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F J White

Publications and source records attributed to F J White.

At least 73 records · Page 4Linked to original sources
PubMed1993

Electrophysiological effects of putative autoreceptor-selective dopamine agonists on A10 dopamine neurons.

The dopamine (DA) hypothesis of schizophrenia proposes hyperactivity of the mesocorticolimbic DA system, originating within the A10 DA cells of the ventral tegmental area (VTA), as a pathophysiological mechanism. Thus, reduction of activity in this system, including that produced by putative "autoreceptor-selective" DA agonists, may be of clinical utility. The present studies compared the ability of eight D2 DA receptor agonists to inhibit the firing of rat A10 DA neurons after i.v. administration. Both N-n-propyl-N-phenylethyl-p(3-hydorxyphenyl)ethylamine hydrochloride (RU 24213) and 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]- azepine dihydrochloride (B-HT 920) were potent, high-efficacy agonists which completely inhibited the firing of A10 DA cells. The putative autoreceptor-selective DA agonists 3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-(1)-butyl)-indole hydrochloride (EMD 23,448) and (+)-3-(3-hydroxy-phenyl)-N-n-propylpiperidine [(+)-3-PPP] were considerably weaker than RU 24213 and B-HT 920, but also exhibited "full" efficacy (i.e., they completely suppressed cell firing). The putative autoreceptor agonist preclamol [(-)-3-PPP] and its trans-fused congener (-)-HW 165 were weak partial agonists that failed to completely inhibit A10 DA cells. The new putative autoreceptor agonist N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,3]dimethylopropa namide (SDZ 208-911) was also a weak partial agonist that exhibited partial antagonist effects (reversed inhibition produced by the D2 agonist quinpirole), whereas its structural analog N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2-dimethylopropa namide (SDZ 208-912) was nearly inactive as an agonist, but was an effective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Electrophysiological effects of cocaine in the rat nucleus accumbens: microiontophoretic studies.

The nucleus accumbens (NAc) is intricately involved in maintaining cocaine self-administration. Cocaine inhibits the firing of most NAc cells due to its ability to prevent the reuptake of dopamine (DA) and 5-hydroxytryptamine (5-HT), both of which predominantly inhibit NAc cell discharge in vivo. The present studies investigated the roles of DA and 5-HT in the effects of iontophoretically applied cocaine. Most NAc cells exhibited negative/positive waveforms (Type I cells). These cells were significantly more sensitive to cocaine than Type II cells (positive/negative waveforms), apparently due to differences in the actions of 5-HT. Whereas DA was equipotent at inhibiting Type I and Type II cells, 5-HT inhibited Type I cells but, primarily excited Type II cells. Thus the ability of cocaine to potentiate the effects of both DA and 5-HT resulted in a pronounced inhibition of Type I cells, whereas the 5-HT-mediated excitation of Type II cells appeared to reduce DA-mediated inhibition. Combined administration of selective DA (GBR 12909) and 5-HT (fluoxetine) uptake inhibitors was required to mimic the effects of cocaine on Type I and Type II NAc cells. Acute depletion of DA (86%) produced by alpha-methyl-p-tyrosine (AMPT) significantly reduced the inhibitory effects of cocaine on all NAc cells. Acute depletion of 5-HT (74%) produced by p-chlorophenylalanine (PCPA) significantly reduced the inhibitory effect of cocaine on Type I cells, but it significantly enhanced the inhibition of Type II cells. Simultaneous reduction of DA and 5-HT levels produced a significantly greater reduction of cocaine-induced inhibition of Type I neurons than did AMPT or PCPA alone. These findings are discussed in relation to proposed roles of DA and 5-HT in cocaine self-administration.

Animals↗
PubMed1992

Acute depolarization block of A10 dopamine neurons: interactions of morphine with dopamine antagonists.

