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F J White

Publications and source records attributed to F J White.

At least 55 records · Page 3Linked to original sources
PubMed1996

A genetic approach to study mechanisms of cocaine action.

The brain dopamine system is thought to be the major target for the neuropharmacological actions of psychomotor stimulants such as cocaine. To investigate the mechanisms of cocaine action, we used a genetic approach, the gene-targeting technique, and generated D1 dopamine receptor mutant mice. Locomotor activity analysis in response to cocaine indicates that, in contrast to control mice which showed a dose-dependent increase in locomotion, D1 receptor mutant mice exhibited a dose-dependent decrease, suggesting that D1 receptors play an essential role in mediating such effects. Extracellular single unit recording of dopamine sensitive nucleus accumbens neurons in the D1 receptor mutant mice and control mice revealed a marked reduction in the inhibitory effects of cocaine and dopamine on the generation of action potentials, suggesting that D1 receptors play a fundamental role in cocaine- and dopamine-mediated neurophysiological effects within the nucleus accumbens. From these analyses, we conclude that the D1 dopamine receptor plays essential roles in mediating these effects of cocaine. In the future, the use of this powerful genetic approach will be essential for elucidating the molecular components of the signal transduction pathway leading to anatomical, cellular and behavioral changes upon cocaine administration and dopamine neurotransmission.

Animals↗
PubMed1996

Glutamate receptor regulation of rat nucleus accumbens neurons in vivo.

Extracellular single cell recording and microiontophoretic techniques were used to characterize the roles of ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs) in glutamate-induced excitation of rat nucleus accumbens (NAc) neurons in vivo. Pulse-ejected glutamate (16-128 nA) induced a current-dependent increase in the firing of quiescent NAc neurons. A stronger excitatory response to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) was observed at much lower ejection currents (0.1-6.4 nA). Compared to AMPA and glutamate, N-methyl-D-aspartate (NMDA) induced a much less potent excitation in a narrow current range (1-4 nA) and only when neurons were previously "primed" with other excitatory amino acids (EAAs). Higher ejection currents of all three EAA agonists drove NAc neurons into a state of apparent depolarization block. AMPA-evoked firing was selectively blocked by the AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) whereas NMDA-induced activity was selectively prevented by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (D-AP5). DNQX, but not D-AP5, significantly attenuated glutamate-evoked activity. The mGluR receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-t-ACPD) failed to evoke activity of NAc neurons, but significantly reduced the excitatory effects of other EAAs. This modulatory effect of 1S,3R-t-ACPD was consistently blocked by the selective mGluR antagonist L(+)-2-amino-3-phopsonopropionic acid (L-AP3) whereas another mGluR antagonist (RS)-4-carboxy-3-hydroxy phenylglycine (4C3HPG) was inconsistent in this regard. These results indicate that the excitatory effects of glutamate on rat NAc neurons in vivo are primarily mediated by non-NMDA iGluRs and that mGluRs function to dampen excessive glutamate transmission through iGluRs.

Animals↗
PubMed1996

Synaptic regulation of mesocorticolimbic dopamine neurons.

The mesocorticolimbic dopamine system is thought to be involved in psychosis and drug addiction. Many intrinsic membrane properties and synaptic regulators have been identified and characterized in the midbrain ventral tegmental dopamine neurons that give rise to this system. Other neuronal properties remain subject to considerable debate. The present review brings together a large literature regarding neurophysiological studies of the synaptic mechanisms thought to regulate the activity of ventral tegmental dopamine neurons. This work is placed within the context of the behavioral responsiveness of midbrain dopamine neurons and the alterations produced in these neurons by repeated treatment with and withdrawal from antipsychotic drugs and drugs of abuse.

Afferent Pathways↗
PubMed1995

The dopamine D1 receptor antagonist SCH 23390 can exert D1 agonist-like effects on rat nucleus accumbens neurons.

