RESUMEN
Traumatic brain injury (TBI) impacts millions worldwide and can cause lasting psychiatric symptoms. Chronic neuroinflammation is a characteristic of post-injury pathology and is also associated with psychiatric conditions such as ADHD and bipolar disorder. Therefore, the current study sought to determine whether TBI-induced impulsivity and inattention could be treated using minocycline, an antibiotic with anti-inflammatory properties. Rats were trained on the five-choice serial reaction time task (5CSRT), a measure of motor impulsivity and attention. After behavior was stable on the 5CSRT, rats received either a bilateral frontal TBI or sham procedure. Minocycline was given at either an early (1 h post-injury) or chronic (9 weeks post-injury) timepoint. Minocycline was delivered every 12 h for 5 days (45 mg/kg, i.p.). Behavioral testing on the 5CSRT began again after one week of recovery and continued for 12 more weeks, then rats were transcardially perfused. Impulsivity and inattention were both substantially increased following TBI. Minocycline had no therapeutic effects at either the early or late time points. TBI rats had increased lesion volume, but minocycline did not attenuate lesion size. Additionally, microglia count measured by IBA-1+ cells was only increased acutely after TBI, and minocycline did not differentially change the number of microglia in TBI rats. Despite this, minocycline had clear effects on the gut microbiome. Based on the results of this study, minocycline may have limited efficacy for post-injury psychiatric-like symptoms.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Conducta Impulsiva/efectos de los fármacos , Minociclina/uso terapéutico , Tiempo de Reacción/efectos de los fármacos , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/psicología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/psicología , Conducta Impulsiva/fisiología , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Masculino , Minociclina/farmacología , Ratas , Ratas Long-Evans , Tiempo de Reacción/fisiología , Insuficiencia del TratamientoRESUMEN
The power of drug-associated cues to instigate drug 'wanting' and consequently promote drug seeking is a corner stone of contemporary theories of addiction. Gambling disorder has recently been added to the pantheon of addictive disorders due to the phenomenological similarities between the diseases. However, the neurobiological mechanism that may mediate increased sensitivity towards conditioned stimuli in addictive disorders is unclear. We have previously demonstrated using a rodent analogue of a simple slot machine that the dopamine D4 receptor is critically engaged in controlling animals' attribution of salience to stimuli associated with reward in this paradigm, and consequently may represent a target for the treatment of gambling disorder. Here, we investigated the role of acute administration of a D4 receptor agonist on animals' responsivity to conditioned stimuli on both a Pavlovian conditioned approach (autoshaping) and a conditioned reinforcement paradigm. Following training on one of the two tasks, separate cohorts of rats (male and female) were administered a dose of PD168077 shown to be maximally effective at precipitating errors in reward expectancy on the rat slot machine task (10mg/kg). However, augmenting the activity of the D4 receptors in this manner did not alter behaviour on either task. These data therefore provide novel evidence that the D4 receptor does not alter incentive motivation in response to cues on simple behavioural tasks.