**10.3. Addiction**

64 Neuroendocrinology and Behavior

associated with human disorders.

negative effects of chronic stress.

**10.2. Depression and anxiety** 

investigating the roles of AVP and OXT in depression, anxiety, or addiction involve exposure to chronic stress. The use of ethologically relevant stressors in animal models, such as social stress, is most likely to produce translationally consistent results (effects in animals which parallel clinical data). Many commonly used chronic stress protocols used in studies of AVP/OXT and depression and anxiety, such as chronic mild stress, do not use stressors

While the role of AVP in the endocrine stress response has been studied in detail at the animal level, the effects of stress on OXT are not as well known. Integrative investigations which include both AVP and OXT may indentify novel interactions between these behaviorally potent peptides. The most promising translational area may be PTSD. There is already evidence that male PTSD patients have high plasma AVP, aggression, depression and anxiety levels and similar behavioral effects have been associated with elevated AVP in animals. While it is difficult to separate the changes in depression and anxiety from impairments in social behavior, an increased focus on OXT in PTSD studies may provide insight on the social deficits in PTSD patients. Social bonds are often negatively impacted by exposure to chronic stress, and these bonds can have a positive buffering effect on the

An indication of the potential value of social support can be seen in the cultural comparison of postpartum depression prevalence. Societies that have high levels of social support for mothers have low rates of depression, and cultures with low levels of support have much higher rates [208]. There is evidence that social support has protective effects in stress related mood disorders, and understanding the role of AVP and OXT in the positive effects of social support may help maximize the value of social support focused interventions.

Increases the prevalence of stress related mood disorders [209] combined with metanalyses reporting that current treatments for depression may not be effective for mild to moderate depression [210] make a compelling argument that a new approach is needed in depression and anxiety research. Both the animal and human studies suggest that AVP is involved in the development of depression and anxiety disorders, and several reports indicate that AVP has gender specific roles. Continuing development of AVP targeted treatments should consider these gender specific actions. It is possible that while V1a antagonists may work for alleviating depression and/or anxiety symptoms in males, AVP or AVP agonists may be more effective in females. As noted by Manning et al. there has been little success with the development of non-peptide agonists and antagonists for AVP despite substantial investments by pharmaceutical companies. In contrast, some progress has been made with OXT peptide based treatments [194, 195]. The recent studies on AVP and maternal behavior in animals suggest that increased focus on AVP in human studies is warranted, especially on stress, maternal behavior, and postpartum depression. One valuable use for non-peptide ligands that have not been successful in clinical trials is as research tools, including the

development of specific AVP and OXT ligands for imaging studies [194].

Both affiliative behavior and addiction are mediated through similar central reward pathways. Central OXT pathways are also altered by addiction. Endogenous OXT activity is suppressed by chronic drug use, and elevated brain OXT levels may attenuate the negative effects of withdrawal [211]. There is preliminary evidence that exogenous OXT is capable of inhibiting stimulant and alcohol self administration and it may prevent stress and priming induced relapse [212]. As with autism, OXT centered treatments may be a useful adjunct to behavioral cognitive techniques. For example, intranasal OXT may augment the positive effects of extinction training for addiction [213] and/or reduce rates of relapse.

Levels of AVP mRNA increase in the amygdala during early withdrawal from cocaine [214], and the blockade of V1b receptors can block reinstatement in rodents [215]. In a rodent model of ethanol dependence, a V1b antagonist decreases excessive levels of ethanol self administration [216]. There is further evidence that AVP secretion is attenuated in response to social stress in the sons of alcohol dependent fathers, but it is unclear how these results relate to the risk of developing an addiction [217]. While data from humans is lacking, the involvement of AVP in the etiology of stress related depression and anxiety suggests that this hormone may be implicated in the long term effects of addiction and the mechanisms mediating relapse. V1b antagonism may be a productive translational target for not only drug dependence, but addiction associated depression and anxiety as well.

#### **10.4. Autism**

While current translational efforts with OXT and autism acknowledge that the effectiveness of intranasal OXT treatments may only be relevant to social behavior deficits, the animal studies of AVP/OXT on learning suggest that there may be additional benefits to focusing translational studies in this area. One animal research topic that may be of particular interest is the developmental role of AVP and OXT. Treatments which only affect social behavior in older children or adults may be effective with other impairments when administered at a younger age. Changes in the brains of autistic children have been observed in children as young as 6 months [218]. Another issue with the current clinical trials of intranasal oxytocin is the level of dosing. There is debate as to how much OXT crosses the blood brain barrier and has central effects. One hypothesis is that developmental AVP manipulation may be able to address the cognitive impairments of autism. While most of the clinical efforts in AVP/OXT and autism are centered on the development of pharmaceutical treatments, environmental changes may also be effective. It is possible that insults during gestation, such as chronic social stress, are affecting the normal development of AVP/OXT mediated cognitive and social pathways. Another potential benefit of an OXT focused therapy may be as an adjunct to behavioral therapies aimed at improving social skills. One of the limitations of the current OXT manipulations is the available administration methods. The prairie vole partner preference model is a valuable tool for the screening of novel OXT treatments and administration methods [219].

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