Interactions between the selective dopamine D1-class receptor antagonist SCH 23390 and the dopamine D2-class receptor agonist quinpirole on nucleus accumbens neurons were investigated with extracellular single cell recording and microiontophoresis. Because dopamine D1 receptor stimulation enables many dopamine D2 receptor-mediated effects, SCH 23390 was expected to antagonize quinpirole-induced inhibition of activity. Although concurrent iontophoretic administration of SCH 23390 attenuated the inhibitory effects of quinpirole on most neurons, the antagonist further suppressed the firing of most neurons during attempts to reverse quinpirole-induced inhibition. SCH 23390 also reinstated (enabled) quinpirole-induced inhibition in rats acutely depleted of dopamine. These findings suggest that under certain conditions, SCH 23390 may exert dopamine D1 agonist-like effects.

Animals↗
PubMed1995

Dopamine receptor antagonists prevent expression, but not development, of morphine sensitization.

The present experiments determined the effects of selective dopamine receptor antagonists on the initiation and expression of sensitization to the locomotor-stimulating effects of morphine in rats. Although both the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride (SCH 23390, 0.25 mg/kg) and the dopamine D2 receptor antagonist eticlopride (0.1 mg/kg) suppressed the ability of morphine (10 mg/kg) to elicit sensitized locomotor activity during the course of a 12 day treatment schedule, subsequent tests with morphine alone revealed significant sensitization. Sensitization in the SCH 23390 + morphine group could not be attributed to dopamine D1 receptor supersensitivity caused by repeated SCH 23390 administration because electrophysiological recordings indicated that nucleus accumbens neurons in SCH 23390-treated rats were not more sensitive to the inhibitory effects of either dopamine or a dopamine D1 receptor-selective agonist. Thus, dopamine receptor stimulation may be involved in expression, but not development, of morphine sensitization.

Animals↗
PubMed1995

The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons.

The mesoaccumbens dopamine system is intricately involved in the locomotor stimulation produced by cocaine and sensitization of this effect following repeated cocaine administration. The mechanisms responsible for the expression of sensitized locomotion appear to involve alterations in both presynaptic (increased dopamine release) and postsynaptic (increased responsiveness of dopamine D1 receptors) aspects of dopamine neurotransmission within the nucleus accumbens. The present experiments used behavioral and single-cell electrophysiological techniques to determine the persistence of sensitization and of enhanced postsynaptic responses to cocaine within the nucleus accumbens following various periods of withdrawal from repeated cocaine treatment (10 mg/kg i.p., twice daily, 14 d). Behavioral sensitization to the locomotor stimulant effects of cocaine was evident after 1 d, 1 week, and 1 month, but not 2 months of withdrawal. A similar time course was observed for the enhanced efficacy of cocaine-induced inhibition of nucleus accumbens neurons, whether cocaine was administered systemically or locally by microiontophoresis. Nucleus accumbens neurons also exhibited sensitized inhibitory responses to iontophoretically applied GABA after 1 d of withdrawal, but not later times. These findings suggest that cocaine sensitization is relatively persistent, but not necessarily permanent, and support the hypothesis that expression of behavioral sensitization to cocaine involves actions within the NAc, particularly those mediated by dopamine D1 receptors.

Animals↗
PubMed1995

Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system.

The development of behavioral sensitization during repeated administration of psychomotor stimulants is a well characterized phenomenon which involves alterations in dopaminergic neurotransmission within the mesoaccumbens system. However, recent evidence indicating that both behavioral sensitization and certain of its neuronal correlates can be prevented by excitatory amino acid receptor antagonists suggests an integral role for glutamate systems in sensitization processes. Therefore, we have determined whether repeated psychomotor stimulant administration can alter responsiveness of the mesoaccumbens dopamine (DA) system to glutamate. After five daily injections of either cocaine (15.0 mg/kg) or d-amphetamine (5.0 mg/kg), rats were subjected to in vivo single cell recording to determine the efficacy of iontophoretically administered glutamate in altering the firing of ventral tegmental area DA neurons and nucleus accumbens neurons. Current-response determinations indicated that the responsiveness of ventral tegmental area DA neurons to glutamate was significantly enhanced in d-amphetamine-treated and cocaine-treated rats in that the neurons entered a state of apparent depolarization block at significantly lower iontophoretic currents. In contrast, nucleus accumbens neurons in psychomotor stimulant-treated rats were significantly less sensitive to the rate-enhancing effects of glutamate. Thus, sensitization appears to be associated with alterations in glutamate transmission at both the origin and termination of the mesoaccumbens DA pathway.

Amphetamine↗
PubMed1994

Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice.

