Biomedical subjects

G V Rebec

Publications and source records attributed to G V Rebec.

At least 19 recordsLinked to original sources

PubMed2005

Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: variations with behavioral state and repeated ascorbate treatment.

Membrane and morphological abnormalities occur in the striatum of R6/2 transgenics, a widely used mouse model of Huntington's disease. To assess changes in behavior-related neuronal activity, we implanted micro-wire bundles in the striatum of symptomatic R6/2 mice and wild-type controls. Unit activity was recorded in an open-field arena once weekly for the next several weeks. For each recording session, firing rate was monitored before, during, and after a period of light anesthesia to assess the influence of behavioral arousal. Because low ascorbate in striatal extracellular fluid may contribute to Huntington's disease symptoms, all animals received an injection of either 300 mg/kg sodium ascorbate or vehicle for three consecutive days prior to each recording session. In R6/2 mice, regardless of treatment, striatal unit activity was significantly faster than in wild-type controls. The difference in mean (+/-S.E.M.) firing was most apparent during wakefulness (6.4+/-0.8 vs. 3.5+/-0.3 spikes/s) but also persisted during anesthesia (2.0+/-0.3 vs. 0.7+/-0.1 spikes/s). Assessment of treatment duration indicated that R6/2 mean waking discharge rate was significantly slower after three weeks than after one week of ascorbate treatment (3.1+/-0.6 vs. 10.2+/-2.7 spikes/s). Vehicle-treated R6/2s showed no such decline in striatal activity ruling out an age- or injection-related effect. Slow-scan voltammetry in separate animals confirmed that ascorbate-injections returned the level of striatal extracellular ascorbate in R6/2 mice to that of wild-type controls. Our results indicate that although striatal neurons modulate firing in relation to behavioral state, impulse activity is consistently elevated in transgenic relative to wild-type mice. Restoring extracellular ascorbate to the wild-type level reverses this effect suggesting a role for ascorbate in normalizing neuronal function in Huntington's disease striatum.

Anesthesia↗

PubMed2003

A role for presynaptic mechanisms in the actions of nomifensine and haloperidol.

Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA](max)) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA](max) and motor activation following nomifensine (r=0.99) and a negative correlation was found between [DA](max) and catalepsy following haloperidol (r=-0.96) in the second experiment. Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought.

Animals↗

PubMed2002

Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task.

Motor-control models of basal ganglia function have emphasized disinhibition through reduction of tonic, inhibitory output. Although these models have shed important light on basal ganglia operations, evidence emerging from electrophysiological studies of behaving primates suggests that disinhibition alone may not adequately explain the role of the basal ganglia in movement. To assess this role in the rat, the most frequently used subject in studies of basal ganglia function, we recorded neuronal activity in the primary output nucleus, the substantia nigra pars reticulata, during an operant task. After rats were trained to nosepoke into an illuminated hole for access to a 10% sucrose solution delivered through a spout, single- and multiple-unit activity was recorded during 60-120 nosepoke trials. Compared to the period 60 s before the start of the first trial in the task, 110 of 225 reticulata units increased firing >200% while 17 of 225 decreased to 40% of baseline. Of these 225 units, >60% responded coincident with specific task events such as nosepokes and spout licking. Most nosepoke-responsive units showed either excitation (>50%) or a combination of excitation and inhibition (>25%) rather than inhibition alone (>20%). Increases in firing were also common during approach and licking at the spout, with inhibitions alone comprising 30% of responses. In some units, there was evidence of reward-related responding, with changes occurring in anticipation of reward delivery or during the delivery of sucrose, but not the persistent licking that continued for several seconds after its offset. While 70% of units responded during both nosepokes and spout licking, changes in firing were typically unique depending on the motor behavior required (i.e. nosepoking vs. licking). Our results, which indicate a prominent role for increases in nigra reticulata activity during movement, add to growing evidence that although inhibitions may allow desired motor responses to emerge, excitations may help shape behavioral output by suppressing competing motor programs.

Animals↗

PubMed2001

Effects of long-term haloperidol treatment on glutamate-evoked ascorbate release in rat striatum.

Repeated haloperidol injections increase extracellular striatal ascorbate. Because ascorbate release depends on glutamate uptake, we assessed this mechanism in the haloperidol effect. Linear staircase voltammetry was combined with intrastriatal infusions of L- or D-glutamate or saline in behaving rats after 7 or 21 days of haloperidol (0.5 mg/kg, s.c.). Control animals, receiving either vehicle or no treatment, responded to L-, but not D-glutamate or saline infusion with a 50% increase in ascorbate. In contrast, glutamate-evoked ascorbate release disappeared after 7 but reappeared after 21 days of haloperidol. Thus, increased striatal ascorbate release following chronic haloperidol cannot be explained by an enhanced response to glutamate.

