Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats
Open accessAbstract
Social deprivation in early life disrupts emotionality and attentional processes in humans. Rearing rats in isolation reproduces some of these abnormalities, which are attenuated by daily handling. However, the neurochemical mechanisms underlying these responses remain poorly understood. We hypothesized that post-weaning social isolation alters the endocannabinoid system, a neuromodulatory system that controls emotional responding. We characterized behavioral consequences of social isolation and evaluated whether handling would reverse social isolation-induced alterations in behavioral reactivity to context and the endocannabinoid system. At weaning, pups were single or group housed and concomitantly handled or not handled daily until adulthood. Rats were tested in emotionality- and attentional-sensitive behavioral assays (open field, elevated plus maze, startle and prepulse inhibition). Cannabinoid receptor densities and endocannabinoid levels were quantified in a separate group of rats. Social isolation negatively altered behavioral responding. Socially-isolated rats that were handled showed less deficits in the open field, elevated plus maze, and prepulse inhibition tests. Social isolation produced site-specific alterations (supraoptic nucleus, ventrolateral thalamus, rostral striatum) in cannabinoid receptor densities compared to group rearing. Handling altered the endocannabinoid system in neural circuitry controlling emotional expression. Handling altered endocannabinoid content (prefrontal and piriform cortices, nucleus accumbens) and cannabinoid receptor densities (lateral globus pallidus, cingulate and piriform cortices, hippocampus) in a region-specific manner. Some effects of social isolation on the endocannabinoid system were moderated by handling. Isolates were unresponsive to handling-induced increases in cannabinoid receptor densities (caudal striatum, anterior thalamus), but were sensitive to handling-induced changes in endocannabinoid content (piriform, prefrontal cortices), compared to group-reared rats. Our findings suggest alterations in the endocannabinoid system may contribute to the abnormal isolate phenotype. Handling modifies the endocannabinoid system and behavioral reactivity to context, but surmounts only some effects of social isolation. These data implicate a pivotal role for the endocannabinoid system in stress adaptation and emotionality-related disturbances.
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Reduced PV and CB1 expression may indicate a reduced activity level in PV cells and an altered endocannabinoid tone.
“This may indicate a reduced activity level in PV cells (Donato et al., 2013;Caballero et al., 2014) and an altered endocannabinoid tone”
From Social Play Behavior Is Critical for the Development of Prefrontal Inhibitory Synapses and Cognitive Flexibility in Rats (2022) · cites this paper as Sciolino et al., 2010
Chronic isolation increases 2-AG in the prefrontal cortex without affecting anandamide.
“For instance, we found that chronic isolation increases 2-AG in the prefrontal cortex, without affecting anandamide, and increases both 2-AG and anandamide in the piriform cortex.35”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [35]
Chronic isolation increases both 2-AG and anandamide in the piriform cortex.
“For instance, we found that chronic isolation increases 2-AG in the prefrontal cortex, without affecting anandamide, and increases both 2-AG and anandamide in the piriform cortex.35”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [35]
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- Authors
- Sciolino, N. R., Bortolato, M., Eisenstein, S. A., Fu, J., Oveisi, F., Hohmann, A. G., & Piomelli, D.
- Affiliations
- University of Georgia (US)
- University of California, Irvine (US)
- Corresponding author
- Hohmann, A.G.
- Piomelli, D.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 168
- Issue
- 2
- Pages
- 371-386
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC2882942
- OpenAlex
- W1985496935
- Cited by
- 89
- References
- 129
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 5 · 2019: 3 · 2018: 1 · 2017: 10 · 2016: 7 · 2015: 6 · 2014: 5 · 2013: 3 · 2012: 6
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- National Institute on Drug Abuse (DA021644S1, R01DA021644, R21DA022702)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- social isolation, endocannabinoid system, cannabinoid receptors, emotionality, attention, prepulse inhibition, startle response, elevated plus maze, open field, stress adaptation, piriform cortex, prefrontal cortex, nucleus accumbens, supraoptic nucleus, ventrolateral thalamic nucleus, cingulate cortex, hippocampus, globus pallidus
- MeSH terms
- Animals, Attention, Behavior, Animal, Brain, Emotions, Female, Handling, Psychological, Male, Social Isolation, Reflex, Startle, Signal Transduction, Rats, Sprague-Dawley, Maze Learning, Receptors, Cannabinoid, Rats, Cannabinoid Receptor Modulators, Endocannabinoids
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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