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A S Freeman

Publications and source records attributed to A S Freeman.

At least 55 records · Page 3Linked to original sources
PubMed1989

Electrophysiological characteristics and pharmacological responsiveness of midbrain dopaminergic neurons of the aged rat.

The extracellular electrophysiological activities of A9 and A10 dopaminergic (DA) neurons were examined in chloral hydrate-anesthetized young (3 months) and aged (24-28 months) Fischer 344 male rats. Average firing rate, firing rate distribution and the incidence of spontaneous activity (cells per electrode track) did not change in either region as a function of age. Next, the inhibitory effects of several DA agonists on the firing rates of antidromically identified nigrostriatal DA cells were compared in young and old rats. The inhibitory potencies of i.v. apomorphine (D1/D2 agonist), quinpirole (D2 agonist) and d-amphetamine (indirect agonist) did not change with age. Similarly, the inhibitory effects of microiontophoretically applied dopamine were unaltered in aged rats. Stimulation of the sciatic nerve resulted in brief periods of inhibition of the activity of nigrostriatal DA neurons in both the young and the old age groups. The duration of this inhibitory response was, however, enhanced markedly in the old rats. The D1 agonist SKF 38393 enhanced the duration of the inhibitory effect of sciatic nerve stimulation in both young and old rats. These results suggest that, although no gross differences in the activity of DA cells in young and old rats were evident, subtle changes in the regulation of the activity of these neurons may occur with age.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

CI-943, a potential antipsychotic agent. III. Evaluation of effects on dopamine neuronal activity.

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2- c]pyrazolo[3,4-e]pyrimidine) has been identified as a novel potential antipsychotic agent that does not bind to dopamine (DA) receptors. In the present studies, the effects of acute and chronic administration of CI-943 on the electrophysiological activity of A9 and A10 DA neurons were assessed and compared to the effects of DA antagonist antipsychotic drugs. Acute administration of CI-943 did not increase the base-line firing rate (10-20 mg/kg i.p.), did not increase the number of spontaneously active DA neurons (40 mg/kg p.o.) and did not antagonize the effects of apomorphine or amphetamine on A9 or A10 DA neurons (20-40 mg/kg i.p.). A high dose of CI-943 (40 mg/kg i.p.) decreased the firing rate of A9 and A10 DA neurons, an effect that was not antagonized by haloperidol. In contrast, haloperidol increased the base-line firing rate (0.5 mg/kg i.p.), increased the number of spontaneously active DA neurons (0.5 mg/kg p.o.) and antagonized the effects of apomorphine and d-amphetamine on A9 and A10 DA neurons (0.1 mg/kg i.p.). Repeated (21 days) administration of CI-943 (36 mg/kg/day p.o.) did not alter the number of spontaneously active A9 DA neurons but increased the number of active A10 DA neurons. In contrast, repeated administration of haloperidol (0.4 mg/kg/day p.o.) decreased the number of spontaneously active DA neurons in A9 and A10, whereas repeated administration of clozapine (19 mg/kg/day p.o.) decreased the number of active A10 DA neurons but increased the number of active A9 DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1988

Electrophysiological effects of cholecystokinin octapeptide on identified rat nigrostriatal dopaminergic neurons.

Cholecystokinin octapeptide (CCK-8) exists in a subpopulation of midbrain dopaminergic (DA) neurons and has been shown to affect the activity of unidentified DA cells. This study describes the effects of the sulfated (CCK-8S) and unsulfated (CCK-8US) peptides (8 micrograms/kg, i.v.) on the ability of apomorphine to inhibit the firing rate of nigrostriatal DA cells identified by antidromic activation from the caudate nucleus of anesthetized rats. CCK-8S excited 9/25 DA cells while CCK-8US was without effect on firing rate (n = 9). CCK-8S pretreatment resulted in complex changes in the sensitivity of nigrostriatal DA cells to apomorphine which were related to whether an initial excitatory response was elicited by CCK-8S. CCK-8US did not alter apomorphine sensitivity. These results suggest that CCK-8S can exert modulatory effects on DA cells independent of a direct excitatory action. The effect of acute CCK-8 injection on the number of spontaneously active DA cells in stereotaxically defined regions of the substantia nigra and ventral tegmental area was also determined. CCK-8S doubled the number of active cells in these areas; CCK-8US did not alter the population activities.

