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F J White

Publications and source records attributed to F J White.

At least 37 records · Page 2Linked to original sources
PubMed1999

Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations.

Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates.

Adaptation, Biological↗
PubMed1999

The expression of cocaine sensitization is not prevented by MK-801 or ibotenic acid lesions of the medial prefrontal cortex.

Previous work has established that the development of cocaine sensitization is prevented by co-administration of the non-competitive NMDA receptor antagonist MK-801 or by prior ibotenic acid lesions of the medial prefrontal cortex (PFC). The present study examined the effect of these treatments on the expression of cocaine sensitization. Rats were treated with 15 mg/kg cocaine for 5 days and then challenged with cocaine 3 days later to establish the presence of sensitization. The next day, rats received 0.1 mg/kg MK-801 30 min before cocaine challenge. This dose of MK-801, which is sufficient to prevent the development of cocaine sensitization, did not prevent its expression. Rather, it augmented the response of sensitized rats to cocaine challenge and produced a non-significant trend towards augmentation of the acute response to cocaine in saline-pretreated rats. For PFC lesion experiments, rats were sensitized to cocaine and then received either ibotenic acid or sham lesions of the PFC. One week later, all rats were challenged with cocaine. Sham lesioned and ibotenic acid lesioned rats exhibited the same degree of sensitization. Thus, neither NMDA receptor transmission nor PFC projections appear necessary for the expression of cocaine sensitization.

Animals↗
PubMed1999

Loss of autoreceptor functions in mice lacking the dopamine transporter.

Autoreceptors provide an important inhibitory feedback mechanism for dopamine neurons by altering neuronal functions in response to changes in extracellular levels of dopamine. Elevated dopamine may be a component of several neuropsychiatric disorders. However, evidence concerning the state of autoreceptors in such conditions has remained elusive. The function of dopamine autoreceptors was assessed in mice lacking the dopamine transporter (DAT). Genetic deletion of the DAT gene in mice results in a persistent elevation in levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and release-regulating autoreceptors in these mice reveals a nearly complete loss of function. These findings may provide insight into the neurochemical consequences of hyperdopaminergia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

DARPP-32: regulator of the efficacy of dopaminergic neurotransmission.

Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.

Amphetamines↗
PubMed1998

Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice.

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expressed at DA nerve terminals regulate both DA synthesis and release. Considerable evidence has indicated that these DA autoreceptors are of the D2 subtype of DA receptors. However, many pharmacological studies have suggested an autoreceptor role for the DA D3 receptor. This possibility was tested with mice lacking the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral tegmental area were not different in D3 receptor mutant and wild-type mice. The putative D3 receptor-selective agonist R(+)-trans-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin+ ++-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the gamma-butyrolactone (GBL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wild-type mice. These results suggest that the effects of PD 128907 on dopamine cell function reflect stimulation of D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA autoreceptor function, they may participate in postsynaptically activated short-loop feedback modulation of DA release.

Animals↗
PubMed1998

Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons.

The nucleus accumbens is a forebrain region that mediates cocaine self-administration and withdrawal effects in animal models of cocaine dependence. Considerable evidence suggests an important role of dopamine D1 receptors in these effects. Using a combination of current-clamp recordings in brain slices and whole-cell patch-clamp recordings from freshly dissociated neurons, we found that nucleus accumbens neurons are less excitable in cocaine withdrawn rats because of a novel form of plasticity: reduced whole-cell sodium currents. Three days after discontinuation of repeated cocaine injections, nucleus accumbens neurons recorded in brain slices were less responsive to depolarizing current injections, had higher action potential thresholds, and had lower spike amplitudes. Freshly dissociated nucleus accumbens neurons from cocaine-pretreated rats exhibited diminished sodium current density and a depolarizing shift in the voltage-dependence of sodium channel activation. These effects appear to be related to enhanced basal phosphorylation of sodium channels because of increased transmission through the dopamine D1 receptor/cAMP-dependent protein kinase pathway. The effects of repeated cocaine administration were not mimicked by repeated injections of the local anesthetic lidocaine and were not observed in neurons within the motor cortex, indicating that they did not result from local anesthetic actions of cocaine. Because nucleus accumbens neurons are normally recruited to coordinate response patterns of movement and affect, the decreased excitability during cocaine withdrawal may be related to symptoms such as anergia, anhedonia, and depression.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Strategies for the treatment of cystathionine beta-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years.