Animals↗

PubMed2001

Behavioral activation in rats requires endogenous ascorbate release in striatum.

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.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Impulse activity of ventral tegmental area neurons during heroin self-administration in rats.

To assess the pattern of mesocorticolimbic dopamine activity associated with drug-seeking and drug-taking behavior, we recorded impulse activity of ventral tegmental area neurons during intravenous heroin self-administration in trained rats. Although these neurons had considerable variability, two major groups-units with triphasic long-duration spikes and biphasic short-duration spikes-were identified. Relative to a slow and irregular basal activity of long-spike units, the first self-administration of each session was preceded by a phasic neuronal activation and followed by a more sustained drug-induced activation that reached a maximum at the time of the second self-injection. After each subsequent heroin self-injection, the discharge rate transiently decreased, correlating with the blockade of preceding motor activation and the appearance of freezing, but slowly and gradually increased again in parallel with searching behavior, reaching a maximum at the time of the next self-injection. Passive drug injections in either drug-naive, freely moving or drug-experienced, anesthetized rats caused much smaller, tonic increases in activity of long-spike units; these monophasic increases changed into biphasic responses with repeated injections. Although short-spike units had highly varying discharge rate and showed phasic activation during movement, during heroin self-injections they generally mimicked the activity pattern seen in long-spike units. Our results indicate that in behaving animals indirect "identification" of dopamine cells based on their distinctive electrophysiological features is more complex than in vitro and in anesthetized preparations. With respect to long-spike units, a candidate group of presumed dopamine neurons, our data agree with the view that mesocorticolimbic dopamine activation is important for the activational and/or motivational aspects of heroin-taking behavior and suggest the role of an abrupt termination of dopamine activation for drug reinforcement (reward). Although the neurochemical nature of long- and short-spike units is obviously different, similar changes in their activity may indicate that they are regulated by similar afferent inputs and that these inputs change similarly during drug-taking behavior.

Animals↗

PubMed2000

gamma-Aminobutyric acid infusion in substantia nigra pars reticulata in rats inhibits ascorbate release in ipsilateral striatum.

A relatively high level of extracellular ascorbate in the striatum, which is known to modulate impulse flow in striatal neurons, originates primarily from glutamate-containing corticostriatal afferents. Increasing evidence suggests that ascorbate release from these fibers is regulated by a multisynaptic loop that includes gamma-aminobutyric acid (GABA) mechanisms in the substantia nigra. To assess the role that nigral GABA plays in striatal ascorbate release, extracellular ascorbate was monitored voltammetrically in the striatum during infusions of GABA into the substantia nigra pars reticulata (SNr) of awake, unrestrained rats. Compared to vehicle infusions, intranigral GABA lowered striatal ascorbate by >50%. In contrast, intranigral application of picrotoxin, a GABA antagonist, had the opposite effect. Neither GABA nor picrotoxin altered striatal 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite. Collectively, these results indicate that intranigral GABA exerts a tonic inhibitory influence on ascorbate release in the striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Effects of crus cerebri lesions and repeated amphetamine treatment on the activity of nigral dopaminergic neurons.

Previous research suggests that the firing rate of dopamine (DA) neurons in the substantia nigra pars compacta (SNC) may be altered by repeated DA agonist treatment. Because changes in the frequency of DA activity could reflect the firing patterns (e.g., bursting) of the neurons sampled, this study examined both the firing rate and pattern of SNC DA neurons after long-term amphetamine (AMPH) treatment (5 mg/kg d-AMPH s.c. twice daily for 6 days). To assess the contribution of postsynaptic feedback from the forebrain, unilateral electrolytic lesions were made to the crus cerebri (CC), containing the striatonigral pathway, prior to AMPH treatment. Single-unit activity of presumed SNC DA neurons was recorded in adult male rats under urethane anesthesia. Spontaneous firing rate was reduced by AMPH treatment, relative to saline vehicle, but was unaffected by CC or sham lesions. Neurons categorized as bursting had faster rates of activity than nonbursting cells. AMPH treatment reduced the number of bursts seen in intact rats but increased bursting in lesioned rats. These results suggest that changes in DA firing rate previously found after chronic AMPH may reflect altered patterns of activity. In addition, the effects of long-term AMPH on the firing patterns of DA neurons appear to be mediated by fibers in the CC.

