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W L Woolverton

Publications and source records attributed to W L Woolverton.

At least 109 records · Page 6Linked to original sources
PubMed1988

Multiple dopamine receptors and the behavioral effects of cocaine.

Cocaine has a number of behavioral effects that are typical of psychomotor stimulants and likely involve DA mechanisms in the brain. These effects include, but are not limited to, reinforcing effects, discriminative stimulus effects, locomotor effects, effects on food intake, and effects on schedule-controlled behavior. The available data suggest that D-2 receptors are involved in the reinforcing effects of cocaine, although the jury is still out concerning the role of D-1 receptors. NE receptors apparently do not play a major role in this effect. The role of D-2 receptors in the discriminative stimulus effects is unclear because of partial substitution and partial blockade effects with D-2 agonists and antagonists, respectively. Data with D-1 agonists and antagonists suggest that D-1 receptors may play a necessary-but-not-sufficient role in the discriminative stimulus effects of cocaine. Moreover, results in several species suggest that NE may be important in this effect of cocaine. Very little data currently exist concerning the role of DA receptor subtypes in the other behavioral effects of cocaine. However, data with d-amphetamine suggest that D-1 as well as D-2 receptors should be investigated. In addition, there is evidence to suggest that NE is involved in some of cocaine's effects as well, an action that should be considered further. So, what mediates the behavioral effects of cocaine? Clearly, the answer is not a simple one, basically because the CNS pharmacology of cocaine is complex. In addition to the effects we have concentrated on, cocaine has effects on other neurotransmitters and local anesthetic effects that must be considered. It is impossible to say that any one pharmacological effect of cocaine mediates its behavioral effects, indeed even that it mediates any one behavioral effect. In fact, the word "mediates" is surely virtually meaningless in the context of the CNS. Perhaps the best that can be said about the role of DA receptors in the reinforcing effects of cocaine is they are likely a link in a chain of events that ultimately results in the sensations produced by cocaine. Surely numerous other, perhaps more critical, links remain to be discovered. It is an exciting time to be doing research with cocaine.

Brain Chemistry↗
PubMed1987

Evaluation of the role of norepinephrine in the reinforcing effects of psychomotor stimulants in rhesus monkeys.

Rhesus monkeys were surgically prepared with intravenous catheters and allowed to self-administer cocaine (0.03-0.1 mg/kg/injection) under a fixed-ratio 10 schedule of drug delivery during daily 2-hour experimental sessions. When responding was stable for cocaine, saline or various doses of nisoxetine, a selective norepinephrine (NE) reuptake blocker, was substituted for cocaine for 5-7 consecutive sessions. Nisoxetine failed to maintain self-administration responding at any dose in 3 of 4 monkeys tested. Pre-session administration of the selective alpha 1 NE receptor blocker prazosin (0.2-1.6 mg/kg, IV, 15 minutes pre-session) did not systematically alter cocaine self-administration in any monkey. The results are in contrast to what has been found with DA agonists and antagonists and are consistent with the belief that NE does not play a primary role in the reinforcing properties of psychomotor stimulants.

Animals↗
PubMed1987

Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.

(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions examined. The highest dose also reduced norepinephrine and/or dopamine in some regions. The 20-mg/kg dose of MDMA depleted 5-HT in all regions of the guinea pig brain assayed. In both species, repeated administration of 20 mg/kg of MDMA reduced the Vmax but not the Km of 5-HT uptake 2 weeks after administration. A single 40-mg/kg injection of MDMA depleted 5-HT 2 and 8 weeks after administration to rats in all regions of the brain examined except the hypothalamus. Administration of 80 mg/kg of MDMA twice a day for 2 days to rats depleted striatal 5-HT and dopamine. Brain sections from rats injected with MDMA according to this dosage regimen were stained by the Fink-Heimer method. Degenerating axon terminals and cell bodies were observed in the striatum and somatosensory cortex, respectively. These findings suggest that MDMA is toxic to serotonergic and, to a lesser extent, catecholaminergic neurons. Some neurons that do not contain these transmitters (neocortical neurons) are also affected.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Discriminative stimulus properties of D1 and D2 dopamine agonists in rats.

