Background-We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption.

The lymphotoxin-B receptor (LTBR) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LTBR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LTBR caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LTBR activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LTBR with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.

Pentobarbital and midazolam produce ethanol-like discriminative stimulus effects in male and female cynomolgus monkeys suggesting a significant GABA(A) component mediating the behavioral effects of ethanol. There was limited evidence that training dose of ethanol influenced substitution pattern of the GABA(A) ligands in cynomolgus monkeys, unlike previous findings in rats. Finally, there appear to be no sex differences in the profile of GABA(A) mechanisms involved in the discriminative stimulus effects of ethanol.

These data suggest that NMDA receptor-mediated activity is a component to the discriminative stimulus effects of ethanol in male and female nonhuman primates. However, NMDA uncompetitive antagonists were less likely to produce discriminative stimulus effects similar to a high ethanol training dose in male monkeys. In comparison to consistent substitution by GABA(A) positive modulators for ethanol, substitution patterns produced by NMDA uncompetitive antagonists suggest a less robust mediation of the ethanol discriminative stimulus through NMDA receptor systems in nonhuman primates.

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Numerous biochemical as well as electrophysiological techniques require tissue that must be retrieved very quickly following death in order to preserve the physiological integrity of the neuronal environment. Therefore, the ability to accurately predict the precise locations of brain regions of interest (ROI) and to retrieve those areas as quickly as possible following the brain harvest is critical for subsequent analyses. One way to achieve this objective is the utilization of high resolution MRI scans to guide the subsequent dissections. In the present study, individual MRI scans of the brains of rhesus and cynomolgus macaques that had chronically self-administered ethanol were employed in order to determine which blocks of dissected tissue contained specific ROIs. MRI-guided brain dissection of discrete brain regions was completely accurate in 100% of the cases. In comparison, approximately 60–70% accuracy was achieved in dissections that relied on external landmarks alone without the aid of MRI. These results clearly demonstrate that the accuracy of targeting specific brain areas can be improved with high-resolution MR imaging.

Appropriate animal models are critical to conduct translational studies of human disorders without variables that can confound clinical studies. Such analytic methods as patch-clamp electrophysiological and voltammetric recordings of neurons in brain slices require living brain tissue. In order to obtain viable tissue from nonhuman primate brains, tissue collection methods must be designed to preserve cardiovascular and respiratory functions for as long as possible. This paper describes a method of necropsy in three species of monkeys that satisfies this requirement. At necropsy, animals were maintained under a deep surgical plane of anesthesia while a craniotomy was conducted to expose the brain. Following the craniotomy, animals were perfused with ice-cold, oxygenated artificial cerebrospinal fluid to displace blood and to reduce the temperature of the entire brain. The brain was removed within minutes of death and specific brain regions were immediately dissected for subsequent in vitro electrophysiology or voltammetry experiments. This necropsy method also provided for the collection of tissue blocks containing all brain regions that were immediately frozen and stored for subsequent genomic, proteomic, autoradiographic and histological studies. An added benefit from the design of this necropsy method is that all major peripheral tissues were also collected and are now being utilized in a wide range of genomic, biochemical and histological assays. This necropsy method has resulted in the establishment and growth of a nonhuman primate alcohol tissue bank designed to distribute central nervous system and peripheral tissues to the larger scientific community.

Rationale Intermittent delivery of an important commodity (e.g., food pellets) generates excessive behaviors as an adjunct to the schedule of reinforcement (adjunctive behaviors) that are hypothesized to be due to conflict between engaging and escaping a situation where reinforcement is delivered, but at sub-optimal rates. Objectives This study characterized the endocrine correlates during schedule-induced polydipsia (SIP) of water and ethanol using a longitudinal approach in non-human primates. Methods Plasma adrenocorticotropic hormone (ACTH) and cortisol were measured in samples from awake cynomolgus monkeys (Macaca fascicularis, 11 adult males) obtained at the onset, midday and offset of their 12-h light cycle. The monkeys were induced to drink water and ethanol (4% w/v, in water) using a fixed time (FT) 300-s interval schedule of pellet delivery. The induction fluid changed every 30 sessions in the following order: water, 0.5 g/kg ethanol, 1.0 g/kg ethanol, and 1.5 g/kg ethanol. Following induction, ethanol and water were concurrently available for 22 h/d. Results The FT300-s schedule gradually increased ACTH, but not cortisol, during water induction to a plateau sustained throughout ethanol induction in every monkey. Upon termination of the schedule, ACTH decreased to baseline and cortisol below baseline. Diurnal ACTH and cortisol were unrelated to the dose of ethanol, but ACTH rhythm flattened at 0.5 g/kg/d and remained flattened. Conclusions The coincidence of elevated ACTH with the initial experience of drinking to intoxication may have altered the mechanisms involved in the transition to heavy drinking.