Drug treatments
Studies have shown that some drug administrations may positively affect or even prevent social isolation consequences in animal models.
1. Opioid drugs:  These are measured by pinning configuration and rats use them to defend nap access. According to previous play investigation, fighting became greater in junior rats during short-term social deprivation. Social grooming, as a behavioral factor by young and adult animals, is performed in rodents and primates. Both behavioral responses among primates, particularly humans, accounted for increasing isolation due to neurochemicals and opioid systems involvements (40, 41, 42).
Naltrexone treatment  by subcutaneous injection in a dose range of 0.03-1 mg/kg body weight was administered. It has decreased pinning duration, frequency, and grooming behavior dose-dependently (41, 43).
Apomorphine  treatment by subcutaneous injection in 2 doses of 60 and 100 pg/kg has significantly reduced pinning duration and frequency in a dose-dependent manner. In addition, a 35 pg/kg dose of apomorphine decreased grooming behavior (41, 44).
β-endorphin treatment  in a dose of 100 pg/kg has decreased the duration of pinning, but not for the time of grooming.
In conclusion, some opioid drugs have improved social activity by regulating the opioid receptors and neuronal systems (41, 45).
2.  Oxytocin:  Genetically, lower levels of oxytocin in some mice or hypersensitive receptors to some stressors caused mental illness and reduced social interaction (46). On the other hand, stressful experiences and accidents may result in overproduction of oxytocin in the central and peripheral nervous system. Long-term SI significantly led rodents to be immobile, less active, and depressed. The social environment has regulated oxytocin productions in specific regions in the CNS (47, 48).
In some rodents, administration of exogenous oxytocin for a long time has blocked weak social contact and behavioral impairments, such as depression during SI(49). However, oxytocin can perform as an antidepressant drug and decrease negative social interactions as well as encourage isolated ones to get over it (50). Other investigations have described how oxytocin developed stress response consequences of separation in female rodents (51-53).
Stress is often accompanied by isolation-induced alternations on neurochemicals; subsequently, depression and anxiety disorder. Previous studies have revealed the injection of oxytocin with inter-central amygdala procedure in mice resulted in improvement in depression and anxiety behavior (54). Many investigations have explained, amygdala activity has been regulated by oxytocin. Oxytocin can also perform as an anti-anxiety and anti-depressant drug to treat isolation-induced social stress after 5-weeks of social isolation. Long-term SI has decreased OXTR mRNA transcription and GABA level in mice and induced anxiety-related behavior and depression (46, 55). Oxytocin administration has attenuated depressive-like, anxiety-like, and destructive social behaviors. Anxiety measurement was performed with an open field test (OFT) and the elevated zero maze test (EZMT) in mice (48, 56).
3.Antidepressant drugs:  According to previous investigations, decreased BDNF level and neuro-steroids in the hippocampus were induced by SI and depression in adults. Published data have shown antidepressant treatment like fluoxetine  and fluvoxamine  increased BDNF mRNA expression (57, 58). Neuro-steroids such as allopregnanolone  reduced aggression and anxiety-like behaviors. The stable emotional mood in rodents has made them successful in improving social support and less isolation because of allopregnanolone performance on GABA neurotransmitters (59, 60).
It has been revealed that a selective serotonin (5-HT) reuptake inhibitor such as Fluoxetine is able to alleviate isolation-induced depression behavior (61). Oral Fluoxetine consumption has improved the depletion of serotonin in the hippocampus; and, anxiety, depression, and social deficits have reversed during social isolation. Moreover, brain neurogenesis has improved, which plays a crucial role in emotional deficit development (62-64). With Fluoxetine treatment, as an anti-depressant, metabolic impairment were also reversed (65). Some documents have claimed that Fluoxetine that is attached to mitochondria can change anion channels voltage, and finally, alleviate depression (64, 66). 
Clozapine  has been known as an effective drug to improve the social deficit induced by SI. This research has shown alternation in corticostriatal ATP levels, anti-inflammatory cytokines, and neuroprotective ratio through isolation condition (67). The whole alternations were reversed by Clozapine, as an atypical antipsychotic, to improve SI detriments and particularly depressive behaviors (68). Anti-depressant properties of Clozapine have made it beneficial to prevent isolation-induced depression in rats (69). Molecular investigations have shown Clozapine has decreased TNF-α, GPX, and glutamate-like receptor significantly; plus, less GLR activity of cyclooxygenase-2 (COX-2) and interleukin-1beta (IL-1β) in the hippocampus were induced by Clozapine (70). Administration of Fluoxetine and Clozapine, as nonsteroidal anti-inflammatory drugs for three weeks in rats, prevented quanta decline in hippocampal parvalbumin-positive (PV+) cells (68, 71).
Increased GSH content and nuclear factor-kappa B (NF-kB) has led to reduced depressive-like and anxiety-like behaviors in isolated rats (72); while Leponex (25 mg of CLZ per tablet) was administrated for 21 days. More research has revealed low doses of Clozapine (0.1, 0.2, and 0.4 mg/kg) can exert anxiolytic properties in isolated rats and reduce anxiety behavior, stress, and depressive mood (68).