Rats were trained to discriminate 8.0 mg/kg of SKF 38393 (SKF) or 1.0 mg/kg of piribedil (PIR) from saline. Drugs were given 10 min before each session in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. SKF (2.0-8.0 mg/kg i.p.) produced a dose-related increase in drug-appropriate responding in the SKF group but not in the PIR group. PIR (0.06-1.0 mg/kg i.p.) produced a dose-related increase in drug-appropriate responding in the PIR group but not in the SKF group. Apomorphine (0.03-0.5 mg/kg i.p. also produced a dose-related increase in PIR-appropriate responding, whereas dopamine (DA; 4.0-16 mg/kg i.p.), which does not readily cross the blood-brain barrier, did not. When pretreatment time was varied, SKF-appropriate responding was maximal when 8.0 mg/kg of SKF was injected 30 min before the session. PIR (1.0 mg/kg i.p.) occasioned maximal PIR-appropriate responding when injected 1 or 10 min before the session but did not when injected 30 or 60 min before the session. In rats trained to discriminate SKF (8.0 mg/kg) using a 30-min pretreatment time, the D1 antagonist SCH 23390 blocked the SKF discriminative stimulus (DS) but did not alter the PIR DS in PIR-trained rats. The D2 antagonist pimozide blocked the PIR DS but did not alter the SKF DS. Thus, the DS properties of D1 and D2 agonists are functionally distinct in rats and are antagonized by DA antagonists selective for D1 or D2 receptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Pharmacological analysis of the apomorphine discriminative stimulus in rhesus monkeys.

Four rhesus monkeys were trained to discriminate apomorphine (APO) from saline in a two lever, food-reinforced drug discrimination paradigm. After acquisition of the discrimination (average = 161 sessions), they were tested with a series of compounds selected to characterize the neuronal mechanism(s) of the discrimination and to determine whether the site of action was central or peripheral. APO produced a dose-related increase in the percentage of responses that occurred on the drug lever during test sessions. The D2 dopamine (DA) agonist piribedil substituted completely for APO and the D2 DA antagonist pimozide antagonized the APO discriminative stimulus in a manner consistent with a competitive antagonism. On the other hand, the D1 agonist SKF 38393 engendered principally saline lever responding in all monkeys, whereas the D1 DA antagonist SCH 23390 was ineffective as an APO antagonist. The APO effect was neither mimicked by DA nor blocked by the D2DA antagonist domperidone, both of which fail to cross the blood-brain barrier to any significant extent. In substitution tests the norepinephrine reuptake blocker nisoxetine, the serotonin agonist quipazine and the cholinesterase inhibitor physostigmine, as well as d-amphetamine, cocaine and morphine engendered principally saline lever responding up to doses that substantially reduced rate of responding. Taken together these results suggest that the APO discriminative stimulus is based principally upon an action at a D2 receptor in the central nervous system and that this preparation can be used for studying the functional properties of central nervous system D2 receptors.

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

Anorectics: effects on food intake and self-administration in rhesus monkeys.