Animals↗
PubMed1988

SKF 38393 alters the rate-dependent D2-mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons.

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single-unit recording techniques to examine whether SKF 38393 can alter D2-mediated inhibition of DA cell activity. Quinpirole-induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole-induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl-specific, feedback pathway-dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2-mediated inhibition of cell firing rate.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Electrophysiological studies on the specificity of the cholecystokinin antagonist proglumide.

Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A9 DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade.

Action Potentials↗
PubMed1987

Activity of A9 and A10 dopaminergic neurons in unrestrained rats: further characterization and effects of apomorphine and cholecystokinin.

The activity of single dopaminergic (DA) neurons (total n = 77) in the midbrain of awake, unrestrained rats was examined. The firing rates and patterns of ventral tegmental area (A10) cells (n = 39) were similar to those of identified DA neurons in anesthetized and paralyzed rats. Unit activity was briefly stimulated (increased firing rate and burst activity) in response to an auditory stimulus and during manual stimulation of the vibrissae. Similar changes occurred during orienting responses and periods of sniffing. Twenty-six percent of A10 cells recorded appeared to be electronically coupled which matched the prevalence previously observed among A9 neurons. The effects on A9 and A10 DA cell activity of apomorphine and the carboxyterminal octapeptide of cholecystokinin (CCK-8) were then determined. Sequential doses of apomorphine (5-320 micrograms/kg, i.v.) reduced the firing rate of each neuron tested (n = 19). Ten of these cells were classified as 'sensitive' to the drug (ED50 less than 20 micrograms/kg), while the remainder were considerably 'less sensitive' (ED50 greater than 30 micrograms/kg). Cells of either sensitivity were as likely to be found in A9 as in A10. Sulfated CCK-8 (1-16 micrograms/kg, i.v.) excited (firing rate and bursting increased) 73% of the A9 neurons sampled but produced inconsistent effects on A10 cell firing. CCK-8 pretreatment increased the percentage of A9 and A10 neurons which were classified as 'sensitive' to apomorphine (82%). Enhanced sensitivity to apomorphine occurred regardless of the effect of CCK-8 on unit firing. Thus, as has been found in anesthetized rats, CCK-8 appeared to enhance the inhibitory effects of a DA agonist on DA neurons.

Animals↗
PubMed1987

Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response.

The effects of acute administration of phencyclidine, an indirect dopamine agonist, on biochemical indices of dopaminergic activation were examined in mesocortical, mesolimbic and nigrostriatal regions of the rat. High doses (10 mg/kg) of phencyclidine resulted in a marked increase in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in all mesolimbic and mesocortical sites examined, as well as in the ventral tegmental area, source of the dopaminergic innervation of mesolimbic/cortical sites. In contrast, levels of both metabolites decreased in the striatum and tended to decrease in the substantia nigra, source of the striatal dopaminergic innervation. The metabolite response to phencyclidine was dose-related. These data indicate that the mesolimbic and mesocortical dopaminergic neurons are activated by phencyclidine. Since the firing rate of both A10 (ventral tegmental area) and A9 (substantia nigra) dopamine neurons has previously been shown to be increased by phencyclidine, these data suggest that phencyclidine results in a differential regulation of presynaptic release of dopamine in mesolimbic/cortical as opposed to nigrostriatal dopaminergic regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Firing properties of substantia nigra dopaminergic neurons in freely moving rats.

