HEAL 1UG3DA050942-01A1: Effect of intranasal pGDNF nanoparticles on oxycodone seeking and central dopamine exocytosis

The ongoing opioid epidemic has underlined the need for treatment of opioid use disorder (OUD) with alternatives to opioid medications. Such interventions should nevertheless impact on central dopamine systems coding for opioid reward and aversive aspects of opioid withdrawal and abstinence. Our prior work has shown that glial cell derived neurotrophic factor (GDNF) has protective effects on midbrain dopamine neurons and synaptically facilitates dopamine. At the same time, we and others have shown chronic use of opioids and the aversive states of opioid withdrawal and abstinence induce defects in mesolimbic dopamine release, which can drive relapse. Our current studies test whether intranasal administration of glial cell derived neurotrophic factor plasmid DNA nanoparticles (pGDNF NPs) can correct central dopamine deficits in a rat model of oxycodone (OXY) intravenous self-administration (IVSA);

We assessed ex vivo dopamine release kinetics in dorsal striatum (DS), nucleus accumbens (Nacc), and medial prefrontal cortex (PFC) of rats previously trained identically in OXY IVSA, followed by 28 days of abstinence from OXY. Amperometric electrodes with 5 µm carbon fibers (Amoco) and a positive 700 mV voltage (vs Ag-AgCl ground) were employed to measure dopamine. The electrodes were placed in the DS, Nacc or PFC in acute 300 μm coronal slices. A bipolar stimulating electrode was placed 100-200 μm away from the carbon fiber electrode and a current stimulus of +500 μA was applied 3 times per site every 5 min for 2 msec. The output was digitized at 50 kHz to record dopamine exocytosis in real time and low-pass filtered at 1 kHz. The number of dopamine molecules oxidized was determined by Faraday’s equation, N=Q/nF where Q is the charge of the spike, n is the number of electrons transferred (two for catecholamines), N is the number of moles, and F is Faraday’s constant (96485 coulombs per unit charge). We further run correlation/regression analyses between behavioral (IVSA) and dopamine release parameters to detect any differences between subpopulations of pGDNF NP and vehicle-treated groups, such as males versus females and high- versus low-responders in the OXY progressive ratio session. Ultimately, these results will determine if correction of dopamine deficiencies may be a mechanism for the efficacy of the pGDNF NPs in reducing relapse behavior.

Results suggest an increase in dopamine release in reward centers of OXY-treated rats given intranasal pGDNF NPs, primarily in the region of medial prefrontal cortex. This mechanism may contribute to the decrease in cued reinstatement and is compatible with previous findings suggesting central dopamine deficits in animal models of OUD and GDNF restoring dopamine exocytosis and enhancing survival of midbrain dopamine neurons.