Action Potentials↗

PubMed2000

Facilitation of preparatory behavior in an artificial prey paradigm by D1-subfamily dopamine receptor activation.

Dopamine agonists facilitate, and antagonists inhibit, conditioned preparatory behaviors in rats. Similar effects are demonstrated on an unconditioned preparatory behavior: predatory search and contact of a moving artificial prey stimulus. Apomorphine (0.1, 0.2 mg/kg), a direct agonist, had no effect relative to a within-subject injection of saline vehicle but d-amphetamine (0.1 mg/kg), an indirect agonist, increased contact frequency without altering overall motor activation. To determine the relative importance of the D1 and D2 subfamilies of receptors in the amphetamine effect, separate groups of animals received amphetamine co-injected with either SCH23390 (0.01 and 0.005 mg/kg) or eticlopride (0.01 mg/kg), D1 and D2 antagonists, respectively. Whereas the eticlopride-amphetamine group showed no change in contact frequency from baseline, co-injections of either dose of SCH23390 and amphetamine led to near total suppression of contact, as did treatment with SCH23390 (0.005 mg/kg) alone. Treatment with 0.01 mg/kg eticlopride alone increased contact frequency while treatment with a higher dose (0.1 mg/kg) had no effect. Treatment with the D1-subfamily agonist SKF81297 (0.1 mg/kg) increased contact frequency. Collectively, these results support the hypothesis that dopamine mediates unconditioned preparatory behavior and suggest differing roles for the D1 and D2 receptor subfamilies.

Amphetamine↗

PubMed2000

Phasic inhibition of dopamine uptake in nucleus accumbens induced by intravenous cocaine in freely behaving rats.

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.

Animals↗

PubMed2000

Dopamine-independent action of cocaine on striatal and accumbal neurons.

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.

Animals↗

PubMed1999

Behavior-related changes in the activity of substantia nigra pars reticulata neurons in freely moving rats.

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.

Action Potentials↗

PubMed1999

Striatal neuronal activity and responsiveness to dopamine and glutamate after selective blockade of D1 and D2 dopamine receptors in freely moving rats.

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.

Animals↗

PubMed1999

Modulation of striatal neuronal activity by glutamate and GABA: iontophoresis in awake, unrestrained rats.

To examine the effects of glutamate (GLU) and gamma-aminobutyric acid (GABA) and their interactions in the striatum under behaviorally relevant conditions, single-unit recording was combined with microiontophoresis in awake, unrestrained rats. Iontophoretically applied GLU (0-40 nA, 20 s) excited all spontaneously active neurons in dorsal (caudate-putamen) and ventral (accumbens, core) striatum; phasic GLU-induced excitations (mean threshold 19.7 nA) were dose-dependent, inversely correlated with rate of basal activity (excitation limit approximately 65 imp/s), and highly stable during repeated GLU applications. GLU also excited silent and sporadically active units, which greatly outnumbered spontaneously active cells, and enhanced neuronal excitations associated with movement. Both spontaneously active and GLU-stimulated striatal neurons were highly sensitive to GABA (0-40 nA, 20 s); most showed short-latency inhibitions during GABA diffusion from the pipette (0 nA) and the response quickly progressed to complete silence with a small increase in current. The GABA-induced inhibition was current-dependent, equally strong on spontaneously active and GLU-stimulated units, and independent of neuronal discharge rate, but less stable than the GLU-induced excitation during repeated drug applications. Prolonged GABA application (0-20 nA, 2-4 min) reduced basal impulse activity, but was less effective in attenuating the neuronal excitations induced by GLU or associated with movement. Our data support the role of GLU afferents in the phasic activation of striatal neurons and suggest that the effects of GLU strongly depend on the level of ongoing neuronal activity. The ability of GABA to modulate both basal and GLU-evoked activity suggests that GABA, released from efferent collaterals and interneurons, plays a critical role in regulating neuronal activity and responsiveness to phasic changes in excitatory input.

Action Potentials↗

PubMed1999

Modulatory effects of ascorbate, alone or with haloperidol, on a lever-release conditioned avoidance response task.