Single unit recordings were obtained from putative dopaminergic neurons in the substantia nigra of awake, freely moving rats. The cells exhibited waveforms, range of firing rates and types of firing patterns identical to those of identified DA neurons of anesthetized or paralyzed rats. Two firing patterns were observed: single spike activity and a bursting mode with spikes of progressively diminished amplitude and increased duration within each burst. The degree of burst firing varied considerably among the cells and individual cells sometimes switched from one pattern of firing (e.g. predominantly single spike) to another (e.g. bursting), although the determinants of these transitions are, at this time, unclear. Putative DA neurons were inhibited by i.v. apomorphine and excited by i.v. haloperidol. Haloperidol also reversed the apomorphine-induced inhibition of firing. Inhibitions and excitations were associated with a reduction and elevation, respectively, in burst firing. The effects of the two drugs were identical to their effects in immobilized rats. In several cases, a putative DA neuron was observed to fire all of its spikes in near coincidence with at least one other cell with identical electrophysiological characteristics. This form of interaction (i.e. presumed electrical coupling) between DA cells is only rarely observed in anesthetized or paralyzed rats and may play a significant role in the normal functioning of the nigrostriatal DA system.

Action Potentials↗
PubMed1985

An electrophysiological analysis of the actions of the 3-PPP enantiomers on the nigrostriatal dopamine system.

Extracellular single unit recording and microiontophoretic studies were carried out in chloral hydrate-anesthetized gallamine-paralyzed rats to investigate the actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, on the nigrostriatal DA system. Intravenously administered (+)- or (-)-3-PPP consistently inhibited nigral DA neuronal activity; these actions were readily antagonized by haloperidol but were not affected by a pretreatment of reserpine plus alpha-methyltyrosine. In contrast to (+)-3-PPP, the (-)-enantiomer produced only partial inhibition of the majority of cells studied and was also capable of partially reversing the inhibitory action of apomorphine. A prior hemitransection of the brain did not alter the inhibitory action of either enantiomer. Whereas iontophoretically ejected (+)-3-PPP consistently reduced DA cell firing rate, similarly applied (-)-3-PPP reduced the activity of only some DA cells, while the majority were not influenced. In addition, iontophoresis of (-)-3-PPP could reduce the inhibitory effect of similarly applied DA or (+)-3-PPP. The (+)-enantiomer reduced caudate neuronal activity both after intravenous administration and iontophoresis. Intravenously administered (-)-3-PPP failed to influence or increased the activity of these neurons and reversed the inhibitory action of apomorphine. However, iontophoretically ejected drug reduced caudate cell activity and did not influence the inhibitory action of DA. The activity of non-DA zona reticulata neurons was inconsistently influenced by the 3-PPP enantiomers. It is concluded that (+)-3-PPP is a directly acting DA agonist, stimulating both DA autoreceptors and postsynaptic DA receptors. In contrast, (-)-3-PPP appears to be a partial agonist at nigral DA autoreceptors, whereas the action of the drug at putative postsynaptic DA receptors in the caudate remains to clarified.

Animals↗
PubMed1984

The effects of phencyclidine and N-allylnormetazocine on midbrain dopamine neuronal activity.

Single unit recording techniques were used to determine the effects of intravenously and microiontophoretically administered phencyclidine (PCP) and the enantiomers of N-allylnormetazocine (SKF-10,047) on the activity of midbrain dopamine (DA) neurons. Intravenous PCP produced a biphasic effect on substantia nigra zona compacta (A9) and ventral tegmental (A10) DA neurons which consisted of excitation followed by inhibition below baseline firing rates as the dose was increased. The high-dose attenuation of firing by PCP, but not the excitatory effects, was antagonized by haloperidol pretreatment. Intravenous (+)- and (-)-SKF-10,047 increased the firing rate of most A9 and A10 DA neurons. In contrast to the intravenous findings, iontophoretic PCP generally exerted only very weak inhibitory actions on neuronal activity, while (+)- and (-)-SKF-10,047 produced no consistent effects. The results suggest that these drugs indirectly influence the activity of DA neurons and that this may be a property shared by drugs classified as sigma receptor agonists.