Strategies for the treatment of cystathionine beta-synthase (CBS) deficiency include (1) increasing residual enzyme activity by giving pyridoxine in those patients with vitamin responsive variants, (2) reducing the load on the affected pathway with a low methionine diet and supplementing the diet with cysteine; and (3) giving betaine in order to utilise alternative pathways to remove homocyst(e)ine. In our experience of over 30 years in the diagnosis and management of patients with CBS deficiency, a normal outcome can only be achieved in patients diagnosed and treated from infancy. Pyridoxine combined with folic acid prevents further deterioration in pyridoxine responsive patients. Dietary treatment of patients with non-pyridoxine responsive CBS deficiency becomes more difficult outside childhood but since late complications are not uncommon must be continued for life. Betaine can be effective in this group but compliance is often poor.

Adolescent↗
PubMed1998

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization.

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D2 autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D1 receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D1 class receptor agonist SKF 38393, the DA D2 class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D1 receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D1 responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D1 receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Dopamine receptor antagonists fail to prevent induction of cocaine sensitization.

We investigated the ability of dopamine D1 and D2 class receptor antagonists to prevent the induction of behavioral sensitization to cocaine. The D2 receptor antagonist eticlopride failed to prevent the induction of cocaine sensitization. An intermediate dose of the D1 receptor antagonist SCH 23390 (0.1 mg/kg) appeared to prevent the induction of cocaine sensitization when tested after 3 days of withdrawal, but sensitization was clearly evident after 10 days of withdrawal. High doses of SCH 23390 alone produced supersensitivity to the behavioral effects of cocaine and to the inhibitory effects of D1 receptor agonists on nucleus accumbens neurons. Co-administration of eticlopride and SCH 23390 also failed to prevent the induction of cocaine sensitization. SCH 23390, but not eticlopride, prevented the expression of cocaine sensitization. We conclude that dopamine receptors are either not involved in the induction of cocaine sensitization or that redundant mechanisms exist to produce the same neuroadaptations.

Animals↗
PubMed1997

Dopamine enhances glutamate-induced excitation of rat striatal neurons by cooperative activation of D1 and D2 class receptors.

Although dopamine (DA) usually inhibits firing of rat striatal neurons in vivo, iontophoresis of DA with low ejection currents can also potentiate glutamate-evoked activity. We used extracellular single cell recording to examine the DA receptor subtypes involved in such potentiation. At low iontophoretic currents (1-8 nA), both the DA D1 class receptor agonist SKF 38393 and the DA D2 class receptor agonist quinpirole mimicked the ability of DA to facilitate glutamate-induced activity. Acute depletion of DA abolished the excitatory modulation produced by either D1 or D2 agonists but not by DA. Co-administration of SKF 38393 and quinpirole restored the facilitation of glutamate effects in DA-depleted rats. Stimulation of both D1 and D2 class receptors appears to be required for DA to enhance glutamate-induced firing of striatal neurons.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine.

We examined the effect of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, on the development and expression of behavioral sensitization to amphetamine and cocaine in rats. A single injection of NBQX (12.5 mg/kg) administered 30 min prior to cocaine during the induction phase (days 1-5) prevented the development of cocaine sensitization, assessed by responsiveness to cocaine challenge on day 8. This NBQX regimen did not affect development of amphetamine sensitization. Two pretreatment injections of NBQX, one 20 min before and one 70 min after amphetamine on each day of the induction phase (days 1-6), did not affect sensitization of stereotypy but prevented sensitization of post-stereotypy ambulatory hyperactivity (both assessed by responsiveness to amphetamine challenge on day 8). The effect of NBQX on ambulatory sensitization was dose-dependent (attenuation with 12.5 mg/kg, complete prevention with 25 mg/kg). In contrast to its effects on development, NBQX (25 mg/kg) did not prevent expression of sensitization to cocaine or amphetamine. NBQX itself exerted no significant effects on locomotor activity in either drug-naive rats or rats that had received either NBQX or amphetamine repeatedly. These findings support a requirement for AMPA receptor stimulation in the development of locomotor sensitization to cocaine and amphetamine, but suggest a different mechanism for sensitization of amphetamine stereotypy.

Amphetamine↗
PubMed1997

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors.

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.

Amphetamine↗
PubMed1997

Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors.

