George V. Rebec
Abstracts of Selected Publications

ABSTRACT
To assess dopamine efflux during novelty-seeking behavior in rats, fast-scan cyclic voltammetry in the nucleus accumbens was combined with free-choice entry into a novel environment. Cyclic voltammograms, confirmed by in vitro testing, revealed that entry into novel, but not familiar, surroundings increased dopamine efflux in a regionally and temporally distinct pattern. Whereas dopamine failed to change in the core region of the accumbens and overlying neostriatum, an abrupt increase occurred in accumbal shell, a limbic-related area implicated in goal-directed behavior. Although the dopamine response was confined to the brief period of entry into novelty (approximately 8 s duration), a less rapid and more persistent dopamine change (> 20 s duration) occurred in the shell-core transition zone, the so-called shore. These results suggest that novelty mimics other positively reinforcing stimuli in enhancing dopamine transmission in the nucleus accumbens, but the regional and temporal heterogeneity of this effect may represent different aspects of accumbal dopamine function.

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Although striatal neurons receive continuous dopamine (DA) input, little information is available on the role of such input in regulating normal striatal functions. To clarify this issue, we assessed how systemic administration of selective D1 and D2 receptor blockers or their combination alters striatal neuronal processing in freely moving rats. Single-unit recording was combined with iontophoresis to monitor basal impulse activity of dorsal and ventral striatal neurons and their responses to glutamate (GLU), a major source of excitatory striatal drive, and DA. SCH-23390 (0.2 mg/kg), a D1 antagonist, strongly elevated basal activity and attenuated neuronal responses to DA compared with control conditions, but GLU-induced excitations were enhanced relative to control as indicated by a reduction in response threshold, an increase in response magnitude, and a more frequent appearance of apparent depolarization inactivation. In contrast, the D2 antagonist eticlopride (0.2 mg/kg) had a weak depressing effect on basal activity and was completely ineffective in blocking the neuronal response to DA. Although eticlopride reduced the magnitude of the GLU response, the response threshold was lower, and depolarization inactivation occurred more often relative to control. The combined administration of these drugs resembled the effects of SCH-23390, but whereas the change in basal activity and the GLU response was weaker, the DA blocking effect was stronger than SCH-23390 alone. Our data support evidence for DA as a modulator of striatal function and suggest that under behaviorally relevant conditions tonically released DA acts mainly via D1 receptors to provide a continuous inhibiting or restraining effect on both basal activity and responsiveness of striatal neurons to GLU-mediated excitatory input.
© 1999 Society for Neuroscience

ABSTRACT
As one of the primary targets of the striatum, the substantia nigra pars reticulata (SNr) has been hypothesized to play a role in normal motor behavior. Specifically, inhibition of usually high, tonic SNr output is predicted to correlate with motor activation. While support for this has come primarily from electrophysiological studies in primates performing goal-directed movements, we tested this hypothesis in rats behaving in an open-field arena. SNr single-unit activity was recorded during spontaneous bouts of open-field behavior (e.g., head and body movements, locomotion) and after rats were given D-amphetamine (1.0 mg/kg, s.c.), which reliably increases motor activity and elevates the firing of motor-related striatal neurons. Prior to drug administration, SNr neurons had either regular, slightly irregular or irregular firing patterns when animals rested quietly. During movement, some inhibitions were observed, but the majority ( approximately 79%) of analyzed units increased firing by as much as 38%. Regardless of the predrug behavioral response of the cell, amphetamine strongly inhibited firing rate ( approximately 90% below nonmovement baseline) and changed firing pattern such that all cells fired irregularly. Subsequent injection with the dopamine antagonist haloperidol (1.0 mg/kg, s.c.) reversed amphetamine-induced inhibitions in all tested cells, which supports a role for dopamine in this effect. These results suggest that the pattern of striatal activity established by amphetamine, which may be critical for determining the drug-induced behavioral pattern, is represented in the SNr regardless of the predrug behavioral response of the cell.
© 1999 Elsevier Science Ltd.