Extracellular single-unit recording techniques were used to determine the effects of morphine, administered either systematically (intravenous) or locally (microiontophoresis), on ventral tegmental area (A10) dopamine (DA) neuronal activity in animals pretreated with D1 (SCH 23390) or D2 (pimozide) DA receptor antagonists. In rats pretreated with the D2 antagonist pimozide, A10 DA neurons readily entered a state of apparent depolarization block in response to either i.v. or iontophoretically applied morphine. Whether the inactivation of DA neurons was induced by systemic or local morphine, it was reversed in 22 of 27 cases by iontophoretic administration of the inhibitory amino acid transmitter gamma-aminobutyric acid (GABA), suggesting depolarization block as the underlying mechanism. Pretreatment of rats with the D1 antagonist SCH 23390 did not significantly alter the tendency of A10 DA neurons to enter apparent depolarization block in response to morphine. These data support recent behavioral evidence suggesting that the combination of systemic pimozide and ventral tegmental area morphine can result in depolarization inactivation of the mesoaccumbens DA reward system.

Analysis of Variance↗
PubMed1992

Decreased activity of rat A10 dopamine neurons following withdrawal from repeated cocaine.

Electrophysiological techniques were used to determine the basal activity of A10 dopamine (DA) neurons in the rat ventral tegmental area after a 10-14 day withdrawal from repeated cocaine treatment (10.0 mg/kg i.p. twice daily for 14 days). The number of spontaneously active A10 DA cells was significantly decreased (42%) in the cocaine-treated rats. This decreased activity may underlie the diminished basal levels of synaptic DA within the nucleus accumbens previously reported in cocaine-withdrawn rats and may account for anhedonia, anergia and cocaine craving reported by withdrawn cocaine addicts.

Animals↗
PubMed1992

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Parametric and pharmacological analyses of the enhanced grooming response elicited by the D1 dopamine receptor agonist SKF 38393 in the rat.

The present report investigated several parametric and pharmacological aspects of the enhanced self-grooming behavior of rats following systemic administration of the selective D1 dopamine (DA) receptor agonist SKF 38393. The amount of time that rats spent grooming themselves was measured continuously for 30 min following drug administration to provide a quantitative measure of the drug-induced behavior. SKF 38393 increased the amount of grooming in a dose-dependent manner (0.5-16 mg/kg, SC). The onset of this effect required at least 5 min and it persisted for at least 60 min. The ability of SKF 38393 to enhance grooming was shared by R-SKF 38393, but not S-SKF 38393, consistent with the affinities of these enantiomers for the D1 DA receptor. Unlike SKF 38393, the peripheral D1 agonist fenoldopam (SKF82526) failed to cause an increased grooming response, suggesting a central site of action for elicitation of this behavior. The SKF 38393-induced increase in grooming was competitively antagonized by the D1 selective antagonist SCH 23390 (0.5 mg/kg, SC). Although the D2 DA receptor-selective antagonist eticlopride reduced SKF 38393-elicited grooming, this antagonism appeared to be of a physiological rather than pharmacological nature. When eticlopride was coadministered with the non-selective (mixed) D1/D2 agonist apomorphine, an increase in grooming behavior similar to that produced by SKF 38393 was observed. Inactivation of D1 and D2 DA receptors produced by pretreatment with the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), at a dose which reduces D1 and D2 receptor density by > or = 50% (8.0 mg/kg, IP), reduced SKF 38393-induced grooming by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Repeated stimulation of D1 dopamine receptors causes time-dependent alterations in the sensitivity of both D1 and D2 dopamine receptors within the rat striatum.