It is well established that behavioral sensitization to psychomotor stimulants is associated with adaptations in the mesoaccumbens dopamine (DA) system. We showed previously that the responsiveness of ventral tegmental area (VTA) DA neurons to glutamate was significantly enhanced in amphetamine- and cocaine-pretreated rats tested after 3 days of withdrawal, which suggests that adaptations in excitatory amino acid transmission also contribute to sensitization. The purpose of the present study was to determine the subtype of excitatory amino acid receptor responsible for this effect and to examine its persistence during withdrawal. Extracellular single cell recording and microiontophoresis were used to investigate possible alterations in the ability of glutamate agonists [(S)-alpha-amino-3- hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA), and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-t-ACPD)] to stimulate the firing of VTA DA neurons after 3 days of withdrawal from repeated administration of saline, cocaine or amphetamine. Current-response curves showed that responses to iontophoretic AMPA, but not NMDA or 1S,3R-t-ACPD were significantly enhanced in cocaine- or amphetamine-pretreated rats in that neurons entered into a state of apparent depolarization block at significantly lower iontophoretic currents. When rats were tested for responsiveness to iontophoretic glutamate after 14 days of withdrawal, there was no significant difference between cocaine- or amphetamine- and saline-pretreated rats with respect to glutamate current-response curves. These results suggest that increased responsiveness of AMPA receptors on VTA DA neurons may contribute to sensitization at early withdrawal times, but that this alteration, like others described within the VTA, is transient.

Amphetamine↗
PubMed1997

DA D2 receptors in the ventral striatum: multiple effects or receptor subtypes?

This short review summarizes work from the authors' laboratory regarding electrophysiological roles for two members of the dopamine (DA) D2 receptor family, the D2 and D2 receptors, and their interactions with DA D1 receptors, within the ventral striatum. The inhibitory effects of D2 receptor class agonists on ventral striatal neurons appears to be mediated by D2 as opposed to D2 receptors. This effect requires simultaneous stimulation of the D1 (D1A) receptor. The inhibitory effects of D1 class receptor agonists may involve both the D1 receptor as well as a D1-like receptor not linked to adenylyl cyclase. This effect does not require co-stimulation of a D2 class receptor. The ability of DA to enhance the excitatory effects of glutamate on ventral striatal neurons requires stimulation of both D1 and D2 class receptors. Stimulation of D2 class receptors can either increase or decrease whole cell sodium currents; the particular D2 receptor subtypes responsible for these effects have yet to be established.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Comparison of enoxaparin, hirulog, and heparin as adjunctive antithrombotic therapy during thrombolysis with rtPA in the stenosed canine coronary artery.

A canine model of electrolytic injury-induced coronary artery thrombosis and rtPA-induced thrombolysis was used to evaluate the relative antithrombotic efficacy of enoxaparin (a low molecular weight heparin), conventional therapy (heparin or heparin plus aspirin), and hirulog (a direct thrombin inhibitor), when used as adjunctive therapy during thrombolysis. After 60 min of clot aging, adjunctive therapy was begun at doses which elevated APTT approximately 2-fold over baseline. Fifteen minutes after the start of adjunctive therapy, recombinant tissue plasminogen activator (rtPA) was administered (100 microg/kg i.v. bolus + 20 microg/kg/min for 60 min). Adjunctive therapy continued for 1 h after termination of rtPA and blood flow was monitored for two additional hours. Enoxaparin (1 mg/kg i.v. bolus + 30 microg/kg/min, n = 10 for each treatment group) was the only adjunctive treatment that significantly increased the total minutes of flow (143 +/- 25 min out of a possible 240 min, vs 54 +/- 25 min for vehicle, p <0.05) and decreased thrombus mass (6.0 +/- 1.3 mg vs 11.8 +/- 3.2 mg for vehicle). Although hirulog (2 mg/kg i.v. bolus + 40 microg/kg/min) did not significantly increase the minutes of flow (120 +/- 27 min, p <0.06) or decrease thrombus mass (8.7 +/- 1.7 mg) compared to vehicle, these values were not significantly different than those measured in the enoxaparin group. However, the results with hirulog were achieved at the expense of a significantly greater increase in template bleeding time than that measured during enoxaparin treatment. Minutes of flow for heparin (50 U/kg i.v. bolus + 0.6 U/kg/min) and heparin plus aspirin (5 mg/kg i.v. bolus) were 69 +/- 20 and 60 +/- 23 min, respectively; thrombus masses were 8.2 +/- 1.3 and 7.3 +/- 1.0 mg, respectively. In summary, enoxaparin was more effective than conventional therapy in this model in terms of vessel patency and thrombus mass, and was as effective as hirulog, at least at a dose of hirulog that only modestly impaired hemostasis. Therefore, enoxaparin may prove to be a safe and effective alternative agent for adjunctive therapy during thrombolysis with rtPA.

Adenosine Diphosphate↗