The role of peripheral Na+ channels in triggering the central excitatory effects of intravenous cocaine

Brown

2007

Neuroscience

Cocaine's (COC) direct interaction with the dopamine (DA) transporter is usually considered the most important action underlying the psychomotor stimulant and reinforcing effects of this drug. However, some physiological, behavioral and psycho-emotional effects of COC are very rapid and brief and they remain intact during DA receptor blockade, suggesting possible involvement of peripheral non-DA neural mechanisms.To assess this issue, single-unit recording with microiontophoresis was used to examine changes in impulse activity of dorsal and ventral striatal neurons to intravenous (iv) COC (0.25-0.5 mg/kg) in the same rats under two conditions: awake with dopamine (DA) receptor blockade and anesthetized with urethane. In the awake preparation ~70% striatal neurons showed rapid and transient (latencỹ 6 s, duration ~15 s) COC-induced excitations. These effects were stronger in ventral than dorsal striatum. During anesthesia, these phasic effects were fully blocked and COC slowly decreased neuronal discharge rate. COC-methiodide (COC-M), a derivative that cannot cross the blood-brain barrier, also caused phasic excitations in the awake, but not anesthetized condition. In contrast to regular COC, COC-M had no tonic effect on discharge rate in either preparation. Most striatal neurons that were phasically excited by both COC forms also showed short-latency excitations during tailtouch and tail-pinch in the awake preparation, an effect strongly attenuated during anesthesia. Finally, most striatal neurons that in awake conditions were phasically excited by somato-sensory stimuli and COC salts were also excited by iontophoretic glutamate (GLU). Although striatal neurons were sensitive to GLU in both preparations, the response magnitude at the same GLU current was higher in awake than anesthetized conditions. These data suggest that in awake animals iv COC, like somato-sensory stimuli, transiently excites striatal neurons via its action on peripheral neural elements and rapid neural transmission. While the nature of these neuronal elements needs to be clarified using other analytical techniques, they might involve voltage-gated K + and Na + channels, which have a high affinity for COC and are located on terminals of visceral sensory nerves that densely innervate peripheral vessels. Therefore, along with direct action on specific brain substrates, central excitatory effects of COC may occur via indirect action, involving afferents of visceral sensory nerves and rapid neural transmission. By providing a rapid sensory signal and triggering transient neural activation, such a peripherally triggered action might play a crucial role in the sensory effects of COC, thus contributing to learning and development of drug-taking behavior.* Correspondence should be addressed to Eugene A. Kiyatkin at the above address. Fax: (410) 550-5553; tel.: (410) 550-5551; e-mail: ekiyatki@intra.nida.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our cus...

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confidence: 99%

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confidence: 99%

I.v. cocaine induces rapid, transient excitation of striatal neurons via its action on peripheral neural elements: Single-cell, iontophoretic study in awake and anesthetized rats

Brown

2007

Neuroscience

“…Cocaine was injected via catheter and extending tubing, in low volume and at low speed, and special care has been taken to exclude any possible sensory cues associated with drug injection. Although the complexity of VTA cell recording in the awake conditions made it difficult to evaluate the effects of saline on each cellular subgroup, we previously showed that such injections performed at the same conditions did not affect animal behavior, brain, skin, and muscle temperatures (Brown and Kiyatkin, 2006) as well as impulse activity of striatal neurons (Kiyatkin and Brown, 2007). No effects of low-volume saline injections on VTA cell activity have been also documented in our heroin self-administration studies (Kiyatkin and Rebec, 2001).…”

Section: Discussionmentioning

confidence: 62%

“…All these effects, moreover, are generally resistant to DA receptor blockade and in cocaine-experienced subjects they could be mimicked by procaine (Adamec and StartAdamec, 1987;Adinoff et al, 1998;Fischman and Schuster, 1983;Gawin 1986;Sherer et al, 1989), which is not an inhibitor of monoamine uptake, suggesting a leading role of peripheral non-DA neural mechanisms in its mediation. Some of rapid, centrally mediated effects of cocaine, moreover, are mimicked by cocaine methiodide (Dickerson et al, 1999;Brown and Kiyatkin, 2006), which cannot cross the blood-brain barrier.…”

Section: Functional Implications: Sensory Effects Of Cocaine and Theimentioning

confidence: 99%

“…Our previous thermorecording work has shown that peripheral neural substrates play an important role in the triggering of the central effects of iv cocaine (Brown and Kiyatkin, 2006). Cocaine, at a typical reinforcing dose (1 mg/kg), induces a central temperature response similar to other salient somato-sensory stimuli such as a tail-pinch and social interaction.…”