Recent evidence suggests that repeated stimulation of D1 dopamine receptors within the rat striatum leads to an enhancement of both D1 and D2 dopamine receptor-mediated responses. The present study used both behavioral observations and extracellular single unit recording techniques to investigate this phenomenon following repeated administration of selective D1 dopamine receptor agonists. Groups of rats received twice daily administration of either saline or the partial D1 dopamine receptor agonist SKF 38393 (8 mg/kg, s.c.) for three weeks. Rats were tolerant to the ability of SKF 38393 to enhance grooming behavior when tested immediately following the last of the 42 treatment injections. However, the ability of this last SKF 38393 injection to potentiate oral stereotyped behavior following administration of the D2 DA agonist quinpirole was still evident. Following a one-day withdrawal, grooming responses to SKF 38393 had returned to normal. At this time, administration of quinpirole, without concomitant SKF 38393, failed to significantly promote oral stereotypies, as is typical of normal rats. Following a one-week withdrawal period, SKF 38393-induced grooming behavior was significantly enhanced and quinpirole, administered without SKF 38393, produced pronounced oral stereotyped behavior in 10 of 12 rats tested. Following a one-month withdrawal, these sensitized responses were no longer evident. Single-cell recordings from rat lateral striatal neurons revealed similar time-dependent alterations in the effects of iontophoretically administered SKF 38393 and quinpirole. Current-response curves revealed that, without a withdrawal period, striatal neurons were subsensitive to the inhibitory effects of SKF 38393 but not quinpirole. The decreased inhibitory responses of striatal neurons to SKF 38393 returned to normal levels after a one-day withdrawal. Following a one-week withdrawal, the effects of both agonists were significantly greater than that in saline-treated controls. Normosensitivity was evident following a one-month withdrawal. Repeated administration of the full D1 DA agonist SKF 81297 (0.5 mg/kg, s.c., twice daily) also resulted in sensitized responses of striatal neurons following a one-week withdrawal, demonstrating that the sensitization to SKF 38393 was not due to its partial agonist character. The present findings provide both behavioral and electrophysiological evidence that repeated stimulation of D1 dopamine receptors results in a brief subsensitivity, followed by transient sensitization of the D1 receptors. The enhanced effects of D2 dopamine agonists might be due to an enhanced synergism (enabling) produced by endogenous dopamine stimulating supersensitive D1 receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Relationship between D1 dopamine receptors, adenylate cyclase, and the electrophysiological responses of rat nucleus accumbens neurons.

The electrophysiological effects of three selective D1 dopamine (DA) receptor agonists, which exhibit different potencies and efficacies for stimulation of adenylate cyclase, were compared in the rat nucleus accumbens (NAc) using single unit recording and microiontophoretic techniques. The partial agonists SKF75670 and SKF38393, and the full agonist SKF81297 produced nearly identical current-response curves for the inhibition of firing of NAc neurons. In rats acutely depleted of DA by alpha-methyl-p-tyrosine (AMPT) pretreatment, all three D1 agonists enabled the inhibition of firing produced by the selective D2 receptor agonist quinpirole, with SKF38393 exerting the greatest efficacy, followed by SKF81297 and SKF75670. Thus, no apparent relationship was found between the previously reported ability of these compounds to stimulate cyclic adenosine monophosphate (cAMP) production and their ability either to inhibit the firing of NAc neurons or to enable quinpirole-mediated inhibition of firing in DA-depleted rats. In addition, the membrane-permeable cAMP analog 8-bromo-cAMP also caused a current-dependent inhibition of the firing of NAc neurons, but failed to enable quinpirole-mediated inhibition in AMPT-pretreated animals. These results suggest either that only a small percentage of D1 receptors need to be stimulated to produce these electrophysiological effects, or that D1 receptors exist within the rat NAc which are linked to transduction mechanisms other than, or in addition to, adenylate cyclase.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens.

The rewarding effects of cocaine are mediated primarily by the mesoaccumbens dopamine (DA) system, which projects from A10 DA cell bodies within the ventral tegmental area to the nucleus accumbens (NAc). This pathway is also intricately involved in the locomotor stimulating effect of cocaine and the progressive increases (sensitization) in this behavior observed after repeated administration of cocaine and other psychomotor stimulants. By using single-cell electrophysiological recording and microiontophoretic techniques, we demonstrated previously that repeated cocaine administration (10 mg/kg i.p., twice daily, 14 days) renders impulse-regulating somatodendritic A10 DA autoreceptors subsensitive, thereby increasing impulse flow within the mesoaccumbens DA system. In striking contrast, inhibitory responses of NAc neurons to iontophoretic DA were significantly increased in cocaine-treated rats tested 16 to 24 hr after the last cocaine injection. In the present study, iontophoretic application of selective D1 (SKF 38393) and D2 (quinpirole) DA receptor agonists was utilized to determine the extent to which each of these DA receptor subtypes is altered by repeated cocaine administration. After 2 weeks of twice daily cocaine (10 mg/kg i.p.) injections, significant increases in the inhibitory responses of NAc neurons to SKF 38393, but not quinpirole, were observed. In addition, this D1 receptor sensitization was still evident when animals were tested either 7 days or 1 month after the final cocaine injection. After 2 months of withdrawal from cocaine treatment, D1 receptor sensitivity in the NAc had returned to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

A10 somatodendritic dopamine autoreceptor sensitivity following withdrawal from repeated cocaine treatment.