The effects of the anorectics benzphetamine, chlorphentermine, clortermine, mazindol, phendimetrazine, and phenmetrazine on food intake were compared to the effects of d-amphetamine in rhesus monkeys given daily access to food pellets. The ability of these compounds to maintain intravenous self-administration under a fixed-ratio 10 schedule was also determined in rhesus monkeys. All drugs reduced food intake in a dose-related manner. d-Amphetamine was the most potent. Mazindol, chlorphentermine, phenmetrazine, and phendimetrazine were approximately 1/5 to 1/9 as potent as d-amphetamine while benzphetamine and clortermine were 1/14 and 1/20 as potent, respectively. Benzphetamine, mazindol, and phenmetrazine were self-administered above saline levels and were approximately equipotent. Chlorphentermine and clortermine were not self-administered and phendimetrazine was self-administered by only one of four monkeys at one dose. Thus, although all of the compounds were effective anorectics, chlorphentermine, clortermine, and phendimetrazine did not function as positive reinforcers. Since the ability of a drug to function as a positive reinforcer is related to its dependence potential, these three compounds might be less subject to abuse when used therapeutically. Within the group of 3 compounds that was self-administered, benzphetamine was relatively more potent as a positive reinforcer than as an anorectic. Therefore, this drug might be a less desirable compound for therapeutic use.

Animals↗
PubMed1986

Effects of central dopamine depletion on the d-amphetamine discriminative stimulus in rats.

The discriminative stimulus properties of d-amphetamine, cocaine, and apomorphine were assessed in rats trained in a two-lever, food-reinforced drug discrimination paradigm to discriminate 1.0 mg/kg d-amphetamine from saline. After determination of these dose-response relationships, the rats were divided into two groups. One group (6-OHDA) was given injections of desmethylimipramine (DMI, 30 mg/kg, IP) and 6-hydroxydopamine (6-OHDA, 100 micrograms/10 microliters each ventricle), while the other group (sham) was given the same dose of DMI and 6-OHDA vehicle (intraventricularly). Beginning approximately 45 days after intraventricular injections, dose-response relationships were redetermined for all three drugs. Larger doses of d-amphetamine were required to elicit the same response in the 6-OHDA group (i.e. the dose-response relationship was shifted to the right), while no change was observed in the sham group. Any changes in the dose-response relationships for cocaine and apomorphine were comparable in the 6-OHDA and sham group. The rate-decreasing effects were not altered in either group for any of the drugs. Upon sacrifice, dopamine (DA) was found to be significantly depleted in the accumbens, caudate and rest of brain of the 6-OHDA group. Levels of norepinephrine and serotonin were unaltered. These data suggest that central DA-containing neurons play a role in the discriminative stimulus properties of psychomotor stimulants in rats.

Animals↗
PubMed1986

Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys.

Rhesus monkeys were surgically prepared with chronic intravenous catheters and allowed to self-administer the indirect dopamine (DA) agonist cocaine (0.03 or 0.1 mg/kg/inj) or the direct D2 agonist piribedil (0.1 or 0.2 mg/kg/inj) on a fixed-ratio 10 schedule of drug delivery during daily 2 hour experimental sessions. When responding was stable, they were injected IV with SCH 23390, a selective D1 antagonist (0.003-0.3 mg/kg, 30 min pre-session) or pimozide, a selective D2 antagonist (0.003-0.3 mg/kg, 2 hours pre-session). Intermediate doses of pimozide generally increased self-administration of cocaine or piribedil, though increases in piribedil self-administration were more reliable. In contrast, intermediate doses of SCH 23390 either did not affect or decreased cocaine and piribedil self-administration. High doses of each antagonist decreased the rate of self-administration of each compound and produced catalepsy. The selective increase in responding maintained by cocaine or piribedil following pimozide pretreatment suggests a role for a D2-like receptor in psychomotor stimulant self-administration.

Animals↗
PubMed1986

A review of the effects of repeated administration of selected phenylethylamines.

Several phenylethylamines are under consideration for international control. The effects of repeated administration of these compounds, including tolerance, physical dependence and central nervous system (CNS) toxicity, are reviewed here. The compounds can be divided into two major chemical groups: those with substituents on the ethylamine portion of the molecule and those with substituents on the phenyl ring. Although the effects of repeated administration have not been directly determined for most of the compounds, certain representative compounds of each chemical group have been examined in some detail. Prominent among the effects of repeated administration are CNS toxicity and tolerance development. Physical dependence has not been reported for any of these compounds. Future research with these compounds should emphasize the investigation of the CNS toxicity and the functional consequences of such effects for the organism.

