Gregory Collins | University of Texas Health Science Center at San Antonio (UTHSCSA) (original) (raw)

Papers by Gregory Collins

Behavioural Pharmacology, 2010

Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and lo... more Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [( ± )-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.

The Journal of pharmacology and experimental therapeutics, 2007

The present study examined the effect of drug and reinforcement history on quinpirole-maintained ... more The present study examined the effect of drug and reinforcement history on quinpirole-maintained responding in rats. Quinpirole (0.01, 0.032, or 0.1 mg/kg per injection) was assessed as a reinforcer in experimentally naive rats, as well as in rats trained to self-administer cocaine, remifentanil, ketamine, or food under a fixed ratio 1 schedule of reinforcement. Quinpirole failed to maintain responding in experimentally naive rats, or in ketamine- or food-trained rats. However, robust responding was maintained in rats with a history of cocaine reinforcement, and modest levels of responding were observed in rats with a history of responding for remifentanil. In a second set of studies, the effects of protracted drug histories on quinpirole-maintained responding in food-trained rats were assessed. Rats were maintained with food reinforcement, and different groups of rats were then allowed to respond for saline, quinpirole, and response-contingent cocaine or were administered noncontin...

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2011

A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; ... more A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; double mutant CocE (DM CocE)) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at (1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, (2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 min after cocaine, and (3) assessing the immunological responses of monkeys to DM CocE following repeated administration. Intravenous administration of cocaine produced dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the 2-h observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable...

Previous studies have demonstrated the capacity of a longacting mutant form of a naturally occurr... more Previous studies have demonstrated the capacity of a longacting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n ϭ 2) and long-lasting increases in MAP and HR (n ϭ 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans.

Behavioural Pharmacology, 2012

Dopamine receptor mechanisms are believed to play a role in the reinforcing effects of cocaine an... more Dopamine receptor mechanisms are believed to play a role in the reinforcing effects of cocaine and other drugs of abuse. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D 3 -preferring agonists, a D 2 -preferring agonist, and a D 4 agonist. The D 2 -preferring agonist did not maintain responding in any monkeys, and the D 4 agonist was self-administered at low rates, just above those maintained by saline, in one monkey. The D 3 -preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate that the apparent limited reinforcing effectiveness of D 2 -like agonists requires activity at D 3 receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by responsecontingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans.

Psychopharmacology, 2012

Rationale Dopamine D 2 -like agonists maintain responding when substituted for cocaine in laborat... more Rationale Dopamine D 2 -like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS). Objectives To evaluate the extent to which the pramipexolemaintained and pramipexole-induced responding are influenced by cocaine-paired stimuli. Methods Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenteradministered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D 2 -(L-741,626) and D 3 -preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated. Results When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dosedependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D 2 and D 3 antagonists differentially affected pramipexoleinduced PR responding, with L-741,626 and PG01037 producing rightward, and downward shifts in the doseresponse curve for CS-maintained responding, respectively. Conclusions These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole.

A series of compounds structurally related to pramipexole were designed, synthesized, and evaluat... more A series of compounds structurally related to pramipexole were designed, synthesized, and evaluated as ligands for the dopamine 3 (D 3) receptor. Compound 12 has a Ki value of 0.41 nM to D3 and a selectivity of >30000and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor. Figure 4. Functional evaluations of the D3 and D2 activity of pramipexole and compounds 5, 6, and 12 in yawning and hypothermia assays in rats. Top and middle panels: induction of yawning or hypothermia by D 3 ligands. Bottom panels: interactions between pramipexole and compound 12 in yawning and hypothermia assays.

Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse i... more Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole.

Cocaine esterase (CocE) is a naturally occurring bacterial enzyme, is a very efficient protein ca... more Cocaine esterase (CocE) is a naturally occurring bacterial enzyme, is a very efficient protein catalyst for the hydrolysis of cocaine, and has previously been shown to protect rodents from the lethal effects of cocaine. The current studies were aimed at evaluating the capacity of a longer acting mutant form (CocE T172R/G173Q; DM CocE) of CocE to protect against the lethal effects of cocaine, and alter ongoing intravenous cocaine self-administration in rats. A dose-response analysis revealed a dose-dependent suppression of cocaine-reinforced responding with 1.0 mg of CocE T172R/G173Q producing saline-like rates of responding. The effects of 1.0 mg of CocE T172R/G173Q on cocaine-reinforced responding were then compared with responding when saline was available for injection, whereas the selectivity of CocE T172R/G173Q&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s effects was assessed by evaluating the effects of 1.0 mg of CocE T172R/G173Q on (-)-2beta-carbomethoxy-3beta-phenyltropane (WIN-35065-2)- and food-reinforced responding. Although 1.0 mg of CocE T172R/G173Q suppressed responding maintained by 0.1 mg/kg/injection cocaine, a significant increase in responding was observed when responding was maintained by 1.0 mg/kg/injection cocaine, resulting in a 10-fold rightward shift in the dose-response curve for cocaine self-administration at a dose that did not significantly alter responding maintained by either WIN-35065-2 or food. These findings demonstrate that a long-acting form of CocE is effective at abruptly reducing the ongoing self-administration of low doses of cocaine, and provides a robust antagonism of cocaine&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s reinforcing effects. Furthermore, these studies provide strong evidence for the potential usefulness of a suitable, stable, and long-acting form of CocE as a pharmacotherapy for cocaine abuse in humans.