Pretreatment with ascorbate, a modulator of dopamine transmission in the striatum, enhances the ability of haloperidol, a dopamine antagonist, to induce catalepsy and block the motor-activating effects of amphetamine. The present study extended this line of work to a lever-release version of the conditioned avoidance response (CAR) task, which is highly sensitive to changes in striatal dopamine. Adult male rats were trained to avoid footshock by releasing a lever within 500 ms of tone onset. Ascorbate (100 and 1000 mg/kg, IP) or vehicle was tested either alone or in conjunction with haloperidol (0.01 and 0.05 mg/kg, SC). Compared to vehicle pretreatment, 1000 mg/kg ascorbate alone or in combination with haloperidol impaired CAR performance by increasing avoidance latency. Latency to escape footshock was not impaired, ruling out a generalized motor deficit. In contrast, 100 mg/kg ascorbate alone or in combination with haloperidol had no consistent effects on CAR performance, even at a haloperidol dose (0.005 mg/kg, SC) known to potentiate dopamine transmission by preferentially blocking autoreceptors. Collectively, these results support an antidopaminergic action of ascorbate on striatal function, but suggest that this effect requires relatively high systemic doses.

Analysis of Variance↗

PubMed1998

Ascorbate modulates glutamate-induced excitations of striatal neurons.

To assess the role of ascorbate (AA), an antioxidant vitamin, in modulating striatal activity, single-unit recording was combined with iontophoresis in awake, unrestrained rats. Brief applications of AA (20 s, 5-80 nA) elicited few changes in either basal activity or activity evoked by continuous application of glutamate (GLU), but relatively high AA ejection currents (>40 nA) often inhibited fast-firing units. Comparable results were obtained with the antioxidant isomer, iso-AA, suggesting the AA-induced inhibition represents a high-dose, antioxidant effect. When applied for prolonged periods (2-4 min) at doses that failed to alter basal activity, AA either enhanced or attenuated the excitatory response to test pulses of GLU. The AA-induced enhancement occurred more frequently (16 vs. 6 applications) and was characterized by a more rapid (shorter onset and peak latencies) and more pronounced (greater peak magnitude) excitation to GLU without an evident change in offset latency. In most cases, further increases in AA ejection current attenuated the GLU response. Iso-AA, in contrast, had only inhibitory effects, which occurred at moderate- to high-dose applications. Collectively, these results suggest that AA, apart from its antioxidant effects, modulates phasic changes in striatal excitability induced by GLU. Because extracellular levels of striatal AA fluctuate in relation to behavioral activation, this neuromodulatory action of AA may contribute to behaviorally relevant changes in sensorimotor responsivity.

Animals↗

PubMed1998

Cocaine-induced activation of striatal neurons during focused stereotypy in rats.

As psychomotor stimulants, both amphetamine and cocaine elicit episodes of repetitive motor activation (focused stereotypy) known to involve the mesostriatal dopamine system. During amphetamine-induced focused stereotypy, motor-related neurons in the striatum respond with either an excitation or inhibition, depending on dose and behavioral pattern, whereas nonmotor-related units are inhibited. To assess striatal activity during the focused stereotypy induced by cocaine, both types of striatal units were recorded in ambulant rats. Either 20 or 40 mg/kg cocaine caused highly focused sniffing and head bobbing, which occurred in conjunction with activation of both motor- and nonmotor-related neurons. The activation of motor-related units was evident even when firing rate was compared during periods of matched pre- and post-drug behavior, arguing against movement as the sole basis for the drug-induced neuronal excitation. Subsequent administration of haloperidol (1.0 mg/kg) reversed but did not completely block the neuronal activation, while the behavioral response shifted away from focused stereotypy toward an increase in ambulation. Thus, the level of activation of both motor- and nonmotor-related striatal neurons may play a critical role in the behavioral response pattern induced by cocaine.

Amphetamine↗

PubMed1998

Circadian activity precedes daily methamphetamine injections in the rat.

Scheduled daily injections of methamphetamine (MA) produced locomotor activity that preceded and followed the usual time of injection in rats housed under conditions of constant, moderately dim light and temporally distributed feeding. A circadian basis for pre-injection time activity was supported by its anticipatory timing in the apparent absence of reliable preceding external cues and by its persistence on a test day on which the rats remained undisturbed. Post-injection time locomotor activity also persisted on the test day, occurring from 24 to 29 h after the final MA injection. These results indicate that MA injections engage circadian processes underlying locomotor activity, and they raise the possibility that intake of drugs of abuse by humans may facilitate drug taking or relapse at times of day related to previous drug use.

Animals↗