3,4-Methylenedioxyamphetamine↗
PubMed1986

The effects of (+/-)-methylenedioxymethamphetamine and (+/-)-methylenedioxyamphetamine in monkeys trained to discriminate (+)-amphetamine from saline.

Recently, attention has been focused on (+/-)-methylenedioxymethamphetamine (MDMA), a psychotomimetic agent chemically closely related to the psychomotor stimulant methamphetamine, and also to the hallucinogen mescaline. In the present experiment, the effects of MDMA and (+/-)-3,4-methylenedioxyamphetamine (MDA) were determined in rhesus monkeys that were trained to discriminate intravenously administered (+)-amphetamine (AMPH) from saline in a two-lever, food-maintained paradigm or to discriminate intragastrically administered AMPH from saline in a signalled electric shock avoidance paradigm. MDMA produced 100% drug-appropriate responding in all six monkeys, regardless of the procedure and route of administration while MDA substituted completely for AMPH in only two of three monkeys in each paradigm. The results suggest that MDMA has subjective effects that are similar to those of AMPH while MDA is somewhat less like AMPH.

3,4-Methylenedioxyamphetamine↗
PubMed1986

Behavioral and neurochemical evaluation of phenylpropanolamine.

(+/-)-Phenylpropanolamine (PPA), a widely available anorectic and decongestant, was evaluated in several behavioral paradigms in rhesus monkeys and for central nervous system neurotoxicity in rats. PPA (1-30 mg/kg intragastric) reduced food intake in rhesus monkeys but was not self-administered i.v. (0.3-10 mg/kg/injection) by monkeys experienced in drug self-administration. PPA (30-100 mg/kg intragastric) resulted in amphetamine-like responding in two of four monkeys trained in a drug discrimination paradigm to discriminate d-amphetamine from saline. In rats, a 4-day injection regimen of high doses of PPA (200 and 400 mg/kg/day) resulted in approximately a 20% depletion of dopamine in the frontal cortex but failed to deplete dopamine, norepinephrine or serotonin in any other brain region studied. Thus, PPA is an effective anorectic in rhesus monkeys that, based upon drug discrimination results, would be expected to have limited amphetamine-like subjective effects and only at doses well in excess of effective anorectic doses. However, based upon self-administration results, PPA would not be predicted to have amphetamine-like dependence potential. Moreover, repeated administration of PPA did not produce the severe central nervous system neurotoxicity associated with many other amphetamine congeners.

Animals↗
PubMed1985

The D1 dopamine agonist SKF 38393 functions as a discriminative stimulus in rats.

Rats (N = 11) were trained to discriminate SKF 38393 (8.0 mg/kg, IP), a D1 dopamine receptor agonist, from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. The discrimination was acquired by nine rats within an average of 77 +/- 6 (SEM) sessions. Subsequently, various doses of SKF 38393 as well as SKF 82526, a potent, selective D1 agonist that does not readily penetrate the blood-brain barrier, were injected prior to test sessions. SKF 38393 (2-16 mg/kg) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. On the other hand, SKF 82526 (0.125 and 1.0 mg/kg) induced no drug-appropriate responding. This experiment establishes that SKF 38393 can serve as a discriminative stimulus in rats. Furthermore, the observation that SKF 82526 did not substitute for SKF 38393 in this paradigm makes it unlikely that this effect involves a peripheral site of action. The results suggest the existence of a functional, behaviorally relevant D1 dopamine receptor in the CNS of rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline.

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

Effects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys.

The effects of prolonged exposure to high doses of stimulants on stimulant self-administration in rhesus monkeys have not been established. In the present experiment, rates of methamphetamine self-administration as well as the effects of methamphetamine on food-maintained responding were determined before and after a regimen of repeated methamphetamine injections. Increases in self-administration of some doses of methamphetamine as well as tolerance to the rate-decreasing effects of the drug on food-maintained responding were observed following the repeated injection regimen. The results suggest that while tolerance may develop to the rate-decreasing effects of the drug, there may be an increased sensitivity to its reinforcing properties. In addition, since this injection regimen has been shown in previous studies to deplete central monoamines, especially dopamine, the results suggest a role for these monoamines in these behavioral effects of methamphetamine.

