Cristhian Calo-Guadalupe¹ , Omaris Velez-Acevedo², Karl Y. Bosque-Cordero², Daisy Consuegra-Garcia¹,
Rafael Vazquez-Torres¹ , Carlos A. Jimenez-Rivera¹
1 Physiology Department, University of Puerto Rico Medical Sciences Campus
2 Biology Department, University of Puerto Rico Rio Piedras Campus
Intermittent Access (IntA) cocaine self-administration is a protocol recommended to better simulate human addictive behavior due to the intermittent pattern of drug administration. It is documented that IntA produces incentive salience, psychomotor sensitization and a neurochemical sensitization of the mesolimbic dopamine (DA) system by increasing both release and uptake of DA. The ventral tegmental area (VTA) DA neurons display a prominent mixed cation current conductance known as the hyperpolarization-activated cyclic nucleotide current, or Ih. Neural processes such as resting membrane potential, firing frequency modulation, and synaptic integration are influenced by the Ih.
Previous results from our laboratory demonstrated that Ih amplitude and membrane capacitance of putative VTA DA neurons are significantly reduced after cocaine sensitization. This Ih and capacitance reduction resulted in an increased temporal summation and excitatory postsynaptic potential (EPSP) amplitude, which enhances neuronal excitability. It is not known how IntA alters the intrinsic properties of VTA DA cells. In the present study we explored if synaptic integration, membrane capacitance and cell activity alterations are present after exposure to cocaine IntA. Our hypothesis is that IntA enhances synaptic integration and neuronal excitability of VTA DA cells.
Whole-cell patch-clamp technique in rat brain slices was used to inject a 33-Hz train of 5 αEPSCs (α = 5 ms; Imax = 50) into the soma of putative VTA DA neurons when clamped at -70 mV and analyze the effects of cocaine IntA, and passive cocaine infusions (yoked controls) on synaptic integration.
Increasing depolarizing current injections were used to evaluate how neurons respond to a depolarizing stimulus. Our results demonstrate that an IntA protocol, but not passive cocaine infusions, produces a significant increase in the number of APs (P<0.05). Temporal summation was increased at depolarized potentials in the IntA group and Yoked controls (P<0.0001). These results suggests that the associative learning of drug cues increases the firing activity of putative VTA DA neurons. The findings also suggest that enhanced synaptic integration could possibly be a cocaine-induced pharmacological effect.
Funding: This research was funded by the National Institute of General Medical Sciences (GM084854), the National Center for Research Resources (5R25GM061838-15, 2G12-RR003051), the National Institute on Minority Health and Health Disparities (8G12-MD007600), NSF-PIRE (OISE- 1545803), the NSF Partnerships in International Research and Education (PIRE) Program Neural Mechanisms of Reward & Decision (OISE-1545803), Research Initiative for Scientific Enhancement NIGMS-RISE R25 GM061838, NIH-BP ENDURE Neuroscience Research Opportunities to Increase Diversity (R25NS080687).