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W L Woolverton

Publications and source records attributed to W L Woolverton.

At least 19 recordsLinked to original sources
PubMed1992

Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey.

In order to determine if repeated injections of cocaine produced long-lasting alterations in catecholaminergic binding sites, rhesus monkeys were treated with saline (1.0 ml/15 kg) or cocaine (3.0-4.0 mg/kg) four times daily for 14 consecutive days and sacrificed two weeks after the last injection. The densities of dopamine D1 receptor binding sites, dopamine transporter binding sites and beta adrenergic receptor binding sites were significantly decreased in caudate nucleus to 51%, 17% and 61% of control, respectively, two weeks after repeated cocaine injections. There were no differences in D2 receptor binding site densities in the caudate, nor were there differences in binding sites between groups in the other brain regions examined: prefrontal cortex (D1, D2, dopamine transporter, beta), nucleus accumbens (D1, D2, dopamine transporter) and substantia nigra (D2). Behavioral observation showed that the cocaine-treated monkeys became sensitized to the repeated injections. Early in the regimen, these animals displayed stereotypic grooming, buccal movements and visual checking after each injection that differed significantly from the saline-treated animals. As the regimen progressed, the frequency of grooming decreased while the frequencies of visual tracking and splayed legs increased in a manner consistent with the development of behavioral sensitization. Together, these findings suggest that the caudate nucleus may be more sensitive than other dopamine-containing brain regions to long-lasting pre- and post-synaptic effects of repeated cocaine administration, and that the changes seen in dopaminergic neurons may be related to behavioral sensitization.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Determinants of cocaine self-administration by laboratory animals.

The reinforcing effect of a drug is that effect that increases the probability that the drug will be self-administered again. Like other drug effects, a reinforcing effect is the result of an interaction between organism, drug and environment. Laboratory research using animal subjects has helped elucidate the contribution of each of these factors to the self-administration of cocaine. A substantial amount of research indicates that increased dopamine neurotransmission in the brain, particularly in mesolimbic and mesocortical regions, plays a major role in cocaine self-administration. Both indirect and direct dopamine agonists can function as positive reinforcers in animals, whereas noradrenergic and serotonergic (5-HT, 5-hydroxytryptamine) agonists have not been found to do so. In addition, evidence suggests that dopamine but not noradrenaline (norepinephrine) or serotonin antagonists can attenuate the reinforcing effect of cocaine. Environmental factors have also been shown to be critical determinants of the reinforcing effect of cocaine. The schedule of reinforcement essentially determines the rate and pattern of drug-maintained behaviour. In addition, punishing self-administration, increasing the value of alternative reinforcers that are available, and increasing the cost of cocaine have all been shown to decrease the reinforcing effect of cocaine. With regard to organismic factors, recent research has suggested that there are significant genetic determinants of cocaine consumption. Taken together these research findings in animals imply that certain individuals may be more sensitive to the reinforcing effect of cocaine but that cocaine abuse can be decreased by pharmacological or behavioural means or by a combination of the two.

Animals↗
PubMed1992

Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys.

Rhesus monkeys were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.01-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When each reinforcer was available under a fixed-ratio (FR) 30 schedule, the frequency of cocaine choice and the total drug intake increased in a dose-related manner for all monkeys. When the FR for cocaine was differentially increased, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right and/or downward. When the FR for cocaine was at least 480, cocaine preference could not be recovered up to doses of 1.0 mg/kg/injection. In a second experiment, when the response requirement for food was differentially increased, the frequency of cocaine choice increased. These results demonstrate that altering the response requirement for cocaine or for alternative reinforcers that are available can substantially affect cocaine self-administration.

Animals↗
PubMed1992

Effects of chronic SCH 23390 or acute EEDQ on the discriminative stimulus effects of SKF 38393.

Three groups of rats (n = 8/group) were trained in a two-lever, food-reinforced drug discrimination paradigm to discriminate the D1 agonist SKF 38393 (SKF; 8.0 mg/kg, IP) from saline. After acquisition of the discrimination, the dose-response function for SKF (2.0-16 mg/kg, IP) was determined using a cumulative dosing procedure. In one group, the SKF dose-response function was redetermined 1 week after a regimen of 0.25 mg/kg of the D1 antagonist SCH 23390 (SCH), IP, once/day for 10 days, again 1 week after a second regimen of 0.5 mg/kg SCH, IP, twice/day for 10 days, and a third time after a regimen of 1.0 mg/kg SCH, IP, twice/day for 21 days. SKF dose-response functions were redetermined in a group of control rats after identical injection regimens of saline. In the third group of rats, SKF dose-response functions were redetermined 24 h after an injection of N-ethoxycarboxyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (irreversible antagonist) vehicle; again 24 h after an injection of 3.0 mg/kg; again 48 h after 6.0 mg/kg EEDQ; and finally 48 h after two consecutive daily injections of 6.0 mg/kg EEDQ (12 mg/kg total). The dose-response function for the percentage of responses that occurred on the SKF lever (%DL) shifted significantly to the left following the second regimen of SCH; there was no further shift after the third regimen. The effects of SKF on response rate were unchanged by SCH administration. Repeated administration of saline did not alter the SKF dose-response function for %DL or response rate.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Evaluation of the discriminative stimulus and reinforcing effects of sertraline in rhesus monkeys.

