Cocaine addiction is an enduring, relapsing, behavioural disorder in which stressors reinstate cocaine-seeking even after prolonged abstinence. Evidence suggests that the 'anxiety-like' behaviour and stress associated with protracted withdrawal may be mediated by increased corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA), a part of the limbic circuitry engaged in the coding and transmission of stimulus-reward associations. In the present study we describe a long-lasting potentiation of glutamatergic transmission induced at lateral amygdala (LA)-to-CeA synapses by rat/human CRF. After 2 weeks of withdrawal from repeated intermittent exposure to cocaine, CRF-induced long-term potentiation (LTP) was greatly enhanced compared to the respective saline control group while, after short-term withdrawal (24 h), there was no significant difference between the two treatment groups, indicating alterations in CRF systems during protracted withdrawal from chronic cocaine. After prolonged withdrawal, CRF-induced LTP was dependent on activation of CRF2, CaV2.3 (R-type) calcium channels and intracellular signalling through protein kinase C in both saline- and cocaine-treated groups. The enhanced CRF-induced LTP after 2 weeks of withdrawal was mediated through augmented CRF1 receptor function, associated with an increased signalling through protein kinase A, and required N-methyl-D-aspartate (NMDA) receptors. Accordingly, single-cell recordings revealed a significantly increased NMDA/AMPA ratio after prolonged withdrawal from the cocaine treatment. These results support a role for CRF1 receptor antagonists as plausible treatment options during withdrawal from chronic cocaine and suggest Ca(V)2.3 blockers as potential candidates for pharmaceutical modulation of CRF systems.

Leão's spreading depression can be observed in clinically standard, continuous scalp EEG, and underlying depolarizations can spread widely across the injured cerebral hemisphere. These results open the possibility of monitoring noninvasively a neuronal pathophysiological mechanism in a wide range of disorders including ischemic stroke, subarachnoid hemorrhage, and brain trauma, and suggest a novel application for continuous EEG.

Basolateral amygdala (BLA) neurons provide a major excitatory input to medial prefrontal cortex (mPFC)-layer V pyramidal neurons. Under stressful conditions, commonly associated with chronic cocaine abuse, altered BLA-to-mPFC synaptic transmission could lead to defective emotional information processing and decision making within the mPFC and result in misguided and inappropriate behaviors. We examined the effects of cocaine administered chronically in vivo on EPSCs recorded from a putative BLA-mPFC pathway in vitro and their modulation by dopamine (DA), corticotropin-releasing factor (CRF), and their combination (DA plus CRF). In saline-treated animals, activation of D 1/5 receptors depressed BLA-mPFC EPSCs, whereas CRF 1 receptor activation alone had no effect on EPSCs. Activating D 1/5 and CRF 1 receptors in combination, however, worked synergistically through presynaptic and postsynaptic mechanisms to depress EPSCs to levels greater than D 1/5 receptor activation alone. After chronic cocaine administration, the function of DA 1/5 and CRF receptors switched from inhibitory to excitatory. In slices from cocaine-treated animals, putative BLA-mPFC EPSCs were depressed through a presynaptic mechanism. Now, activation of either D 1/5 or CRF 2 receptors increased the cocaine-induced, depressed EPSCs. Additionally, simultaneous activation of presynaptic D 1/5 and CRF 2 receptors led to further enhancement of EPSCs. These data indicate that CRF acting synergistically with DA normally potentiates D 1/5 -induced synaptic depression. However, after chronic cocaine, the combined synergistic actions of DA and CRF switched polarity to enhance facilitation of BLA-mPFC glutamatergic transmission. Also unmasked after acute withdrawal from chronic cocaine are endogenous, tonic-inhibitory D 2 -like and tonic-facilitatory CRF 2 receptor actions. These multiple functional and receptor changes may underlie the altered, possibly aberrant, decision-making process after chronic cocaine.