The brain mesoaccumbens dopamine system is intricately involved in the psychomotor stimulant activities of cocaine. However, the extent to which different dopamine receptors mediate these effects has not yet been firmly established. The present study used dopamine D1 receptor mutant mice produced by gene targeting to investigate the role of this receptor in the effects induced by cocaine. In contrast with wild-type mice, which showed a dose-dependent increase in locomotion, D1 mutant mice exhibited a dose-dependent decrease. Electrophysiological studies of dopamine-sensitive nucleus accumbens neurons demonstrated a marked reduction in the inhibitory effects of cocaine on the generation of action potentials. In addition, the inhibitory effects of dopamine as well as D1 and D2 agonists were almost completely abolished, whereas those of serotonin were unaffected. D2-like dopamine receptor binding was also normal. These results demonstrate the essential role of the D1 receptor in the locomotor stimulant effects of cocaine and in dopamine-mediated neurophysiological effects within the nucleus accumbens.

Animals↗
PubMed1994

MK-801 does not prevent acute stimulatory effects of amphetamine or cocaine on locomotor activity or extracellular dopamine levels in rat nucleus accumbens.

Recent work has shown that the development of behavioral sensitization to cocaine, amphetamine, and morphine is prevented by coadministration of N-methyl-D-aspartate (NMDA) antagonists such as MK-801. This suggests that NMDA receptors mediate long-term changes in neuronal responsiveness essential for the development of behavioral sensitization, similar to their role in other forms of neuronal plasticity. However, other studies, suggesting that NMDA receptor antagonists interfere with acute behavioral effects of psychomotor stimulants, call this interpretation into question and suggest that the ability of NMDA antagonists to prevent sensitization may reflect blockade of the acute effects of psychomotor stimulants. To examine this issue, behavioral and microdialysis studies assessed the effect of pretreatment with 0.1 mg/kg MK-801 on the ability of amphetamine and cocaine to stimulate locomotor activity and elevate extracellular dopamine (DA) levels in nucleus accumbens; this dose of MK-801 prevents sensitization when coadministered repeatedly with these stimulants. MK-801 pretreatment enhanced amphetamine-stimulated horizontal locomotion and stereotyped behavior. MK-801 pretreatment produced a modest attenuation of cocaine-stimulated horizontal locomotion, which may have reflected enhancement by MK-801 of certain components of cocaine-stimulated stereotypy. There was no effect of MK-801 pretreatment on the ability of amphetamine or cocaine to elevate extracellular DA levels in nucleus accumbens. These results suggest that the acute effects of cocaine and amphetamine on locomotor activity and extracellular DA levels are not prevented by MK-801, and that MK-801 must act through other mechanisms to prevent the development of behavioral sensitization.

Amphetamine↗
PubMed1994

MK-801 prevents the development of behavioral sensitization during repeated morphine administration.

Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 mg/kg) and horizontal locomotion at higher doses (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects.

Animals↗
PubMed1994

Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: electrophysiological and behavioral studies.

Many effects resulting from D2 dopamine (DA) receptor stimulation are manifest only when D1 DA receptors are stimulated by endogenous DA. When D1 receptor stimulation is enhanced by administration of selective D1 receptor agonists, the functional effects of selective D2 agonists are markedly increased. These qualitative and quantitative forms of D1/D2 DA receptor synergism are abolished by chronic DA depletion when both D1 and D2 DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D1 and D2 receptor supersensitivity, induced by repeated administration of selective D1 or D2 receptor antagonists, on the synergistic relationships between D1 and D2 receptors. Daily administration of the selective D2 antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D2 agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D1 agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D2 receptors from the necessity of D1 receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (stereotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D1 receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D1 receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such D1-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D1-sensitized rats are due to a heterologous sensitization of D2 receptors rather than to enhanced enabling resulting from supersensitive D1 receptors. It is suggested that supersensitivity of either D1 or D2 receptors can lead to an uncoupling of normal qualitative and quantitative D1/D2 synergisms and that the heterologous regulation of D2 receptor sensitivity by D1 receptors may be related to uncoupling of functional D1/D2 synergisms.

Animals↗
PubMed1994

Contrasting chimpanzees and bonobos: nearest neighbor distances and choices.

