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Schizophrenia (SZ) is a neurological disorder that presents with paranoia, hallucinations, and negative affect. A neurobiological hallmark of SZ is increased dopamine D2 receptor sensitivity. Antipsychotics that treat SZ have demonstrated limited efficacy as well as harmful and sometimes fatal side effects. Additionally, nicotine abuse is greatly increased in individuals diagnosed with SZ compared to the normal population. Treatment of this comorbidity is important, because cigarette smoking diminishes the quality of life in individuals with SZ and shortens their lifespan. The adenosine system is a potential novel target for SZ treatment. Adenosine A2a receptors form a heteromeric complex with dopamine D2 receptors that is mutually inhibitory, meaning each receptor exhibits lower sensitivity to its agonist after the opposing receptor agonist is bound. This study investigated the efficacy of an adenosine A2a agonist, CGS 21680, in alleviating the rewarding aspects of nicotine in the neonatal quinpirole rodent model of SZ. Rats were treated neonatally from postnatal (P)day 1 through 21 with the dopamine D2/D3 agonist quinpirole, raised to P41, and tested on conditioned place preference (CPP). CPP is a behavioral measure of the rewarding properties of a drug through temporal pairing of a drug with a distinct environmental context. Rats were given a drug free pre-conditioning preference test, and then conditioned to saline or nicotine (0.6 mg/kg base) from P43-51. Groups receiving CGS 21680 (0.03 or 0.09 mg/kg) were given the agonist 15 min before nicotine was administered. A drug-free post-conditioning test was administered on P52 to determine preference. The following day, brain tissue was analyzed for brain-derived neurotrophic factor (BDNF) and glial cell-lined neurotrophic factor (GDNF). BDNF is a ubiquitous neurotrophic factor involved in synaptic growth throughout the brain, whereas GDNF is important in dopamine plasticity. Results revealed that neonatal quinpirole enhanced nicotine CPP, replicating previous work, and both doses of CGS 21680 alleviated this enhancement. Nicotine resulted in a CPP in controls, and both doses of CGS 21680 also alleviated this preference. Therefore, CGS 21680 alleviated the rewarding aspects of nicotine. BDNF analyses in the nucleus accumbens (Nacc), a brain area that mediates drug reward, revealed that BDNF closely followed the behavioral results: CGS 21680 alleviated the enhancement in Nacc BDNF in neonatal quinpirole-treated animals, and eliminated the increase in Nacc BDNF produced by nicotine in controls. GDNF analyses revealed that neonatal quinpirole animals conditioned to nicotine resulted in an increase of GDNF in the NAacc, but this was eliminated by CGS 21680. This project revealed that an adenosine agonist with antispsychotic properties may have utility towards decreasing the rewarding aspects of nicotine and its accompanying neural plasticity changes in a model of SZ. |