ABSTRACT
Increasing evidence suggests that dopamine (DA) mechanisms alone cannot fully explain the psychoemotional and behavioural effects of cocaine, including its ability to induce drug-taking behaviour. Although it is known that cocaine, after intravenous administration or smoking, may reach brain levels high enough to inhibit Na+ transport, the role of this action remains unclear. To examine the contribution of local anaesthetic and DA mechanisms to changes in striatal and accumbal neuronal activity induced by cocaine, single-unit recording was combined with iontophoresis in awake, unrestrained rats. Most spontaneously active and glutamate-stimulated neurons were highly sensitive to brief cocaine applications (0-40 nA); cocaine-induced inhibitions occurred at small ejection currents (0-5 nA), were dose-dependent, highly stable during repeated applications and strongly dependent on basal activity rates. These neuronal responses remained almost unchanged after systemic administration of either a selective D1 antagonist (SCH-23390, 0.2 mg/kg) or a combination of SCH-23390 (1 mg/kg) and eticlopride (1 mg/kg), a D2 antagonist. Whereas SCH-23390 alone had a weak attenuating effect, no effect and even a slight enhancement of responses to cocaine occurred in fast-firing glutamate (GLU)-stimulated units after the combined blockade of D1 and D2 receptors. Responses to cocaine were mimicked by iontophoretic procaine (0-40 nA), a short-acting local anaesthetic with minimal effect on DA uptake. Procaine-induced inhibitions occurred at the same low currents, had a similar time-course, and were also strongly dependent on basal discharge rate. Our data support the existence of a DA-independent mechanism for the action of cocaine involving a direct interaction with Na+ channels. Although further studies are required to clarify this mechanism and its interaction with other pharmacological and behavioural variables, a direct interaction with Na+ channels may contribute to changes in neuronal activity induced by self-injected cocaine, thereby playing a role in mediating the psychoemotional and behavioural effects of this drug.
© 2000 Federation of European Neuroscience Societies

ABSTRACT
A new approach combining fast-scan cyclic voltammetry with iontophoretic dopamine delivery was used in freely behaving rats to evaluate the time-course of dopamine uptake inhibition in nucleus accumbens induced by intravenous cocaine at a dose (1.0mg/kg) known to maintain self-administration behavior. Cocaine significantly increased the decay time of the dopamine response without altering its magnitude or time to peak. An increase in decay time was evident at 2 min, peaked at 6 min (+87%), and decreased to baseline at 18 min after a single cocaine injection. The change in decay time was similar in all rats and remained essentially the same, albeit slightly larger, for subsequent cocaine injections both within a session and over repeated sessions. The change in dopamine decay time did not correlate with cocaine-induced motor activation, which was maximal during the first minute after injection and decreased slowly over the next 20 min. Our data provide direct evidence for a phasic change in dopamine uptake induced by intravenous cocaine under behaviorally relevant conditions. The relatively slow and gradual development of dopamine uptake inhibition, which peaks at times when behaving rats self-inject cocaine, is inconsistent with the suggested role of this mechanism in the acute rewarding (euphoric) effects of self-injected cocaine, but supports its role in the activational and motivational aspects of drug-seeking and drug-taking behavior. Because intravenous cocaine enters the brain rapidly and peaks in neural tissue (1-2 min) long before it effectively inhibits dopamine uptake (6 min), it appears that some of the acute psychoemotional ("rush"), behavioral, autonomic, and neuronal effects of this drug, which are apparently resistant to dopamine receptor blockade, are mediated via rapid central or peripheral mechanisms independent of monoamine uptake.

ABSTRACT
Ascorbate (vitamin C) is found in high concentrations in the striatum in which it may play a role in behavioral activation. To test this hypothesis, freely behaving rats received bilateral intrastriatal infusions of ascorbate oxidase (AAO) to inactivate extracellular ascorbate. Slow-scan voltammetry was used simultaneously to assess changes in ascorbate and 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, near the infusion site. Intrastriatal AAO, but not saline vehicle, caused a rapid decline in both ascorbate and behavioral activation. Within 20 min, an ascorbate loss of 50-70% led to a near-total inhibition of all recorded behavior, including open-field locomotion, approach of novel objects, and social interactions with other rats. DOPAC levels remained stable, arguing against an AAO-induced disruption of dopamine transmission. Consistent with this interpretation, subsequent injection of 1.0 mg/kg d-amphetamine, an indirect dopamine agonist, quickly restored behavioral activation, which also was accompanied by a marked rise in extracellular ascorbate. Bilateral AAO infusions into dorsal hippocampus, which also has a high level of extracellular ascorbate, failed to alter behavioral activation, indicating that a loss of brain ascorbate per se does not suppress behavior. Collectively, these results implicate ascorbate in the behavioral operations of the striatum and suggest that the extracellular level of this vitamin plays a critical role in behavioral activation.
© 2001 Society for Neuroscience

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