Section: Introductionmentioning

confidence: 99%

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Sensory effects of intravenous cocaine on dopamine and non-dopamine ventral tegmental area neurons

Brown

2008

Brain Research

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Intravenous (iv) cocaine mimics salient somato-sensory stimuli in their ability to induce rapid physiological effects, which appear to involve its action on peripherally located neural elements and fast neural transmission via somato-sensory pathways. To further clarify this mechanism, single-unit recording with fine glass electrodes was used in awake rats to examine responses of ventral tegmental area (VTA) neurons, both presumed dopamine (DA) and non-DA, to iv cocaine and tail-press, a typical somato-sensory stimulus. To exclude the contribution of DA mechanisms to the observed neuronal responses to sensory stimuli and cocaine, recordings were conducted during full DA receptor blockade (SCH23390+eticloptide).Iv cocaine (0.25 mg/kg delivered over 10 s) induces significant excitations of ~63% of long-spike (presumed DA) and ~70% of short-spike (presumed non-DA) VTA neurons. In both subgroups, neuronal excitations occurred with short latencies (4-8 s), peaked at 10-20 s (30-40% increase over baseline) and disappeared at 30-40 s after the injection onset. Most long-(67%) and short-spike (89%) VTA neurons also showed phasic responses to tail-press (5-s). All responsive long-spike cells were excited by tail-press; excitations were very rapid (peak at 1 s) and strong (100% rate increase over baseline) but brief (2-3 s). In contrast, both excitations (60%) and inhibitions (29%) were seen in short-spike cells. These responses were also rapid and transient, but excitations of short-spike units were more prolonged and sustained (10-15 s) than in long-spike cells.These data suggest that in awake animals iv cocaine, like somato-sensory stimuli, rapidly and transiently excites VTA neurons of different subtypes. Therefore, along with direct action on specific brain substrates, central effects of cocaine may occur via indirect mechanism, involving peripheral neural elements, visceral sensory nerves and rapid neural transmission. Via this mechanism, cocaine, like somato-sensory stimuli, can rapidly activate DA neurons and induce phasic DA release, creating the conditions for DA accumulation by a later occurring and prolonged direct inhibiting action on DA uptake. By providing a rapid neural signal and triggering transient neural activation, such a peripherally driven action might play a crucial role in the sensory effects of COC, thus contributing to learning and development of drug-taking behavior.

Electrophysiological evaluation of the time-course of dopamine uptake inhibition induced by intravenous cocaine at a reinforcing dose

Wakazono

2008

Neuroscience

Cocaine effectively inhibits dopamine (DA) uptake and this action appears to be the primary cause for increased DA transmission following systemic cocaine administration. Although this action had been reliably demonstrated in vivo with cocaine at high doses, data on the extent and the time-course of DA uptake inhibition induced by i.v. cocaine at low, reinforcing doses remain controversial. To clarify this issue, we examined how cocaine affects striatal neuronal responses to repeated iontophoretic DA applications in urethane-anesthetized rats. Because most striatal neurons during anesthesia have low, sporadic activity, DA tests were performed on cells tonically activated by continuous glutamate application. DA phasically decreased the activity of most dorsal and ventral striatal neurons; these responses in control conditions (i.v. saline) were current (dose) -dependent and remained highly stable following repeated DA applications at the same currents. DA also consistently decreased the activity of striatal neurons after i.v. cocaine (1 mg/kg); the magnitude of DA-induced inhibition slowly increased from approximately 5 min, became significantly larger from approximately 9 min, and peaked at 13-15 min after a single i.v. injection. Then, the difference in the DA response slowly decreased toward the pre-cocaine baseline. A similar enhancement of DA induced-inhibition was also seen after i.p. cocaine administration at a high dose (15 mg/kg). In this case, the DA response became significantly stronger at 7-9 min and remained enhanced vs. a pre-drug control up to 24-26 min after the injection. Both regimens of cocaine treatment did not result in evident changes in either onset or offset of the DA-induced inhibitions. Our data confirm that cocaine at low, reinforcing doses inhibits DA uptake, resulting in potentiation of DA-induced neuronal inhibitions, but they suggest that this effect is relatively weak and delayed from the time of i.v. injection. These slow and prolonged effects of i.v. cocaine on DA-induced neuronal responses are consistent with previous binding and our electrochemical evaluations of DA uptake, presumably reflecting the total time necessary for i.v.-delivered cocaine to reach brain microvessels, cross the blood-brain barrier, passively diffuse within brain tissue, interact with the DA transporters, and finally inhibit DA uptake.