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Attentional deficits are core symptoms of schizophrenia, contributing strongly to disability. Prefrontal dysfunction has emerged as a candidate mechanism, with clinical evidence for prefrontal hypoactivation and disinhibition (reduced GABAergic inhibition), possibly reflecting different patient subpopulations. Here, we tested in rats whether imbalanced prefrontal neural activity impairs attention. To induce prefrontal hypoactivation or disinhibition, we microinfused the GABA-A receptor agonist muscimol (C 4 H 6 N 2 O 2 ; 62.5, 125, 250 ng/side) or antagonist picrotoxin (C 30 H 34 O 13 ; 75, 150, 300 ng/side), respectively, into the medial prefrontal cortex. Using the five-choice serial reaction time (5CSRT) test, we showed that both muscimol and picrotoxin impaired attention (reduced accuracy, increased omissions). Muscimol also impaired response control (increased premature responses). In addition, muscimol dose dependently reduced open-field locomotor activity, whereas 300 ng of picrotoxin caused locomotor hyperactivity; sensorimotor gating (startle prepulse inhibition) was unaffected. Therefore, infusion effects on the 5CSRT test can be dissociated from sensorimotor effects. Combining microinfusions with in vivo electrophysiology, we showed that muscimol inhibited prefrontal firing, whereas picrotoxin increased firing, mainly within bursts. Muscimol reduced and picrotoxin enhanced bursting and both drugs changed the temporal pattern of bursting. Picrotoxin also markedly enhanced prefrontal LFP power. Therefore, prefrontal hypoactivation and disinhibition both cause attentional deficits. Considering the electrophysiological findings, this suggests that attention requires appropriately tuned prefrontal activity. Apart from attentional deficits, prefrontal disinhibition caused additional neurobehavioral changes that may be relevant to schizophrenia pathophysiology, including enhanced prefrontal bursting and locomotor hyperactivity, which have been linked to psychosis-related dopamine hyperfunction.

Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but not fear conditioning. They also showed more spontaneous fear recovery and more contextual fear before extinction and its recall. Moreover, enhanced learned fear expression in females was associated with sustained prelimbic (PL) cortex activity. These results suggest that sex differences in learned fear expression may involve persistent PL activation.Women are at increased risk of developing fear-related anxiety disorders compared to men. For example, the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as in men (Lebron-Milad and Milad 2012). These disorders are characterized by impaired inhibition of learned fear (Milad et al. 2009a;Jovanovic et al. 2010) and a growing number of studies in humans and animals have shown sex differences in fear extinction (Milad et al. 2006;Baran et al. 2009Baran et al. , 2010Glover et al. 2012;ter Horst et al. 2012;Baker-Andresen et al. 2013), the reduction in learned fear that occurs with repeated nonreinforced presentations of the conditioned stimulus (CS).The neural circuitry mediating fear extinction is dysfunctional in PTSD. The medial prefrontal cortex (mPFC) is a heterogeneous area that plays a crucial role in this circuit through its involvement in learned fear and extinction processing. The dorsal anterior cingulate cortex (dACC) in humans and its rodent homolog, the prelimbic cortex (PL), are important for conditioned fear expression. In contrast, the human ventromedial prefrontal cortex (vmPFC) and the homologous infralimbic cortex (IL) in rodents are involved in fear suppression and extinction (Vidal-Gonzalez et al. 2006;Sierra-Mercado et al. 2011;Linnman et al. 2012). Importantly, PTSD is associated with dACC and vmPFC dysfunction (Milad et al. 2009a;Shin et al. 2009). Although a role for mPFC in mediating sex differences in fear extinction is emerging (Baran et al. 2010;Zeidan et al. 2011;Merz et al. 2012), the potential contribution of individual mPFC subregions remains unknown.We examined sex differences in local field potential (LFP) activity in PL and IL during fear extinction in male and naturally cycling female Lister hooded rats (Harlan, UK). All experimental procedures were conducted with internal ethical approval and in accordance with the Animals (Scientific Procedures) Act 1986, UK. Electrodes (Teflon-coated stainless-steel wires, 50 mm diameter) were implanted into PL and IL (2.7 mm anterior and 0.5 mm lateral to bregma, 3.3 mm (PL) and 4.3 mm (IL) ventral to the brain surface) under isoflurane anesthesia. Rats received peri-and post-operative analgesia (buprenorphine and meloxicam) and were singly housed during recovery and behavioral testing, which started 10 -14 d after surgery. ...

It has been suggested that agmatine (decarboxylated arginine) is an endogenous clonidine-displacing substance (CDS) which recognizes alpha 2-adrenoceptor and non-adrenoceptor, imidazoline binding sites. We have examined the effect of agmatine at alpha 2-adrenoceptor binding sites and pre- and postjunctional alpha 2-adrenoceptors. Agmatine produced a concentration-dependent inhibition of 1 nmol/l 3H-clonidine binding to both rat (pKi-5.10 +/- 0.05) and bovine (pKi-4.77 +/- 0.38) cerebral cortex membranes. However, agmatine (0.1-100 microM) failed to activate pre-junctional alpha 2-adrenoceptors regulating transmitter release in the guinea-pig isolated ileum and rat isolated vas deferens, nor did it activate postjunctional alpha 2-adrenoceptors of the porcine isolated palmar lateral vein which mediate contraction or inhibition of forskolin-stimulated cyclic AMP formation. High concentrations of agmatine (10-30-fold the pKi at alpha 2-adrenoceptor binding sites) failed to influence alpha 2-adrenoceptor activation by either clonidine or UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate) in any of the peripheral preparations examined. Moreover, even in a preparation where an interaction with alpha 2-adrenoceptor binding sites on cell membranes can be demonstrated, the rat cerebral cortex, agmatine failed to inhibit forskolin-stimulated cyclic AMP in the intact tissue or affect the inhibition produced by the selective alpha 2-adrenoceptor agonist UK-14304. Agmatine was also devoid of agonist activity in two preparations, the rat isolated thoracic aorta and the rat isolated gastric fundus, in which CDS has been reported to produce non-adrenoceptor effects. Thus, we have confirmed that agmatine recognizes alpha 2-adrenoceptor binding sites and, therefore, is a CDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex differences in learned fear expression and extinction involve the medial prefrontal cortex (mPFC). We recently demonstrated that enhanced learned fear expression during auditory fear extinction and its recall is linked to persistent theta activation in the prelimbic (PL) but not infralimbic (IL) cortex of female rats. Emerging evidence indicates that gamma oscillations in mPFC are also implicated in the expression and extinction of learned fear. Therefore we re-examined our in vivo electrophysiology data and found that females showed persistent PL gamma activation during extinction and a failure of IL gamma activation during extinction recall. Altered prefrontal gamma oscillations thus accompany sex differences in learned fear expression and its extinction. These findings are relevant for understanding the neural basis of post-traumatic stress disorder, which is more prevalent in women and involves impaired extinction and mPFC dysfunction.

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