Polysubstance addiction vulnerability in mental illness: Concurrent alcohol and nicotine self‐administration in the neurodevelopmental hippocampal lesion rat model of schizophrenia

Abstract

Multiple addictions frequently occur in patients with mental illness. However, basic research on the brain‐based linkages between these comorbidities is extremely limited. Toward characterizing the first animal modeling of polysubstance use and addiction vulnerability in schizophrenia, adolescent rats with neonatal ventral hippocampal lesions (NVHLs) and controls had 19 weekdays of 1 hour/day free access to alcohol/sucrose solutions (fading from 10% sucrose to 10% alcohol/2% sucrose on day 10) during postnatal days (PD 35‐60). Starting in adulthood (PD 63), rats acquired lever pressing for concurrent oral alcohol (10% with 2% sucrose) and iv nicotine (0.015 mg/kg/injection) across 15 sessions. Subsequently, 10 operant extinction sessions and 3 reinstatement sessions examined drug seeking upon withholding of nicotine, then both nicotine and alcohol, then reintroduction. Adolescent alcohol consumption did not differ between NVHLs and controls. However, in adulthood, NVHLs showed increased lever pressing at alcohol and nicotine levers that progressed more strongly at the nicotine lever, even as most pressing by both groups was at the alcohol lever. In extinction, both groups showed expected declines in effort as drugs were withheld, but NVHLs persisted with greater pressing at both alcohol and nicotine levers. In reinstatement, alcohol reaccess increased pressing, with NVHLs showing greater nicotine lever activity overall. Developmental temporal‐limbic abnormalities that produce mental illness can thus generate adult polydrug addiction vulnerability as a mechanism independent from putative cross‐sensitization effects between addictive drugs. Further preclinical modeling of third‐order (and higher) addiction‐mental illness comorbidities may advance our understanding and treatment of these complex, yet common brain illnesses.