The mesoaccumbens dopamine (DA) pathway is known to be involved in both the rewarding properties of cocaine and in behavioral sensitization to its locomotor-stimulating effects. We investigated changes in DA neurons in this pathway following withdrawal from repeated cocaine treatment. Rats were injected with 10 mg/kg cocaine or 1 ml/kg saline twice daily for 14 days. One day, 4 days and 8 days after treatment, inhibition of cell firing by the DA agonist apomorphine was measured in DA neurons using in vivo single cell recording techniques. As previously reported, the somatodendritic autoreceptor appeared subsensitive one day after treatment. This autoreceptor subsensitivity persisted four days, but not eight days, after treatment. Although not a persistent alteration, autoreceptor subsensitivity may be necessary to trigger other permanent changes involved in behavioral sensitization.

Animals↗
PubMed1990

Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation.

Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine.

Animals↗
PubMed1989

Dopamine agonists at repeated "autoreceptor-selective" doses: effects upon the sensitivity of A10 dopamine autoreceptors.

Previous reports have established the ability of dopamine (DA) agonists to stimulate inhibitory DA autoreceptors at doses which minimally stimulate postsynaptic DA receptors, suggesting that hyperactive DA transmission may be controlled clinically by treatment with DA agonists. Little is known, however, about the possible loss of autoreceptor sensitivity that may occur after repeated treatment with low doses of DA agonists. Extracellular single cell recording and microiontophoretic techniques were used to measure the sensitivity of impulse-regulating DA autoreceptors on A10 DA cells in the ventral tegmental area (VTA) of chloral hydrate-anesthetized rats pretreated for seven days with repeated subcutaneous (s.c.) doses of the DA agonist apomorphine (APO). The ability of intravenous (i.v.) administration of the potent D2 DA agonist quinpirole (QUIN) to inhibit the firing of A10 cells was not attenuated in rats pretreated with repeated low doses (2 x 50 micrograms/kg/day, s.c.) of APO for 7 days, although higher doses (2 x 250 or 500 micrograms/kg/day) did cause subsensitive responses to QUIN. In rats pretreated with repeated low doses of APO, microiontophoretic application of DA on A10 cells revealed somewhat subsensitive responses. However, ibotenic acid lesions of postsynaptic cells in the nucleus accumbens (NAc) prior to initiation of APO treatment (2 x 50 micrograms/kg/day) did not alter the response of A10 cells to systemic QUIN, contradicting the possibility that the feedback projection from the NAc to the VTA was compensating for autoreceptor down-regulation during systemic challenge with QUIN. In contrast, administration of the irreversible DA antagonist EEDQ (2 mg/kg, i.p.) to control and APO-treated rats (2 x 50 micrograms/kg/day) 24 hr prior to recording did reveal a difference in A10 cell sensitivity to systemic QUIN and to microiontophoretic DA between the two groups, suggesting that "spare" DA autoreceptors may have concealed the down-regulation of autoreceptors induced by repeated low doses of APO. Challenge of A10 DA cells with the partial DA autoreceptor agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)3-PPP], for which an autoreceptor reserve should not exist, produced slightly attenuated responses in APO-treated rats (2 x 50 micrograms/kg/day). These findings provide evidence for the existence of spare somatodendritic DA autoreceptors on A10 DA cells with respect to potent DA agonists, suggesting that repeated administration of "autoreceptor-selective" doses of DA agonists may not result in a diminished inhibition of DA neuronal activity.

Action Potentials↗
PubMed1989

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems.

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.

Animals↗