**4. Potential therapeutic approaches for treating autism**

#### **4.1 Current understanding of the role of OT**

Autism spectrum disorder (ASD) encompasses multiple complex and behaviorally defined disorders characterized by impairments in social interaction, memory, communication and language, repetitive behaviors, as well as in the range of interests and activities shown by autistic patients [47–52]. Genetic [53] and environmental factors [49, 53–57] have been identified in the development of ASD. For example, the use of the anticonvulsant drug valproate during pregnancy increases the risk for the

development of autism in children. Elevated OT levels within various brain networks have been associated with enhanced social cognition and emotional recognition [9]. A strong OT receptor labeling pattern has been observed in the medial prefrontal cortex, ventral-tegmental area, limbic and prelimbic areas [58], which are brain areas associated with social bonding, cognition, emotion, and reward. Conversely, low OT levels and a downregulated OTR gene are found in people diagnosed with various forms of ASD [59–61].

Conversely, Williams syndrome is characterized by abnormal social behavior (characterized by reduced social inhibition, an increased affinity toward attending to faces, and reduced sensitivity to fear-related social stimuli) and increased oxytocin functioning [62]. Furthermore, an empirical research study [63] demonstrated that the OT receptor is overexpressed in Williams syndrome.

#### **4.2 Treatments currently in use and their prognosis**

Importantly, OT and OT receptor knockout (KO) mice exhibit social impairments similar to those associated with ASD [58], and administration of OT to these KO mice can "rescue" them from ASD-like behaviors [8], showing that such therapy is possible. Similarly, a defective OT release process has been found to mediate the drop in OT levels in another autistic animal model, CD38 KOs [22, 23]. But, so far, treatments (as with OT injections or sprays) have focused on systemic OT levels. For example, Higashida et al. [22] have used agents (all-trans-retinoic acid) that target CD38 in the neurohypophysis. We hypothesize that instead treatments should target brain regions such as magnocellular somata (**Figure 2**) and their central nervous system (CNS) projections (e.g., medial prefrontal cortex, ventral-tegmental area, limbic and prelimbic areas) [58]. This could be done by agents that affect IP3Rs instead of RyRs (**Figures 1** and **2**).

#### **4.3 Alternatives mediated by targeting central OT release**

Release from the hypothalamic cell bodies (see **Figure 2**) is indicative of release into the CNS [9]. Such release is also thought to act hormonally to affect surrounding CNS areas [64]. Activation of multiple types of endogenous (ryanodine, cADPr, and opioid) receptors in OT-releasing rat nerve endings can specifically regulate the in vitro release of this neuropeptide [13, 65, 66]. These receptor types play a role in modulating intracellular Ca2+ levels, either through a Ca2+-induced Ca2+ release (CICR)-dependent mechanism (**Figure 2**) or by regulating Ca2+ inflow from the extracellular environment. These receptor types are easily targeted by drugs that can cross the blood–brain barrier [67] and will facilitate novel pharmacological studies with therapeutic relevance for ASD. Furthermore, our collaborators [25, 68, 69] have already shown that the hypothalamic release of OT specifically can be potentiated by other agents that affect [Ca2+], e.g., IP3 (but not ryanodine). Thus, it should be possible to specifically potentiate/inhibit endogenous levels of central OT in response to physiological stimulations. That is, IP3R agonists would increase central, local release and electrical activity in OT cell bodies while RyR agonists would increase release from OT terminals both in NH and in central projections.

### **4.4 Future perspectives**

CD38 knockouts (KOs) do not release OT and, consequently, have social behavioral deficits [23]. Similarly, VPA is associated with a high incidence of ASD

#### *Modulation of Oxytocin Release by Internal Calcium Stores DOI: http://dx.doi.org/10.5772/intechopen.112630*

phenotypes in children [55, 70] and it acts similarly in rats. These KO mice and valproic acid (VPA)-injected rats are extremely useful experimental models for studying potential causes of ASD [47] and exploring new therapeutic approaches.

To target OT vs. AVP release in the relevant areas of the brain [58] for behavioral defects associated with ASD, it will be important to determine if there are differences between central and peripheral OT release using the HNS (**Figure 2**) in a compartmentalized chamber [71] or in fluorescently labeled rats [72]. Next, we have to determine central OT vs. AVP levels in the CD38 KO and VPA autistic animal models. Finally, can known regulators of OT vs. AVP release "correct" OT levels in such models (see **Figure 2**)? These receptor types are easily targeted by drugs that can cross the blood–brain barrier [67] and will facilitate novel studies with therapeutic relevance. Some, or perhaps all, of these agents, will increase OT vs. AVP release, in general, but it should be determined if any (e.g., IP3, cADPr, mu opioid receptor (MOR) agonists) will specifically increase the central release of OT. Thus, it should make them potential therapeutic agents to test on ASD patients. This approach has been recently validated since a small molecule vasopressin V1a (V1a)-specific antagonist is sufficient to rescue normal behavior in prenatally exposed VPA rats [67]. Furthermore, these findings could eventually lead to the ability to perform clinical trials to assess the efficacy of such agents on ASD patients.
