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BEHAVIORAL PHARMACOLOGY
-Hydroxybutyrate and Related Compounds in Rats Discriminating Baclofen or Diazepam: The Role of GABAB and GABAA Receptors
Department of Pharmacology (L.P.C., A.W.U., W.K., C.P.F.) and Psychiatry (W.K., C.P.F.), The University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Department of Pharmaceutical Sciences (H.W., W.C., A.C.), University of Maryland, Baltimore, Maryland
Received November 12, 2003; accepted January 22, 2004.
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Abstract |
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-hydroxybutyrate (GHB) can be mimicked by GABAA receptor-positive modulators (e.g., diazepam) and GABAB receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors -butyrolactone and 1,4-butanediol occasioned >80% responding on the drug-associated lever in rats discriminating baclofen and <11% in rats discriminating diazepam. Diazepam and other GABAA receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABAB receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABAB, mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABAA mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.
-Hydroxybutyric acid (GHB) is an emerging drug of abuse (Nicholson and Balster, 2001
) that occurs naturally in the brain and is a putative neurotransmitter (Maitre et al., 2000). GHB has anxiolytic, hypnotic, and anesthetic effects (Bernasconi et al., 1999) and can induce amnesia, sedation, absence seizures, and, at very large doses, coma and death (Roth and Suhr, 1970; Snead and Liu, 1993). GHB is approved for the treatment of narcolepsy and has been evaluated for treating alcohol and opioid dependence and withdrawal (Mason and Kerns, 2002; Caputo et al., 2003). The mechanism of action of GHB is not fully understood, although it is becoming clear that activity at more than one receptor contributes to its effects in vivo. GHB has high affinity for sites labeled with [3H]NCS-382, the purported GHB receptor antagonist (Mehta et al., 2001), and comparatively low affinity for GABAB receptors (Xie and Smart, 1992; Mathivet et al., 1997). GHB can also act indirectly on GABAA or GABAB receptors through its metabolic conversion to GABA in vivo (Roth, 1970; Doherty et al., 1975; Gold and Roth, 1977; Snead et al., 1989) and through GABAB receptor-mediated increases in neurosteroids that can modulate GABAA receptor function (Barbaccia et al., 2002).
Drug discrimination has been used extensively to investigate mechanisms of action partly because it has a high degree of pharmacologic specificity (Colpaert, 1978; Ator and Griffiths, 1989; Mansbach and Balster, 1991); i.e., drugs with similar discriminative stimulus effects typically share a mechanism of action. GHB can be discriminated by rats (Winter, 1981; Colombo et al., 1998; Metcalf et al., 2001; Carter et al., 2003) and pigeons (Koek et al., 2004), and previous studies have implicated both GABAA and GABAB receptors in the discriminative stimulus effects of GHB. For example, baclofen, the prototypical GABAB receptor agonist, occasioned GHB-appropriate responding in rats trained to discriminate GHB (Winter, 1981; Colombo et al., 1998; Carter et al., 2003), and CGP 35348, a GABAB receptor antagonist that blocks GHB binding to GABAB receptors (Xie and Smart, 1992), attenuated the discriminative stimulus effects of GHB (Colombo et al., 1998; Carter et al., 2003).
Compounds that bind to the GABAA receptor complex also can share discriminative stimulus effects with GHB. For instance, the GABAA positive modulators diazepam (Colombo et al., 1998; Carter et al., 2003) and chlordiazepoxide (Winter, 1981), as well as the direct-acting GABAA agonist muscimol (Winter, 1981), occasion some drug-appropriate responding in rats discriminating GHB. Although GHB does not bind to GABAA receptors (Serra et al., 1991), GHB is metabolically converted to GABA (Doherty et al., 1975), and activation of GABAB receptors by GHB can stimulate the synthesis of neurosteroids that positively modulate the actions of GABA at the GABAA receptor complex (Barbaccia et al., 2002). Furthermore, pharmacologically unrelated compounds (i.e., ketamine and morphine) do not share discriminative stimulus effects with GHB (Winter, 1981; Carter et al., 2003). These studies have begun to identify the relative importance of GABAA and GABAB receptors in the complex discriminative stimulus effects of GHB; however, additional studies in animals discriminating specific GABAA or GABAB receptor ligands would provide a further, important test of the notion of a shared mechanism of action between GHB and GABAergic compounds.
The goal of the current study was to further characterize the role of GABAergic mechanisms in the discriminative stimulus effects of GHB and related compounds. Separate groups of rats were trained to discriminate either the GABAB receptor agonist baclofen or the positive GABAA receptor modulator diazepam from vehicle. To date, GHB and related compounds have not been thoroughly evaluated in animals discriminating a GABAA receptor agonist or positive modulator (Woolverton et al., 1999; McMahon et al., 2003); moreover, there does not appear to be any published report on the discrimination of a direct-acting GABAB receptor agonist. Thus, one initial objective of this study was to determine whether reliable stimulus control could be established with the GABAB receptor agonist baclofen. Once separate groups of rats were trained to discriminate either baclofen or diazepam, the effects of GHB and related compounds, including pharmacologically relevant antagonists, were evaluated in both groups.
