In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

Abstract

Background: Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life. Aims: This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability. Methods: Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2). Results: In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber. Conclusion: Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return

“…Positive immunofluorescence was quantified for each image as integrated density over threshold using Image J and verified by a trained experimenter. For each NAc section, the value was calculated as the mean of the core and shell quantifications [ 56 ].…”

Environmental Enrichment During Adolescence Mitigates Cognitive Deficits and Alcohol Vulnerability due to Continuous and Intermittent Perinatal Alcohol Exposure in Adult Rats

“…Declarative learning and memory were tested in the novel object recognition test, as previously described (Brancato et al, 2020 ). On day 1, a 5-min habituation session was performed at 10.00 a.m., in order to let the animals freely explore the arena (44 × 44 × 44 cm) in a dim light-illuminated room.…”

Social Interactions of Dat-Het Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy

“…Immunofluorescence was performed as previously described [27], with a few modifications. Sections (six per animal) were washed in PBS for 30 min and incubated in blocking solution (3% normal goat serum (NGS), 0.3% Triton X-100 in PBS) for 2 h at room temperature under gentle shaking.…”