. The amygdala is part of the brain reward circuitry that plays a role in cocaine-seeking and abstinence in animals and cocaine craving and relapse in humans. Cocaine-seeking is elicited by cocaine-associated cues, and the basolateral amygdala (BLA) and CeA are essential in forming and communicating drugrelated associations that are thought to be critical in long-lasting relapse risk associated with drug addiction. Here we simulated a cue stimulus with high-frequency stimulation (HFS) of the BLA-CeA pathway to examine mechanisms that may contribute to drug-related associations. We found enhanced long-term potentiation (LTP) after 14-day but not 1-day withdrawal from 7-day cocaine treatment mediated through N-methyl-D-aspartate (NMDA) receptors (NRs), Ltype voltage-gated calcium channels (L-VGCCs), and corticotropinreleasing factor (CRF) 1 receptors; this was accompanied by increased phosphorylated NR1 and CRF 1 protein not associated with changes in NMDA/AMPA ratios in amygdalae from cocaine-treated animals. We suggest that these signaling mechanisms may provide therapeutic targets for the treatment of cocaine cravings.The amygdala is essential in forming stimulus-reward associations and associational processing of conditioned cues (Aggleton 1992;Shinnick-Gallagher et al. 2003). Drug-associated cues can induce craving in cocaine users and alter neural activity in the amygdala (Childress et al. 1999), and electrical stimulation of the basolateral amygdala (BLA) can reinstate drug-seeking in animals (Hayes et al. 2003). Drug-cue associations are not well understood, but the mechanisms may be similar to forms of synaptic plasticity and the induction and expression of cocaine sensitization, a model for long-term neuroadaptations important in addiction (De Vries et al. 1999; Kalivas and Alesdatter 1993;Robinson and Berridge 1993). Antagonizing N-methyl-D-aspartate (NMDA) receptors (NRs) in the amygdala can prevent and block locomotor sensitizing effects of chronic cocaine (Kalivas and Alesdatter 1993), and amygdala NR1 protein levels are increased after acute and chronic cocaine (Turchan et al. 2003). Likewise, activation of L-type calcium channels mimics the induction (Lin et al. 2001) and antagonists block expression of cocaine sensitization (Pierce et al. 1998). Furthermore, corticotropin-releasing factor (CRF) systems in the amygdala play a significant role in cocaine addiction (Sarnyai et al. 2001). In cocaine-treated animals, CRF release in the amygdala is enhanced during acute withdrawal (Richter and Weiss 1999) and in response to a cocaine challenge (Richter et al. 1995). Amygdala CRF immunolabeling decreases after short-term, but increases after long-term withdrawal from chronic cocaine (Zorrilla et al. 2001). Furthermore, cocaine-induced locomotor activity is blocked by intracerebroventricular injection of a CRF antagonist (Sarnyai et al. 1992). These data provide strong rationale for testing the role of CRF receptors in synaptic plasticity in the central amygdala (CeA). This study shows that specific coca...

Corticotropin-releasing factor (CRF or CRH) and its family of related peptides have long been recognized as hypothalamic-pituitary-adrenal (HPA) axis peptides that function to regulate the release of other hormones, e.g., ACTH. In addition, CRF acts outside the HPA axis not as a hormone, but as a regulator of synaptic transmission, pre- and post-synaptically, within specific CNS neuronal circuits. Synaptic transmission within the nervous system is today understood to be a more complex process compared to the concepts associated with the term 'synapse' introduced by Sherrington in 1897. Based on more than a century of progress with modern cellular and molecular experimental techniques, prior definitions and functions of synaptic molecules and their receptors need to be reconsidered (see Glossary and Fig. 1), especially in light of the important roles for CRF, its family of peptides and other potential endogenous regulators of neurotransmission, e.g., vasopressin, NPY, etc. (see Glossary). In addition, the property of 'constitutive activity' which is associated with G-protein coupled receptors (GPCRs) provides a persistent tonic mechanism to fine-tune synaptic transmission during both acute and chronic information transfer. We have applied the term 'regulator', adapted from the hormone literature, to CRF, as an example of a specific endogenous substance that functions to facilitate or depress the actions of neuromodulators on fast and slow synaptic responses. As such, synaptic neuroregulators provide a basic substrate to prime or initiate silently plastic processes underlying neurotransmitter-mediated information transfer at CNS synapses. Here we review the role of CRF to regulate CNS synaptic transmission and also suggest how under a variety of allostatic changes, e.g., associated with normal plasticity, or adaptations resulting from mental disorders, the synaptic regulatory role for CRF may be 'switched' in its polarity and/or magnitude in order to provide a coping mechanism to deal with daily and life-long stressors. Thus, a prominent role we assign to non-HPA axis CRF, its family of peptides, and their receptors, is to maintain both acute and chronic synaptic stability.