumption by Sham and NE depleted groups (milk chocolate in control, MCh; milk chocolate in food restricted MCh+FR; white chocolate in control, WCh) during microdialysis experiments.

<p>Data are expressed as total mean grams±SE. * P<0.005 in comparison with MCh group receiving the same pretreatment (Sham or NE depleted); # P<0.005 in comparison with the MCh+FR group receiving the same pretreatment (Sham or NE depleted).</p

Overall mean percent increase of norepinephrine in medial prefrontal cortex (mpFC) induced by rewarding and aversive stimuli.

<p>Extracellular norepinephrine (NE) in mpFC of Sham animals exposed to chocolate (1 g) or light (milk chocolate in control, MCh; milk chocolate in food restricted, MCh+FR; white chocolate in control, WCh; intermittent light in control, IL; intermittent light in food restricted, IL+FR; intermittent-pulsating light in control, IPL). Results are the sum of time points (n = 8 for chocolate and 6 for light experiments) expressed as percent changes from basal levels (point 0) of each experimental group (<i>n</i> = 8–9 per group). All data are expressed as mean±SE. *, P<0.05 in comparison with the MCh+FR group for chocolate or the IL+FR group for light; #, P<0.05 in comparison with the WCh group for chocolate or the IPL group for light.</p

Prefrontal cortical norepinephrine depletion on extracellular norepinephrine in mpFC.

<p>Extracellular norepinephrine (NE) in mpFC of Sham or norepinephrine-depleteted (NE Depleted) animals exposed to chocolate (1 g) or light (milk chocolate in control, MCh; milk chocolate in food restricted, MCh+FR; white chocolate in control, WCh; intermittent light in control, IL; intermittent light in food restricted, IL+FR; intermittent-pulsating light in control, IPL). Results are expressed as percent changes from basal levels of each experimental group (<i>n</i> = 6–9 per group). Statistical analyses were carried out on raw data. Chocolate and light were administrated at time 0. All data are expressed as mean±SE. §, P<0.05 in comparison with the corresponding time point of MCh for chocolate or IL for light; *, P<0.05 in comparison with basal levels.</p

Prefrontal cortical norepinephrine depletion on place conditioning in isolated animals.

<p>Effects of milk chocolate consumption (1 g.) in place conditioning shown by Sham and norepinephrine-depleted (NE Depleted) animals submitted to social isolation. All data are expressed as mean (sec±SE) time spent in Center, Paired, and Unpaired chambers (<i>n</i> = 8 per group). *, P<0.05 in comparison with the Unpaired chamber.</p

Chocolate consumption by Sham (upper panel) and NE depleted groups (lower panel) throughout conditioning procedure (day (d) 1, 3, 5 and 7 of pairing).

<p>Data are expressed as total mean grams±SE. * P<0.005 in comparison with the MCh and WCh groups; # P<0.05 in comparison with the MCh group.</p