In an effort to understand factors underlying differences in the social organization of Pan troglodytes and P. paniscus, we measured the nearest neighbor distances and choices for chimpanzees in Kibale National Park, Uganda, and for bonobos in Lomako Forest, Zaire. We assume that the spatial organization of a set of individuals should reflect the underlying relationships between them. Bonobos were found to have smaller nearest neighbor distances than chimpanzees. The distribution and variability of the distances suggested that chimpanzees have a more restricted range of nearest neighbor distances than bonobos, avoiding situations of very close proximity. Selection of the sex of the nearest neighbor by a focal animal differed between the species. For example, male bonobos rarely had another male as their nearest neighbor, while male chimpanzees frequently did. Similarly, male bonobos tended to move apart when observed together, while it was female chimpanzees who tended to move apart when together. These observations are considered with respect to the nature of the social interactions in these species.

Animals↗
PubMed1994

MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine.

Behavioral sensitization to psychomotor stimulants has been shown to be accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA), postsynaptic D1 receptor supersensitivity in the nucleus accumbens (NAc), and augmentation of the DA-releasing effects of stimulants in the NAc. The present study examined whether coadministration of the noncompetitive NMDA antagonist MK-801 with amphetamine, which has been shown to prevent the development of behavioral sensitization to amphetamine, would also prevent these changes in mesoaccumbens DA function. Rats were treated for 5 d with amphetamine according to a regimen known to produce lasting sensitization. Extracellular single-unit recordings from VTA DA neurons in amphetamine-treated rats, performed after 1 d of abstinence, revealed robust autoreceptor subsensitivity to DA agonists. This was prevented in rats coadministered MK-801 with amphetamine during the 5 d pretreatment period. Recordings from NAc neurons in amphetamine-treated rats demonstrated supersensitivity of D1 receptors to iontophoretic administration of selective agonists when tested after 7 d of abstinence. This was also prevented by MK-801 coadministration. Microdialysis studies performed in awake rats after 7 d of abstinence failed to demonstrate augmentation of amphetamine-stimulated DA release in amphetamine-treated rats as compared to water controls, despite the fact that behavioral sensitization was evident in the former group during microdialysis experiments. MK-801 coadministration prevented behavioral sensitization in microdialysis rats but did not alter amphetamine-stimulated DA release. These results suggest (1) NMDA receptor stimulation is required for the development of both autoreceptor subsensitivity in the VTA and postsynaptic D1 receptor supersensitivity in the NAc during repeated amphetamine treatment, (2) these functional changes therefore appear to be closely associated with the development of behavioral sensitization, and (3) a dissociation can be demonstrated between the intensity of amphetamine-stimulated behavioral responses and amphetamine-stimulated DA release in the NAc.

Amphetamine↗
PubMed1993

Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization.

Various changes in the function of dopamine neurons have been proposed to underly the development of behavioral sensitization to the locomotor stimulant effects of d-amphetamine. The present study examined the relative importance of two such mechanisms after both short (3-4 days off) and longer (10-14 days off) withdrawals from repeated amphetamine or saline injection (1 mg/kg/day, days 1-5 and 8-12). First, single-unit recording was used to examine the sensitivity of impulse-regulating somatodendritic autoreceptors located on mesoaccumbens dopamine neurons in the rat ventral tegmental area. Second, in vivo microdialysis was used to examine the ability of amphetamine challenge to increase extracellular dopamine levels in the rat nucleus accumbens. Amphetamine-treated rats exhibited robust behavioral sensitization at both time points as compared to saline-treated rats. At 3 to 4 days off, autoreceptor subsensitivity was observed in the ventral tegmental area of amphetamine-treated rats, but there was no significant change in the ability of amphetamine to increase extracellular dopamine levels in nucleus accumbens. However, after 10 to 14 days off, autoreceptor subsensitivity was no longer observed, but amphetamine challenge resulted in a significantly greater increase in extracellular dopamine levels in amphetamine-treated as compared to saline-treated rats. These findings suggest that autoreceptor subsensitivity is a transient effect which may be related to the development of sensitization, whereas enhancement of amphetamine-stimulated dopamine release does not accompany early stages of behavioral sensitization, but may be involved in the persistence of the phenomenon after longer withdrawal periods.

Amphetamine↗