Animals↗
PubMed1984

Relationship between the development of behavioral tolerance and the biodisposition of phencyclidine in mice.

Mice trained on a differential reinforcement of low rate 10-sec schedule (DRL 10) were treated daily with either IP saline or 10 mg/kg of phencyclidine hydrochloride (PCP). After 21 consecutive days of treatment, dose-effect determinations for PCP were obtained in both groups. Chronic treatment with PCP resulted in approximately 1.5-fold development of tolerance to the PCP-induced reduction of reinforcement rate. Following completion of the dose-effect determinations, the mice were treated for an additional 13 days with either saline or PCP (10 mg/kg, IP). On the fourteenth day, the biodisposition of 3H-PCP-HCl (10 mg/kg, IP) was studied in both groups. The ratio of the brain levels of PCP in the saline-trained animals to that in the PCP-trained animals was 1.3 to 1 which accounted in large part for the development of tolerance. It appears that dispositional factors are involved in the development of tolerance of mice to the disruptive effects of PCP on DRL performance.

Animals↗
PubMed1983

Interactions between phencyclidine and delta 9-tetrahydrocannabinol in mice following smoke exposure.

The behavioral and pharmacological interactions between delta 9-tetrahydrocannabinol (delta 9-THC) and phencyclidine (PCP) were studied following coadministration of the drugs in smoke to mice. While delta 9-THC (25, 50 or 100 mg/cigarette) had little effect on spontaneous motor activity, all doses attenuated the hyperactivity elicited by PCP X HCl (25 and 50 mg/cigarette). delta 9-THC produced a dose-related hypothermia. PCP X HCl (50 mg/cigarette) had no effect on body temperature but enhanced hypothermia when combined with 25 mg of delta 9-THC. delta 9-THC (100 mg/cigarette) had no effect on the biodisposition of 3H-PCP and its pyrolytic product, 3H-phenylcyclohexene (3H-PC), when examined immediately after 3H-PCP X HCl (50 mg/ cigarette) exposure. At 30 min, brain, liver, lung and plasma contained higher concentrations of 3H-PC and fat and plasma contained lower concentrations of 3H-PCP in the mice exposed to both drugs compared to 3H-PCP X HCl alone. It appears, therefore, that delta 9-THC has the potential for altering the behavioral, pharmacological and pharmacokinetic sequelae of PCP abuse.

Adipose Tissue↗
PubMed1983

Disposition of phencyclidine and its pyrolytic products in mice exposed to smoke.

Phencyclidine (PCP) is a drug that is frequently misused by smoking. Recent popularity of PCP abuse by this method probably stems from the fact that smoking allows users to titrate themselves as well as reduce the incidence of adverse reactions. PCP is pyrolyzed at high temperatures to form predominantly 1-phenyl-1-cyclohexene (PC). Piperidine and related products are formed in smaller quantities. Smoke from cigarettes impregnated with PCP contains approximately equimolar concentrations of PCP and PC. It has been shown that PCP and PC are present in the circulation of individuals after they smoke PCP-laden cigarettes. In addition, PCP and PC can be found in plasma as well as in all major organs of mice exposed to smoke from PCP-containing cigarettes. The brain concentrations of PC in mice are comparable to those of PCP immediately after exposure but the PC levels decline somewhat more rapidly. Actually the time course of behavioral activity correlates better with PCP levels than with PC levels. In addition, PC and its major metabolites, as well as piperidine, are considerably less active behaviorally than PCP, which suggests that pyrolysis represents an inactivation process for PCP. However, a total lack of contribution of pyrolysis products to PCP's actions has not been ruled out.

Animals↗
PubMed1982

Pharmacological activity and toxicity of phencyclidine (PCP) and phenylcyclohexene (PC), a pyrolysis product.