Rhesus monkeys (N = 4) were allowed to self-administer cocaine (0.03 mg/kg/injection) under a fixed-ratio 10 (FR 10) schedule during daily 2-h experimental sessions. When responding was stable, a variety of doses of sertraline, a serotonin reuptake blocker under development as an antidepressant, were made available for self-administration. Baseline conditions were reinstated between doses of sertraline. Cocaine 0.03 mg/kg/injection maintained high rates of injection, while total saline injections decreased to low levels within four to seven sessions. Sertraline (0.05-0.4 mg/kg/injection) did not maintain self-administration above saline levels in three of the four monkeys. In the fourth, responding was marginally above saline levels at two doses but was not systematically related to dose. In a second experiment, rhesus monkeys (N = 6) were trained to discriminate either d-amphetamine (0.56-1.0 mg/kg, IG) or pentobarbital (10 mg/kg, IG) from saline in a discrete-trials shock avoidance/escape paradigm. Sertraline (4.0-32 mg/kg) failed to substitute for either d-amphetamine or pentobarbital as a discriminative stimulus. These results suggest that sertraline is unlikely to have abuse potential in humans and is unlikely to have either d-amphetamine-like or pentobarbital-like subjective effects.

1-Naphthylamine↗
PubMed1992

Neurobiology of cocaine abuse.

The recent escalation of cocaine abuse has increased awareness of the need to understand the behavioral effects of cocaine and the determinants of those effects. Cocaine alters both conditioned and unconditioned behavior, and has prominent reinforcing and subjective effects that are particularly relevant to its abuse. An increase in CNS dopamine neurotransmission, resulting from a competitive blockade of high-affinity dopamine uptake mediated by both D1 and D2 dopamine receptors, is a primary determinant of the behavioral effects of cocaine. Either tolerance or sensitization may develop with repeated administration of cocaine. Dependence also develops, although the behavioral changes associated with cocaine withdrawal are subtle. Although numerous CNS changes have been associated with repeated administration of cocaine, the neuropharmacological mechanisms that underlie the behavioral changes that occur with repeated administration remain to be firmly established. Bill Woolverton and Ken Johnson stress that continued collaboration between behavioral pharmacologists and neuroscientists is critical for a complete understanding of the effects of cocaine.

Animals↗
PubMed1992

Cocaine self-administration: pharmacology and behavior.

I would like to stress several major points. The first is that CNS pharmacology is important in drug self-administration. In the case of cocaine, the necessary effect seems to be blockade of reuptake of DA rather than blockade of reuptake of NE or 5-HT or local anesthetic effects. An action of that DA on the D2 subtype of DA receptors appears to play an important role. The second point is that increased DA in synapses in the CNS is not sufficient to explain drug-maintained behavior. The schedule of reinforcement critically determines rates and patterns of drug-maintained behavior. Barrett (this volume) has presented convincing evidence that behavioral history, i.e., the sequential exposure to alternative behavioral conditions, can dramatically alter drug effects. What I hope to have made clear is that the simultaneous opportunity to engage in other behaviors can dramatically alter the reinforcing effects of drugs. Indeed, under appropriate conditions, a drug can function as both a positive and a negative reinforcer simultaneously in the same animal. The drug-choice studies I have described emphasize the dynamic nature of the interaction between behavioral and pharmacologic variables. The frequency of choosing to self-administer cocaine varied with the magnitude of the dose of cocaine (a pharmacologic variable) and the magnitude of an alternative positive reinforcer that was available (a behavioral variable). Increasing the magnitude of the alternative reinforcer decreased cocaine choice, but increasing the magnitude of the cocaine dose reestablished drug preference. In a sense, this is not a surprising result. The rhetoric of the times, however, would have it that drug self-administration, particularly cocaine self-administration, is somehow a different class of behavior that is not subject to the usual laws governing the behavior of organisms. As our understanding of drug self-administration evolves, however, that position will become increasingly untenable. These experimental findings challenge simple neurobiological assumptions about the determinants of drug self-administration. Clearly, a reinforcing effect, like any other behavioral effect of a drug, is not simply an immutable effect of a pharmacologic property of the drug. Given the pivotal role of reinforcing effects in drug abuse, this realization is critical to a comprehensive understanding of drug abuse. Any complete neurobiological model of drug abuse will have to account for these effects. Apparently, increasing the concentration of DA in synapses in the brain is not sufficient to account for drug-maintained behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Discriminative and reinforcing effects of brotizolam in rhesus monkeys.

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N = 3 group) were trained to discriminate pentobarbital (10 mg/kg, IG) or d-amphetamine. (0.56-1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6-10 mg/kg), diazepam (1.0-1.7 mg/kg), and brotizolam (0.3-1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. In d-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01-0.3 mg/kg/injection) and diazepam (0.003-0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001-0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.

Animals↗
PubMed1991

Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure.

