Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

The finding that intermittent exposure produces more rapid increases in self-administration of ethanol relative to continuous exposure suggests that intermittent exposure may be associated with a more rapid escalation of the allostatic processes responsible for excessive ethanol self-administration. The mechanisms that drive the increases in drinking during withdrawal are similar after 2 and 8 hr of withdrawal and seem to be specific to ethanol.

Self-administration Excessive drinking of ethanol in animals can be produced by a number of factors including altering palatability, genetics, and history of consumption. There is evidence that certain symptoms of withdrawal can persist for a number of weeks or even months following chronic ethanol exposure in humans (Kissin 1979;Begleiter and Porjesz 1979;Alling et al. 1982;Roelofs 1985;Grant et al. 1987) as well as in animals (Begleiter and Porjesz 1979). In human alcoholics, one of the factors leading to excessive drinking is the use of alcohol to relieve or avoid withdrawal symptoms (U.S. Department of Health and Human Services 1990). Fatigue and tension persisted for approximately five weeks following withdrawal in a group of 68 chronic alcoholics (Alling et al. 1982), and periods of hyperventilatory symptomology and anxiety (as determined by the Spielberger State-Trait Anxiety Inventory, a self-report inventory), which correlated with intensity of alcohol craving, were reported for up to nine months following withdrawal in a group of 37 chronic alcoholics (Roelofs 1985).In a larger cohort of 312 abstinent alcoholics, 20-25% of them showed signs of anxiety and depression, as determined from the Symptom Check-List 90 (self-report inventory with coverage of areas of symptomology and psychopathology) six months to two years following withdrawal (De Soto et al. 1985). In a follow-up study, it was shown that distress-related symptoms correlated with relapse in alcoholics who were abstinent for less than two years (De Soto et al. 1989). The more pro- Received March 2, 1999; revised August 25, 1999; accepted December 6, 1999. 582 A.J. Roberts et al. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 6 tracted symptoms tended to be subacute, were often affective in nature, and appeared to precede relapses into uncontrolled alcohol drinking. For example, depression and anxiety associated with withdrawal were found to provoke drinking in 83 of 100 male alcoholics who experienced these symptoms (Hershon 1977). These patients reported that they drank alcoholic beverages when they experienced anxiety and depressed mood. In another study, both male and female alcoholics reported negative emotions as the most common trigger of relapse (Annis et al. 1998). The clinical literature suggests that alterations in affective state persist for quite some time following alcohol withdrawal and may actually be partly responsible for some relapse episodes in alcoholics.Potential rodent models of excessive ethanol drinking include the alcohol deprivation effect in nondependent animals, ethanol self-administration in dependent withdrawing animals, and ethanol self-administration in animals with a history of dependence following periods of abstinence. The alcohol deprivation effect is a transient increase in ethanol self-administration in animals following periods of abstinence from ethanol for several days to several weeks (Sinclair and Senter 1967;Spanagel et al. 1996;Heyser et al. 1997;Hölter et al. 1998). This increase in e...

The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. We tested whether the hypocretinergic system is a critical component of the stress response activated by the corticotropin-releasing factor (CRF). Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors. We also demonstrate that application of CRF to hypothalamic slices containing identified hypocretin neurons depolarizes membrane potential and increases firing rate in a subpopulation of hypocretinergic cells. CRF-induced depolarization was tetrodotoxin insensitive and was blocked by the peptidergic CRF-R1 antagonist astressin. Moreover, activation of hypocretinergic neurons in response to acute stress was severely impaired in CRF-R1 knock-out mice. Together, our data provide evidence of a direct neuroanatomical and physiological input from CRF peptidergic system onto hypocretin neurons. We propose that, after stressor stimuli, CRF stimulates the release of hypocretins and that this circuit contributes to activation and maintenance of arousal associated with the stress response.

Dependence is an important factor motivating continued alcohol use in human alcoholics. Development of a model of ethanol (EtOH) consumption in dependent animals would advance the understanding of reinforcement after chronic EtOH exposure and allow for the investigation of the neuropharmacological mechanisms mediating reinforcement in dependent versus nondependent animals. In the present study, rats were trained to lever press for 10% EtOH, surgically implanted with bilateral guide cannulae in the amygdala, and either made dependent on EtOH by exposure for 2 weeks to EtOH or exposed to air in identical vapor chambers. Upon removal, the rats were placed in operant boxes and allowed to respond on levers for 10% EtOH or water during a 12-hr period. Rats were removed briefly at approximately 6.5 hr for intra-amygdala injections of saline or the GABAA receptor agonist muscimol. After the test period, rats were returned to the vapor chambers for 4 days before retest. EtOH-dependent animals responded more for EtOH across the 12-hr test period than did air control nondependent rats; this difference became more pronounced with repeated test sessions. Intra-amygdala muscimol significantly decreased responding for EtOH in EtOH-dependent rats, but had no effect in nondependent controls. These data suggest that the reinforcing effects of EtOH and neurotransmitter pathways mediating reward are altered after the development of dependence, and they support the use of this paradigm for further investigations into the neuropharmacology of EtOH dependence.