Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents.

RATIONALE: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. OBJECTIVES: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4"- and 4',4"-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. METHODS: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. RESULTS: All of the compounds displaced [3H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [3H]pirenzepine binding to muscarinic M1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs. CONCLUSIONS: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.

Discriminative stimulus effects of putative D3 dopamine receptor agonists in rats.

Three separate groups of rats were trained to discriminate the putative D3 dopamine receptor agonists (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT) (0.03 mg/kg), PD 128,907 (1.0 mg/kg) and quinpirole (0.03 mg/kg) from saline. Food was presented after each 10 (7-OH-DPAT and PD 128,907) or 20 (quinpirole) consecutive responses on one lever after administration of the training drug, and the other lever after the administration of saline. Once stable performances were obtained, the effects of various doses of several dopaminergic agonists were assessed during test sessions in which responses on either lever were reinforced. The substitution tests were conducted to determine if differences in potencies would be obtained, which would be suggestive of differences in the mechanisms underlying the discriminative effects of the training drugs. Non-selective agonists with activity at both D2 and D3 dopamine receptors (D2-like agonists) substituted for each of the three training drugs. In addition, the selective D2 dopamine receptor agonist U91356A also generalized to both 7-OH-DPAT and PD 128,907. The potencies of the D2-like agonists in substituting for each training drug were highly correlated with potencies in substituting for the others. SKF 82958 and SKF 81297, agonists with selectivity for D1 and D5 dopamine receptors (D1-like agonists), partially substituted for 7-OH-DPAT but not PD 128,907. The D1-like partial agonist SKF 38393 did not substitute for any of the training drugs for which it was tested. Cocaine produced intermediate substitution in 7-OH-DPAT- and PD 128,907-trained subjects and did not substitute at all in quinpirole-trained subjects. The dopamine D1-like antagonist SCH 39166 (0.001-0.03 mg/kg) did not alter the discriminative stimulus effects of PD 128,907, whereas the D2-like dopamine antagonist spiperone (0.001-0.1 mg/kg) produced at the highest dose an insurmountable antagonism of the discriminative effects of PD 128,907. In contrast, there was no appreciable antagonism of the effects of PD 128,907 on response rates. The data collected are consistent with a distinction between the effects of each of these training drugs and the indirectly acting agonist cocaine. Further, these data indicate that there are differences in the mechanisms underlying the discriminative effects of PD 128,907 and its effects on response rates. Moreover, these data indicate that each of the training drugs is distinct from drugs acting through D1 dopaminergic mechanisms. However, there were no data that clearly distinguished these training drugs from each other or from drugs acting through D2 dopaminergic mechanisms.

Choice under concurrent VI schedules: comparison of behavior maintained by cocaine or food.

Previous research has shown that concurrent schedule responding maintained by cocaine under short variable-interval (VI) schedules is well described by the generalized matching law. That is, drug-maintained behavior was apportioned in accordance with relative frequency of reinforcement. The purpose of the present experiment was to examine the ability of the generalized matching law to account for choice under longer VI schedules of cocaine availability, and to compare cocaine-maintained to food-maintained behavior in this regard. One group of rhesus monkeys (n = 4) was prepared with indwelling IV catheters and allowed to respond under concurrent VI (conc VI) schedules of cocaine delivery (0.025, 0.05 or 0.1 mg/kg per injection) with an average inter-reinforcer interval (IRI) of 10 or 30 min. In a second group of monkeys (n = 4), a comparable experiment was conducted but with responding maintained by different amounts of food (one, two, or four 1-g banana-flavored pellets). For both groups, the same reinforcer followed responding on either lever, the only difference between the options being the VI schedule, i.e., frequency of reinforcement. The behavior of the cocaine-maintained group was well predicted by the generalized matching law. While both groups evidenced undermatching of both response and time allocation, lever pressing of monkeys whose behavior was maintained by food showed more undermatching than that of the cocaine-maintained group. In addition, a consistent and unexplained bias in responding toward the right lever developed in the food-maintained, but not the cocaine-maintained monkeys. Considering the present results with those of previous experiments, it appears that food-, but not cocaine-maintained behavior, deviates increasingly from strict matching as the IRI is extended. This difference across reinforcers could be due to differences between cocaine and food in the mechanisms by which they maintain behavior, or a direct effect of cocaine on choice performance.

Characterization of unconditioned behavioral effects of dopamine D3/D2 receptor agonists.