Initial acute behavioral studies in mice indicated that phencyclidine (PCP) produced marked motor impairment as measured by the inverted screen technique with an ED50 value of 4.1 muMole/kg (i.v.). Phenylcyclohexene (PC) was considerably less active with an ED50 value of 325 muMole/kg (i.v.). PCP was also shown to be more lethal than PC as acute (24 hr; i.v. injection) LD50 values (muMoles/kg) in males were 57 and 448, and in females were /6 and 425, respectively. A greater acute lethality was also produced by PCP after i.p. and p.o. administration. Subchronic (14-day) exposure (i.p.) to PCP at doses up to approximately 40 percent of the acute LD50 value (123.6 muMole/kg, i.p., daily) was without significant effect on body and organ weights, hematology and clinical chemistry, and humoral and cell-mediated immunity. Higher doses of PCP were not possible because of acute lethality. Subchronic exposure to PC (63.4, 317, and 634.5 muMoles/kg; 4 percent, 20 percent and 40 percent of acute i.p. LD50 value, respectively) produced several marked effects. At the highest dose tested, body weight and thymus weight in both males and females, and liver weight in males were significantly decreased. The spleen weight of males exposed to 317 muMole/kg PC was also significantly decreased. Humoral immunity (production of antibody forming cells) was significantly inhibited in both males and females exposed to PC. In contrast, cell-mediated immunity (development of a delayed-type hypersensitivity response) was only significantly inhibited in females. As PCP has no measurable toxicity under these conditions and PC produced significant effects at relatively high doses, the results suggest that neither chemical is exceptionally toxic following subchronic exposure.

Animals↗
PubMed1981

Quantification of phencyclidine in mainstream smoke and identification of phenylcyclohex-1-ene as pyrolysis product.

Parsley cigarettes containing [3H]phencyclidine were machine smoked, and the mainstream smoke was trapped in glass wool filters. Radioactivity was extracted from these filters with chloroform. The average recoveries of radioactivity were 76, 85, 70, and 69% for cigarettes containing 3, 10, 30, and 50 mg of [3H]phencyclidine hydrochloride, respectively. TLC and GLC-mass spectrometry were employed to identify and quantify compounds in the filter extracts. Approximately one-half of the recovered radioactivity represented a pyrolysis product, phenylcyclohex-1-ene. Formation of this product involved loss of piperidine from phencyclidine. Piperidine, which was not radiolabeled, also may appear in smoke intact. The remainder of the radiolabeled material represented unchanged phencyclidine. Therefore, the percentage of [3H]phencyclidine delivered was approximately 40% of the amount smoked. This result was independent of puff frequency and quantity of phencyclidine hydrochloride smoked over the range tested. The [3H]phencyclidine delivery was compared to the quantities of [3H]-delta 9-tetrahydrocannabinol and [3H]nicotine delivered in mainstream smoke. The recovery of unchanged [3H]-delta 9-tetrahydrocannabinol from placebo marijuana cigarettes injected with a solution containing 3 mg of delta 9-tetrahydrocannabinol was 60%. Tobacco cigarettes injected with [3H]nicotine yielded 70% unchanged nicotine in mainstream smoke.

Cannabis↗
PubMedDate not supplied

Effects of the CCK-A receptor antagonist CR 1409 on the activity of rat midbrain dopamine neurons.

Previous studies have shown that acute intravenous treatment with sulfated cholecystokinin octapeptide (CCK-8S) but not unsulfated CCK-8 increases the number of spontaneously active midbrain dopamine (DA) neurons. This suggested that a peripheral-type (CCK-A) CCK receptor mediates this effect. Proglumide does not discriminate between CCK-A and CCK-B (central-type) receptors. In the present study, rats were treated acutely or repeatedly (14 days) with the selective CCK-A antagonist CR 1409. Repeated treatment with 5 mg/kg (IP) increased the number of spontaneously active DA cells in the A10 (ventral tegmental area) but not the A9 (substantia nigra zona compacta) region, which suggests that these DA populations are differentially affected by prolonged CCK-A receptor blockade. The sensitivity of impulse-regulating DA autoreceptors to the DA agonist quinpirole was not altered by CR 1409.

Action Potentials↗