Intermittent Access (IntA) cocaine self‐administration is a protocol suggested to better simulate human drug use patterns due to its temporal dynamics of drug administration. IntA is also known to produce incentive salience and psychomotor sensitization. Dopaminergic (DA) neurons display a prominent mixed cation current conductance known as the hyperpolarization‐activated cyclic nucleotide current, or Ih, which contributes to neural processes such as resting membrane potential, firing frequency modulation, and synaptic integration. Previous results from our laboratory demonstrated that Ih amplitude is reduced significantly after cocaine sensitization. This Ih reduction resulted in an increased temporal summation, mean depolarization, and excitatory postsynaptic potential (EPSP) amplitude, all factors related to an enhanced excitability state. Since the cocaine sensitization model involves noncontingent drug injections administered by the experimenter, it is crucial to determine if electrophysiological changes in ventral tegmental area (VTA) DA cells are present when drugs are self‐administered (contingent). In the present study, we explored if DA neurons present an alteration in Ih after exposure to IntA. We hypothesize that VTA DA cells’ Ih modulation is dependent on the associative learning processes acquired during operant conditioning. Using the whole‐cell patch‐clamp technique in brain slices, we investigated the effects of cocaine IntA, and passive cocaine infusions (yoked controls) on Ihamplitude and rebound excitability. Our results demonstrate that an IntA protocol, but not passive cocaine infusions, produces a significant Ih amplitude reduction (P<0.05). No differences in rebound action potentials (APs) were observed. A depolarizing current protocol showed a significant increase in the number of APs (P<0.05). These results suggest that Ih modulation and intrinsic activity regulation are dependent on associative learning to drug cues.
The hyperpolarization‐activated cation current (H‐current) is a major determinant of neuronal intrinsic excitability in various cells including dopaminergic neurons of the Ventral Tegmental Area (VTA DA). In contrast to other cellular conductances, the H‐current activates through hyperpolarizing voltage steps to potentials negative to −55mV and depolarizes the membrane potential. We explored through in vivo anesthetized single unit extracellular electrophysiology the contribution of the H‐current on VTA DA neurons spontaneous firing patterns in naïve rats. A key feature of evaluating spontaneous excitability is the detection of bursting activity. Bursting is defined as trains of two or more spikes occurring within a short interval and followed by a prolonged period of inactivity (Grace et al., 1984). It has been well documented that burst formation increases the reliability of information transfer. Additionally, bursts and spikes can develop a parallel code, in which they can promote various stimulus features in the same spike train. To elucidate the contribution of H‐current on VTA DA neurons spontaneous firing patterns we perfused H‐current blocker (ZD 7288) through a double barrel pipette and evaluated its effect. H‐current blockade significantly reduced firing rate, bursting frequency and percent of spikes in burst in VTA DA neurons. Neuroadaptations in this network are hypothesized to trigger various neurobiological diseases including drug addiction. Reduction of spontaneous firing patterns through H‐current blockade could serve as a possible modulator of conditions related to VTA DA hyperexcitability.
Support or Funding Information
National Institute of General Medical Sciences (2SC1GM084854) National Center for Research Resources (5R25GM061838‐15, 2G12‐RR003051) National Institute on Minority Health and Health Disparities (8G12‐MD007600) NSF Partnerships in International Research and Education (PIRE) program Neural Mechanisms of Reward & Decision (OISE‐1545803) Research initiative for Scientific Enhancement RISE (5R25GM061151‐18)
The control of firing pattern in nigral dopamine neurons: burst firingA. A.GraceB. S.BunneyJournal of neuroscience41128772890
Cocaine use produces different effects in the Mesocorticolimbic System (MCL) depending on the temporal pattern in which they are consumed. The Intermittent Access (IntA) cocaine self‐administration is a protocol that better simulates human behavior due to the intermittent pattern of drug administration. Unlike Long Access (LgA) cocaine self‐administration, which generates tolerance, IntA, produces psychomotor, incentive, and neural sensitization of the MCL. Dopamine (DA) neurons display a prominent mixed cation current conductance known as the hyperpolarization‐activated cyclic nucleotide current, or Ih, that contributes to neural processes such as resting membrane potential, firing frequency modulation, and synaptic transmission. Since experimenter administered drug sensitization alters the intrinsic properties of DA neurons from the ventral tegmental area (VTA), we asked if neural sensitization of this system after exposure to IntA includes these intrinsic alterations in DA neurons. Using the whole‐cell patch‐clamp technique in brain slices, we investigated the effects of IntA on Ih and neuronal excitability. Hyperpolarizing current injections followed by sudden depolarizing steps were used to analyze rebound excitation. Increasing depolarizing current injections were used to evaluate how neurons respond to the depolarizing stimulus. Our preliminary results demonstrate that IntA protocol produces a significant Ih amplitude reduction (P<0.05) and an increase in number of rebound action potentials. Additionally, the depolarizing current step protocol showed a significant increase in the number of action potentials (APs)(P<0.05). These results suggest that the Ih modulation is present in both models that sensitize the MCL. Such reduction of Ih amplitude and the increase in APs may be considered one of the neuronal plasticity changes that contributes to the development of drug addiction. In addition, the incentive‐sensitization view of addiction which states that drug‐seeking and taking is produced by a hyper‐responsive DA system could also involve these modifications. Therefore, we conclude that this reduction may be part of an homeostatic mechanism in response to the hyper‐responsive DA system.
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