A series of experiments examined the ability of dopamine D3/D2 receptor agonists [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]b enzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD 128,907), (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT), quinpirole and bromocriptine] to produce a variety of dopaminergically mediated behaviors. The effects of these drugs with selectivity for D3/D2 receptors over D1 receptors were compared with those produced by the selective D1 agonists [(+/-)-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), (+/-)-6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF 82958)], a nonselective dopaminergic agonist (apomorphine), and an indirect dopamine agonist (cocaine). The D3/D2 agonists decreased locomotor activity, had no effect on gnawing and only inconsistently induced climbing in mice. Further, these agonists dose-dependently produced scratching in squirrel monkeys. In contrast, the D1 agonists, SKF 82958 and SKF 38393, did not produce scratching in squirrel monkeys. Whereas the full D1 agonist, SKF 82958, produced increases in locomotor activity and in climbing and gnawing, the partial D1 agonist, SKF 38393, did not increase the frequencies of these behaviors. The nonselective dopamine agonist, apomorphine, produced decreases in locomotor activity and increases in climbing and gnawing in mice. Apomorphine dose-dependently produced scratching in squirrel monkeys. The indirect dopamine agonist, cocaine, produced increases in locomotor activity and climbing, but had no effect on climbing or gnawing in mice and did not produce scratching in squirrel monkeys. These findings suggest that D3/D2 agonists can be distinguished on various behavioral measures from the nonselective agonist, apomorphine (gnawing), D1 agonists (scratching) and the indirect agonist, cocaine (locomotor activity and scratching). Behaviors once attributed to stimulation of D2 (locomotor activity and scratching) or D1/D2 (climbing and gnawing) receptors may also involve dopamine D3 receptors.

Assessment of cocaine-like discriminative stimulus effects of dopamine D3 receptor ligands.

The highly selective dopamine D3 receptor ligand, (+)-PD 128907 4aR10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H5H[4,3- b]-1,4- oxazin-9-ol), and other dopamine D3 receptor ligands, (+/-)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin and (+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin, substituted for the discriminative stimulus effects of cocaine in rats, an animal model of subjective effects in humans. Substitution only occurred at doses that markedly decreased responding. These results suggest that dopamine D3 receptors may be involved in the subjective effects of cocaine, and therefore may be a target for the discovery of treatments for cocaine dependence.

The effects of differing response-force requirements on fixed-ratio responding of rats.

Rats were exposed to two-component multiple schedules of food delivery. In the first experiment, 15 responses were required to produce food in both components. A downward force of 0.25 N (25 g) was always required to operate the response lever in one component. In the other, the required force was 0.25, 0.50, 1.00, or 2.00 N (25, 50, 100, or 200 g). In the second experiment, 0.25 N of force operated the lever in one component, but in the other, the force requirement for five consecutive responses at the beginning, middle, or end of each ratio was increased from 0.25 to 2.00 N. In the third experiment, the number of responses required to produce food was reduced from 15 to 5, and then to 1. Again, the effects of altering response force from 0.25 to 2.00 N were examined. In general, as response force increased in all experiments, mean response rates decreased and mean interresponse times increased.

Pharmacological analysis of the scratching produced by dopamine D2 agonists in squirrel monkeys.

Several dopamine agonists, administered i.m., produced persistent, excessive and non-localized scratching in squirrel monkeys (Saimiri sciureus). Studies were conducted with a series of drugs to determine the pharmacological mechanisms responsible for this effect. All of the dopamine D2 agonists studied produced dose-related increases in scratching, whereas several dopamine D1 receptor agonists, indirect dopamine agonists and drugs acting on other receptors failed to produce dose-related increases in scratching. The scratching produced by D2 agonists was stereospecific; (-)-NPA produced scratching whereas its (+)-enantiomer was inactive up to doses 300-fold higher. Scratching induced by quinpirole was attenuated by both D2 and D1 antagonists, and this antagonism was stereospecific, with the D2 antagonist (-)-eticlopride, but not its enantiomer, active. Sensitivity developed to the effects of D2 agonists with the quinpirole dose-effect curve shifting to the left by a factor of approximately 64. Two partial D2 receptor agonists (SDZ 208-911 and SDZ 208-912) had limited efficacy in producing scratching, however, one partial D2 receptor agonist (terguride) was fully efficacious, suggesting that there are spare receptors for this effect. The peripherally active dopamine antagonist domperidone and the histamine antagonist diphenhydramine also reduced the scratching induced by D2 agonists, but not to the same extent as centrally acting D2 antagonists. Scratching in squirrel monkeys is an effect that appears to be due to agonist actions at D2 receptors, and may be mediated by a release of histamine. This behavioral activity may be useful as an in vivo indication of D2 receptor activity in primates.

Effects of D1 dopamine agonists on schedule-controlled behavior in the squirrel monkey.

Behavioral effects of several dopamine D1 receptor agonists were compared with those of cocaine and (+)-amphetamine in squirrel monkeys trained to press a response key under a fixed-interval schedule of electric shock presentation. Cocaine (0.03 to 0.3mg/kg) and (+)-amphetamine (0.01 to 0.1mg/kg) at low to intermediate doses increased rates of responding under the fixed-interval schedule; at higher doses each of these drugs decreased response rates. In contrast, neither full nor partial D1 receptor agonists produced reliable increases in response rates. Rather, these drugs decreased rates of responding in a dose-related manner. These results with schedule-controlled behavior in primates support earlier findings in rodents that indicate that D1 agonist actions result in effects quite different from the characteristic psychomotor stimulant effects produced by cocaine or (+)-amphetamine; and they further suggest that those characteristic stimulant effects are more probably due to stimulation of other dopamine receptors.

Effects of cocaine on fixed-ratio responding of rats: modulation by required response force.