Rhesus monkeys were trained in a discrete-trials choice procedure and allowed to choose between food delivery (1-16 pellets; 1 g/pellet) and intravenous injections of cocaine (0.03-0.56 mg/kg/injection; N = 4) or procaine (1.0-10 mg/kg/injection; N = 4) during daily 3-h sessions. Injections were available as the alternative to food. When the amount of food available as the alternative to drug was held constant and dose of drug was varied, the frequency of drug choice and total drug intake increased in a dose-related fashion for both cocaine and procaine. For both drugs, when the amount of food available as the alternative to drug was increased and the dose of the drug was held constant, the frequency of drug choice and total drug intake decreased. Thus, increases in the magnitude of an alternative non-drug reinforcer decreased cocaine and procaine self-administration. Further, the results suggest that while increasing the magnitude of the alternative reinforcer decreased the potency of cocaine as a positive reinforcer, the reinforcing efficacy of procaine was decreased. Because drug use by humans typically occurs in a context in which other reinforcers are available, the present results are consistent with the hypothesis that drug self-administration by humans can be decreased by increasing the value of alternative positive reinforcers. In addition, these results suggest that the extent to which drug self-administration is sensitive to this manipulation varies across drugs.

Animals↗
PubMed1991

Attenuation of the effects of cocaine on milk consumption in rats by dopamine antagonists.

Recent research suggest the both D1 and D2 dopamine (DA) receptors play an important role in the behavioral effects of psychomotor stimulants. The present study utilized selective DA antagonists to examine the role of DA receptors in the effects of cocaine on milk intake in rats. Male Sprague-Dawley rats were given access to a milk solution (2:1 tap water:Bordens sweetened condensed milk) for 15 min each day. When milk intake was stable, dose-response functions were determined for cocaine (4.0-32 mg/kg, IP, 10 min presession) administered alone or in combination with the D1 antagonist SCH 23390 (0.12-0.5 mg/kg, IP, 30 min presession) or the D2 antagonist raclopride (0.25-1.0 mg/kg, IP, 30 min presession). As a control for the serotonin (5-HT2) antagonist effects of SCH 23390, the 5-HT2 antagonist ketanserin (4.0-16 mg/kg) was evaluated as well. To control for nonspecific drug effects on fluid consumption, the effects of cocaine alone on water intake were determined in a separate group of rats. All drugs decreased milk intake when given alone. Both SCH 23390 and raclopride attenuated the effects of at least one dose of cocaine. Ketanserin did not alter the effects of cocaine. These results suggest that stimulation of both D1 and D2, but not 5-HT2, receptors is involved in the effects of cocaine on milk intake in rats.

Animals↗
PubMed1990

Effects of repeated injections of cocaine on D1 and D2 dopamine receptors in rat brain.

In order to determine if chronic administration of cocaine produced long-lasting alterations in dopamine receptor binding, rats were treated with single daily injections of cocaine (0, 10, or 20 mg/kg) for 15 consecutive days and killed either 20 min or 2 weeks after the last injection. The density of D1 binding sites in frontal cortex was either unchanged (10 mg/kg) or slightly increased (20 mg/kg) 20 min after the last daily injection, but was decreased 2 weeks later. D1 sites in striatum were decreased both immediately and 2 weeks after the injection regimen. Decreases in D1 binding site density in nucleus accumbens were observed only immediately after the last injection. In contrast to these effects on D1 binding sites, D2 binding sites were decreased in striatum and frontal cortex and increased in the nucleus accumbens 20 min after repeated cocaine, but were unaffected 2 weeks after repeated cocaine. Computer-assisted analysis of the saturation isotherms revealed that chronic administration of cocaine did not affect the affinity (Kd) of the radioligands used to label D1 or D2 sites. These findings suggest that repeated administration of cocaine results in long-term decreases in D1 binding sites in striatum and frontal cortex and transient decreases in D2 binding sites. Furthermore, cocaine caused opposite, transient effects on D1 and D2 site density in nucleus accumbens.

Animals↗
PubMed1990

Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys.

This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8-6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8-12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.

Animals↗
PubMed1990

Buspirone blocks the discriminative stimulus effects of apomorphine in monkeys.

Three rhesus monkeys were trained to discriminate apomorphine (APO) from saline in a two-lever, food-reinforced drug discrimination procedure. After acquisition of the discrimination, the monkeys were given various doses of APO in combination with saline or buspirone before test sessions in which responses occurring on either lever were reinforced. Combinations of APO (0.01-0.08 mg/kg, IV) and saline resulted in a dose-related increase from 0 to 100% in the percentage of responses that occurred on the APO-appropriate lever. When buspirone (0.04-0.16 mg/kg, IV) was combined with APO, reductions from 100% to 0% APO-appropriate responding were seen following at least one dose combination in all three monkeys. A parallel shift to the right of the APO dose-response curve with buspirone was evident in 2 monkeys, indicating surmountable antagonism. In one case, a further increase in buspirone dose resulted in an insurmountable antagonism, i.e., increasing APO dose still resulted in primarily saline-appropriate responding. These results suggest that buspirone can function as a D2 dopamine (DA) receptor antagonist at behaviorally relevant doses.

Animals↗