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).