The effects of acute cocaine administrations (5.6-32 mg/kg) were determined in rats responding under a multiple fixed-ratio 15 (FR 15) FR 15 schedule of food delivery. The minimum response effort required in one schedule component was 25 g, whereas in the other component it was 200 g. Cocaine produced generally dose-dependent decreases in rate of responding and increases in preratio pause time under each component. There was, however, a significant interaction between force and drug dose, and drug effects were larger in the component requiring 200 g for lever operation. Although a number of other parameters have been shown previously to modulate the effects of cocaine on schedule-controlled responding, the present data constitute the first demonstration that minimum response effort does so.

Self- and cross-citations in the Journal of Applied Behavior Analysis and the Journal of the Experimental Analysis of Behavior: 1983-1992.

We examined self- and cross-citation practices in JABA and JEAB from 1983 through 1992. Mean levels of self-citation for JABA and for JEAB were 22.6% and 36.1%, respectively. Overall, 2.4% of JABA citations were JEAB articles, and 0.6% of JEAB citations were JABA articles, which suggests limited integration of basic and applied research.

Fixed-ratio size as a determinant of tolerance to cocaine: is relative or absolute size important?

Six studies, examining five drugs in three species, have demonstrated that tolerance development is impaired under relatively long fixed-ratio (FR) schedules compared with relatively short FR schedules. One such study demonstrated that substantial tolerance to the rate-reducing effects of cocaine in pigeons developed under the FR 5 and 25 components of a multiple schedule of food delivery, but little or no tolerance developed under the FR 125 component. The present study examined the acute and chronic effects of cocaine in three groups of pigeons. One group was exposed to a simple FR 5 schedule of food delivery, a second to a simple FR 125 schedule of food delivery, and a third to a simple FR 125 schedule that alternated across sessions with a multiple FR 125 FR 250 schedule. When administered acutely, cocaine (1-10mg/kg) produced dose-dependent rate decreases under all schedules. With chronic exposure to 5.56mg/kg cocaine, tolerance clearly developed under the FR 5 schedule. Evidence of tolerance under the FR 125 schedule was equivocal, but strongest when that schedule alternated with an FR 250 component under a multiple schedule arrangement. There was no consistent evidence of tolerance under the FR 250 component. These results suggest that, although the development of tolerance under an FR schedule may be affected by exposure to a longer schedule, tolerance to cocaine does not develop readily under "long" FR schedules, regardless of the context in which they appear.

Effects of d-amphetamine and ethosuximide on responding under delayed-matching-to-sample procedures with differential and nondifferential outcomes.

Pigeons were exposed to delayed-matching-to-sample (DMTS) procedures in which food or a flash of the feeder light followed correct responses. When these consequences were correlated with a particular stimulus (e.g., food followed matching responses to red and a flash of the feeder light followed matching responses to green), accuracy was higher (i.e., stimulus control was greater) than when discriminative stimuli and consequences were not correlated. Although stimulus control in the absence of drug appeared to be weaker under the uncorrelated procedure, neither d-amphetamine (0.5-3.0 mg/kg) in Experiment 1 nor ethosuximide (40-160 mg/kg) in Experiment 2 disrupted accuracy to a greater extent under that procedure. These results, like those of a prior investigation, suggest that drug effects are similar under DMTS procedures regardless of whether correlated or uncorrelated outcomes are arranged.

The effects of phenobarbital on responding under delayed-matching-to-sample procedures with differential and nondifferential outcomes.

Pigeons were exposed to delayed-matching-to-sample procedures in which food or a flash of the feeder light followed correct responses. When these consequences were correlated with a particular stimulus (e.g., food followed matching responses to red and a flash of the feeder light followed matching responses to green), accuracy was significantly higher (i.e., stimulus control was greater) than when discriminative stimuli and consequences were not correlated. Acute administrations of phenobarbital (10-40 mg/kg) produced similar effects regardless of whether or not differential outcomes were arranged for correct responses to a particular stimulus. At doses of 30 and 40 mg/kg, phenobarbital significantly decreased accuracy under both variations of the delayed-matching-to-sample procedure. Given these results, it appears that degree of stimulus control in the absence of drug did not modulate drug effects in the present study.

Free birds aren't fat: Weight gain in captured wild pigeons maintained under laboratory conditions.

Nine feral pigeons, 5 from an urban setting and 4 from a rural setting, were captured and maintained for 42 days under free-feeding conditions comparable to those arranged for laboratory subjects. On average, birds increased their body weights by 17% over this period. The range of increase across birds was 9 to 30%. These findings suggest that the food deprivation arranged for laboratory pigeons, which is characteristically 80% of free-feeding weights, may in some sense be less severe than it first appears.

A program for normal glycemic control of insulin-dependent diabetes.

A method of instruction enabling patients to control their diabetes is described. The patients learn through home glucose monitoring how their blood sugar levels vary with changes in diet, exercise, and insulin. They learn to chart accurately all the factors influencing their control in a manner that enables them, as well as the physician, to analyze them quickly. From this information they learn to anticipate the results of various changes in life-style and, thus, to live beyond the customary constraints of the disease without loss of glycemic control. Significant improvements in neuritis, impotence, and creatinine clearance rates are reported.