Animals↗
PubMed1984

Preference in rhesus monkeys given a choice between cocaine and d,l-cathinone.

Previous experiments have shown that both cocaine and d,l-cathinone can function as positive reinforces when delivered intravenously to rhesus monkeys. However, the relative reinforcing efficacies of these compounds have not been established. In the present experiment, three rhesus monkeys were allowed to choose between saline and several doses of d,l-cathinone or cocaine as well as between several doses of both drugs in a discrete-trial choice procedure. Sufficient doses (.05 to .2 mg/kg/injection) of either drug maintained self-administration and the higher doses were reliably preferred to saline. Doses of d,l-cathinone that were preferred to saline were then compared to a range of cocaine doses in drug-drug choice. As the dose of d,l-cathinone that was available was increased, an increase in cocaine dose was necessary to maintain cocaine preference. Comparison of drug-drug choice data to dose combinations predicted to be chosen with equal frequency revealed that the reinforcing efficacy of d,l-cathinone was equivalent to that of cocaine.

Alkaloids↗
PubMed1984

Intravenous self-administration of dopamine receptor agonists by rhesus monkeys.

Pharmacological studies have provided important information relevant to the behavioral role of central nervous system (CNS) dopamine (DA) as well as the existence of multiple DA receptors in the CNS. In the present experiment, the i.v. self-administration of several compounds that are direct DA receptor agonists was evaluated in rhesus monkeys. Apomorphine, piribedil, propylbutyldopamine and bromocriptine were self-administered by at least half of the animals tested, whereas SKF 38393 failed to maintain self-administration. Each of the compounds that was self-administered is an agonist at the DA2 receptor that has been demonstrated in the periphery, whereas SKF 38393 is principally a DA1 agonist. The results suggest that a DA receptor that is similar to the DA2 receptor is involved in this behavioral effect. In addition, the results are consistent with the hypothesis that CNS DA is involved in the reinforcing properties of psychomotor stimulants.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

Behavioral dependence produced by continuous phencyclidine infusion in rhesus monkeys.

The effects of continuous i.v. phencyclidine (PCP) infusion and withdrawal on operant behavior were studied in rhesus monkeys. The monkeys were trained to lever press under a fixed-ratio 100 schedule of food presentation. They responded under this schedule during four daily 30-min periods conducted every 6 hr. After at least 5 days of continuous saline infusion through indwelling i.v. catheters, the subjects received 10 days of continuous infusion of 0.05 mg/kg/hr of PCP. During chronic PCP, rates of responding increased above saline control values. When saline was substituted for PCP, responding was suppressed markedly. This suppression of responding occurred within 8 hr of saline substitution and lasted several days. Mild signs of withdrawal were seen within 3 hr after saline substitution and dissipated by 48 hr. These signs included muscle tremors, oculomotor hyperactivity and increased aggressiveness. After responding during saline infusion had returned to control levels, continuous PCP infusion was resumed. Withdrawal effects on behavior decreased in intensity after repeated withdrawals and it was necessary to raise the infusion dose to produce consistent withdrawal disruption of behavior. Withdrawal-induced disruption in responding was reversed by acute pretreatment with PCP (0.01-0.3 mg/kg i.m.) in a dose-related fashion. Presession administration of naloxone (0.1-1.0 mg/kg i.m.) during chronic PCP infusion failed to precipitate withdrawal signs or disrupt operant responding, suggesting that PCP dependence is not of the opioid type. The results of this study indicate that operant behavior is disrupted during withdrawal from chronic PCP and can be used as evidence of behavioral dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