Rationale: The efficacy of nicotine replacement therapy (NRT) for smoking cessation is limited. O... more Rationale: The efficacy of nicotine replacement therapy (NRT) for smoking cessation is limited. One reason for this limited efficacy may be that typical serum nicotine concentrations provided by NRT do not match the peak arterial nicotine concentrations achieved from smoking. Objective: The purpose of the present study was to determine whether continuous nicotine infusion at a rate producing serum nicotine concentrations that match the estimated peak arterial nicotine concentrations associated with nicotine self-administration (NSA) in rats produces greater suppression of NSA than lower infusion rates. Methods: The effects of continuous nicotine infusion were studied by intravenously administering nicotine at various rates (1.0, 3.0, and 8.0 mg/kg per day) to rats concurrently self-administering nicotine (0.03 mg/ kg per infusion) during 23-h sessions or cocaine (0.17 mg/ kg per infusion) during 2-h sessions. Results: Continuous nicotine infusion suppressed NSA in a rate-related fashion. NSA was suppressed by 17, 50, and 73% at infusion rates of 1.0, 3.0 and 8.0 mg/kg per day, respectively. The 8.0-mg/kg per day infusion rate, which provided venous serum nicotine concentrations equaling the peak arterial concentrations associated with NSA, suppressed NSA to a greater extent than lower infusion rates. The 8.0-mg/kg per day nicotine infusion rate had no effect on cocaine-maintained responding, demonstrating that its effects were specific for suppression of NSA. This infusion rate provided a mean percentage replacement of nicotine from NSA of more than 700%. Reacquisition of NSA after suppression by the two highest infusion rates was delayed compared with reacquisition after saline extinction. Conclusions: Continuous nicotine infusion produced an infusion rate-related suppression of NSA that was greatest when the infusion provided nicotine doses and venous serum concentrations substantially higher than those typically associated with NRT in humans.

A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report ... more A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [(S)-(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], 908 5a,6,7,8, 9,9a,10-octahydro-6-propylpyrido [2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (N′ -propyl-4,5,6,7tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(±)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(−)-(4aR)-4, 4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(+)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl) ergotaman-3′,6′-18-trione methanesulfonate], and apomorphine [(R)-(−)-5,6,6a,7-tetrahydro-6methyl-4H-dibenzo-[de,g]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The antagonists L-741,626 (3-[4-(4chlorophenyl)-4-hydroxypiperidin-L-yl]methyl-1 H-indole), haloperidol (4-[4-(4-chlorophenyl)-4hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone HCl), nafadotride (N-[(1-butyl-2pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphthalenecarboxamide), U99194 (2,3-dihydro-5,6dimethoxy-N,N-dipropyl-1H-inden-2-amine maleate), SB-277011A (trans-N-[4-[2-(6cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide), and PG01037 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-ylbenzamide HCl) were used to determine effects on dose-response curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [(a,S)-a-(hydroxymethyl)benzeneacetic acid (1a,2b,4b,5a,7b)-9-methyl-3-oxa-9-azatricyclo [3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo [c,f]pyrazino[1,2-a]azepine HCl), and the D3-preferring antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by 907,2,3,3a,8,3a,indol-5-ol

… of Pharmacology and …, 2009

Dopamine D 2 -like agonists induce penile erection (PE) and yawning in a variety of species, effe... more Dopamine D 2 -like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D 4 and D 3 receptors, respectively. The current studies were aimed at characterizing a series of D 2 , D 3 , and D 4 agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(Ϫ)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D 4 receptor (R) knockout (KO) mice. All D 3 agonists induced dosedependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D 4 agonists. Likewise, D 2 , D 3 , and D 4 antagonists were assessed for their capacity to alter apomorphine-and pramipexole (NЈ-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D 3 antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D 2 antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-L-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D 4 antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine-or pramipexole-induced PE or yawning. A role for the D 3 receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D 4 R KO mice, effects that were inhibited by the D 3 antagonist, PG01037, in both wild-type and D 4 R KO mice. Together, these studies provide strong support that D 2 -like agonist-induced PE and yawning are differentially mediated by the D 3 (induction) and D 2 (inhibition) receptors. These studies fail to support a role for the D 4 receptor in the regulation of PE or yawning by D 2 -like agonists.

Psychopharmacology, 2007

Rationale Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors ... more Rationale Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases. Objectives These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia. Materials and methods The relative potencies of a series of

ACS Medicinal Chemistry Letters, 2011

We have identified several ligands with high binding affinities to the dopamine D3 receptor and e... more We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a K i value of 0.50 nM and displays a selectivity of >5000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a K i value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.

Psychopharmacology, 2011

Rationale Cocaine-induced changes in D 2 receptors have been implicated in the expression of sens... more Rationale Cocaine-induced changes in D 2 receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D 3 receptors is less clear. Objectives To characterize the effects of repeated cocaine administration on the sensitivity of rats to D 2 -and D 3mediated behaviors, as well as the binding properties of ventral striatal D 2 -like and D 3 receptors. Methods Pramipexole was used to assess the sensitivity of rats to D 3 /D 2 agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D 2 -like and D 3 receptors (24 h and 42 days) were also evaluated.