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

Abstract

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...

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

“…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).…”

“…Most striatal neurons show rapid, transient excitations of a similar amplitude and time course following tail-press, tail-pinch, iv cocaine and cocaine methiodide in awake conditions, but these effects are dramatically attenuated or fully blocked during urethane anesthesia (Kiyatkin and Brown, 2007). While this study was limited to the awake conditions and we were unable to test the effects of peripherally acting cocaine methiodide (experiments in progress), it is reasonable to assume that general anesthesia, in addition to modulating spontaneous impulse activity, should inhibit the sensory responses of VTA neurons.…”

“…These data are also consistent with large body of neurochemical data (DA metabolism, [DA] evaluated by microdialysis or electrochemistry) suggesting increased DA release, especially in cortical projections, associated with arousing and aversive stimulation (Abercrombie et al, 1989;Deutch et al, 1985;Fadda et al, 1978;Feenstra et al, 2000Feenstra et al, , 2001Kiyatkin, 1995;Le Moal and Simon, 1991;Thierry et al, 1976). It appears that this response is typical to the awake conditions when sensory effects and activation mechanisms are intact and functional; somatosensory-evoked discharges typical to most striatal neurons were greatly eliminated during general anesthesia (see Kiyatkin and Brown, 2007;West, 1996). During general anesthesia presumed DA cells generally show no changes in activity following mild sensory stimulation (Coizet et al, 2006;Schultz and Romo, 1987;Tsai et al, 1980) but are both inhibited and activated by very strong, "noxious" stimuli (Chiodo et al, 1980;Coizet et al, 2006;Hommer and Bunney, 1980;Maeda and Mogenson, 1982;Schultz and Romo, 1987;Ungless et al, 2004).…”

“…In support of this indirect mechanism, most striatal neurons showed rapid, transient excitations (5-25 s) following iv cocaine administration in awake rats (Kiyatkin and Brown, 2007). Neuronal excitations began during an iv infusion-too rapid to reflect a direct interaction with central substrates.…”

“…Therefore, similar to our previous study, recordings were performed in animals administered with a mixture of D1-and D2-selective antagonists (SCH233900 and eticlopride), providing an effective blockade of DA transmission. DA receptor blockade greatly attenuates cocaine-induced motor activation, thus allowing artifact-free neuronal recording, but it keeps neuronal responses to sensory stimuli relatively intact (Kiyatkin and Rebec, 1999;Kiyatkin and Brown, 2007). The use of DA antagonists also excludes any possible contribution of DA mechanisms to the observed neuronal responses to sensory stimuli and cocaine.…”