title: Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats.
abstract: Although several findings indicate an association between adolescent cannabis abuse and the risk to develop schizophrenia later in life, the evidence for a causal relationship is still inconclusive. In the present study, we investigated the emergence of psychotic-like behavior in adult female rats chronically exposed to delta-9-tetrahydrocannabinol (THC) during adolescence. To this aim, female Sprague-Dawley rats were treated with THC during adolescence (PND 35-45) and, in adulthood (PND 75), a series of behavioral tests and biochemical assays were performed in order to investigate the long-term effects of adolescent THC exposure. Adolescent THC pretreatment leads to long-term behavioral alterations, characterized by recognition memory deficits, social withdrawal, altered emotional reactivity and sensitization to the locomotor activating effects of acute PCP. Moreover, since cortical disinhibition seems to be a key feature of many different animal models of schizophrenia and GABAergic hypofunction in the prefrontal cortex (PFC) has been observed in postmortem brains from schizophrenic patients, we then investigated the long-lasting consequences of adolescent THC exposure on GABAergic transmission in the adult rat PFC. Biochemical analyses revealed that adolescent THC exposure results in reduced GAD67 and basal GABA levels within the adult PFC. GAD67 expression is reduced both in parvalbumin (PV)- and cholecystokinin (CCK)-containing interneurons; this alteration may be related to the altered emotional reactivity triggered by adolescent THC, as silencing PFC GAD67 expression through a siRNA-mediated approach is sufficient to impact rats' behavior in the forced swim test. Finally, the cellular underpinnings of the observed sensitized response to acute PCP in adult THC-treated rats could be ascribed to the increased cFos immunoreactivity and glutamate levels in the PFC and dorsal striatum. The present findings support the hypothesis that adolescent THC exposure may represent a risk factor for the development of a complex psychotic-like behavior in adulthood.
authors.affiliation: Dept. of Theoretical and Applied Sciences, Biomedical Division and Center of Neuroscience, Univ. of Insubria, Busto Arsizio (VA), Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Zamberletti
authors.affiliation: Dept. of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Beggiato
authors.affiliation: Dept. of Psychiatry, Univ. of Naples SUN, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
authors.affiliation: Dept. of Theoretical and Applied Sciences, Biomedical Division and Center of Neuroscience, Univ. of Insubria, Busto Arsizio (VA), Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Prini
authors.affiliation: Dept. of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Antonelli
authors.affiliation: Dept. of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.affiliation: Dept. of Theoretical and Applied Sciences, Biomedical Division and Center of Neuroscience, Univ. of Insubria, Busto Arsizio (VA), Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.affiliation: Dept. of Theoretical and Applied Sciences, Biomedical Division and Center of Neuroscience, Univ. of Insubria, Busto Arsizio (VA), Italy; Zardi-Gori Foundation, Milan, Italy. Electronic address: daniela.parolaro@uninsubria.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D063386:Cannabinoid Receptor Agonists / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011618:Psychotic Disorders / Q000209:etiology* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; D018691:Excitatory Amino Acid Antagonists; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010622:Phencyclidine
keywords: Adolescent THC treatment; Behavior; GABA; GAD67; Glutamate; Prefrontal cortex