Besides, chronic administration of Fluoxetine is effective in treating SI-induced impairments of spatial learning and memory, cognition, neurogenesis, emotion‐related, and depressive-like behaviors in rodents (65). Further, Clozapine has found to improve behavioral deficits and activate some regions in the brain, such as dHIPP and RSC, associated with memory, learning, and spatial orientation in socially isolated rats. Moreover, long-term administration (6-8 weeks) of Clozapine (5 or 10 mg/kg) has shown to improve the reversal learning deficit in SI rats (66, 73, 74).
Another investigation revealed that 5 to 10 days of consumption of antipsychotic drugs, like Ampakine and Aniracetam, have reversed the impairment of recognition memory in isolation-reared rats (75-77). Further, administration of Methylphenidate (1–10 mg/kg) and Caffeine (0.5–1 mg/kg), which are commonly used for attention deficit hyperactivity disorder (ADHD), have shown to be efficient for latent learning and spatial attention impairment (78). Moreover, a low dose of corticosterone increased the expression of the activity-regulated cytoskeletal associated protein (Arc) and improved long-term memory in socially isolated rats. Other studies have shown that inhibiting receptors via antagonist drugs might reverse SI impairment in rodents (79-81).
Administration of 5-HT6 receptor antagonist drugs  can potentially bring back learning, cognition, and recognition memory deficit by up-regulating glutamate and serotonin in cortical and hippocampal regions in SI-reared rats (82). Results suggeste that PRX-07034 and PRX-07037 , as 5-HT6 antagonists, reverse the isolation rearing-induced memory deficit, while Ro 04-6790  diminishes the effect of isolation on reversal learning impairment (75, 83, 84). In addition, Ro 4368554 has been able to reverse a scopolamine-induced impairment in emotional learning (85).
SI has shown to elevate Rac1 activity in hippocampal tissue, inducing social recognition memory (SRM) forgetting and long-term potentiation (LTP) decline in mice; According to this finding, Inhibiting of Rac1 Activity Blocked Progressed Decline of LTP  and suppressed forgetting of SRM in isolated adult mice. However, Rac1 activity had no influence on short-term (15-min) memory in the socially isolated period (86).
Additionally, Results have revealed that in socially isolated mice, the excitatory presynaptic release of pyramidal neurons in the mPFC has attenuated, and metabotropic glutamate receptor 2/3 (mGluR2/3) antagonist , LY341495 , played a crucial role in recovering working memory by building reasonably vast synaptic strength in the mPFC in SI-reared mice (87, 88). Further, a single treatment with LY341495  improved isolated mice performance in the Y maze test but not in the novel object recognition test, while repeating the treatments were efficient for both tasks (87, 89). Conversely, mGluR2/3 agonist, LY379268 , has also improved recognition memory impairment in SI rats (87, 90). Earlier investigations have suggested that stress and anxiety-like behaviors have appeared due to a mediator called the Corticotropin-releasing factor (CRF). CRF agonist injection has shown additional anxiety in the Elevated plus Maze and open field tests in rats. During isolation and social impairment, the CRF receptor has been increasingly activated in the DRN and this result in anxiety-like behaviors. Subsequently, researchers have administered CRF receptor antagonists , which  decreased stress and anxiety (91, 92).
4. Antioxidants:  Isolation-induced oxidation stress has led to many cognitive impairments, such as violence, aggression, and anxiety. Reactive Oxygen Species have been produced by oxidative stress and they caused variable damages to the brain structurally and physiologically (93). Researchers have decided to evaluate the administration of antioxidants in isolated mice to reduce social and behavior deficits like aggression for 14 days. Eventually, results have revealed vitamin E in high doses and N-acetyl cysteine in low doses were effective to decline aggression in isolated mice. A low dose of vitamin E and N-acetyl cysteine beta-carotene in high doses, were effective in reducing acute isolation-induced aggressive behaviors. However, ascorbic acid has exhibited a more dose-dependent behavior. Biochemistry procedures have evaluated antioxidant markers; while, molecular results have shown the level of catalase, superoxide dismutase enzymes, and glutathione. Data have suggested an increase in biomarkers among isolated mice treated with antioxidants. Researchers found that antioxidants consumption after 14 days has improved aggressive behavior in isolated mice (94, 95).
5. Herbal drugs:  Central nervous system disease had been treated in ancient Korea and China until now, by Uwhangchungsimwon  (UCW)  as a herbal drug. Researchers have kept mice in separate cages to induce isolation for 31 days. Isolated mice were shown to be depressed, while those mice, which had oral administration of UCW every day, after 17 days, have shown improvement in behavioral tests and significantly reduced depressive-like behaviors. Improvements were justified according to an increased level of serum corticosterone and a higher level of dopamine, serotonin, and norepinephrine in the hippocampus. This investigation has shown that UCW  consumption has diminished isolation-induced depression in mice by ameliorating neurochemicals (96).