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Materials and Methods |
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Operant Chambers
For daily experimental sessions, animals were transported from the colony room to an adjacent room supplied with white noise. Sessions were conducted in commercially available operant chambers (model ENV-008CT; MED Associates Inc., St. Albans, VT) located within sound-attenuating, ventilated cubicles (model ENV-022M; MED Associates Inc.). The chambers were equipped with two levers, associated stimulus lights, and a food hopper. Data were collected using MED-PC IV software (MED Associates Inc.) and an interface.
Experimental Sessions
Baclofen versus Saline Discrimination. The procedure for training baclofen as a discriminative stimulus was similar to what has been reported previously for rats discriminating GHB (Carter et al., 2003). Eleven rats were trained to press levers for food pellets (45 mg) (Research Diets, Inc., New Brunswick, NJ) under a concurrent schedule of continuous reinforcement. After a rat received 100 food pellets during a maximum 60-min session, discrimination training started with 3.2 mg/kg baclofen. The response requirement was systematically increased across days to a final value of fixed ratio (FR) 10, the session duration was decreased from 60 to 30 min, and a pretreatment (timeout) was introduced, during which time the chamber was dark and responding had no programmed consequence. Under terminal conditions, a 15-min timeout preceded a 15-min response period during which stimulus lights were illuminated, and 10 consecutive responses on 1 of the 2 levers resulted in the delivery of food. A response on the incorrect lever reset the FR requirement on the correct lever. An injection administered immediately prior to the timeout determined whether responding on the right or left lever was reinforced (left lever after baclofen and right lever after saline for six rats and the opposite designation for the remaining rats). Drug and vehicle were administered i.p. in a volume of 0.1 to 1.0 ml, and sessions were conducted 5 to 7 days per week. The order of training sessions was generally double alternation (i.e., baclofen, baclofen, saline, saline).
The dose of baclofen that was chosen for training was the dose (3.2 mg/kg) that occasioned the greatest amount of drug lever-responding in rats discriminating 200 mg/kg GHB from vehicle (Carter et al., 2003). Because initially this dose had marked rate-decreasing effects, the training dose was temporarily decreased. The rate of responding was used as a guide to determine when to increase the training dose. A dose of 1.0 mg/kg baclofen was administered over the first 18 drug training days (i.e., approximately half of the sessions were drug training and the remaining were vehicle training), and 1.78 mg/kg baclofen was administered for the next 10 drug training days. Thereafter, and for the remainder of this study, the training dose of baclofen was 3.2 mg/kg.
Rats were considered to be under adequate stimulus control for testing when at least 90% of the total responses on the injection-appropriate lever and fewer than 10 responses (1 FR) on the incorrect lever prior to delivery of the first food pellet were satisfied for 5 consecutive or 6 of 7 training sessions. Thereafter, tests were conducted whenever these criteria were satisfied in 2 of 3 days, including the day immediately before a scheduled test.
Test sessions were the same as training sessions except that 10 consecutive responses on either lever resulted in the delivery of food. For time course studies, the response period was shortened to 5 min to evaluate discriminative stimulus effects in a narrower interval of time. The timeout period was 15 min except when the time course of the test compound was studied 10 min after drug administration, in which case the timeout was shortened to 10 min. For pretreatment periods longer than 15 min, rats remained in the home cage after drug administration and were placed in the chamber 15 min prior to the response period. Antagonists were administered 10 min prior to the test compound.
Diazepam versus Vehicle Discrimination. Ten rats were trained to discriminate diazepam using a similar method as described above for baclofen. That is, rats were first trained to press a lever for food then to discriminate between 1.0 mg/kg diazepam (i.p.) and vehicle while responding under a FR10 schedule of food presentation in sessions comprising a 15-min timeout and 15-min response period. The dose of 1.0 mg/kg diazepam was chosen for training because this dose occasioned substantial drug lever-responding in rats discriminating 200 mg/kg GHB from vehicle (Carter et al., 2003) and has been studied extensively in rats (e.g., Ator and Griffiths, 1989).
Drugs
Compounds studied included (±)baclofen, GHB (sodium salt), -butyrolactone (GBL), 1,4-butanediol (1,4-BDL), pentobarbital sodium, muscimol (Sigma-Aldrich, St. Louis, MO), diazepam (Sigma/RBI, Natick, MA), pregnanolone (Steraloids, Newport, RI), morphine sulfate (National Institute on Drug Abuse, Research Technology Branch, Rockville, MD), ketamine hydrochloride (Ketaset; Fort Dodge Laboratories Inc., Fort Dodge, IA), NCS-382 (sodium salt), and CGP 35348 (sodium salt). NCS-382 was synthesized as previously described by Maitre et al. (1990), and CGP 35348 was synthesized as described by Froestl et al. (1995). Diazepam was dissolved in a vehicle solution of 70% Emulphor (EL-620, a polyoxyethylated vegetable oil; GAF Corporation, Linden, NJ), 20% sterile water, and 10% ethanol (by volume). Pregnanolone was dissolved in 45% -cyclodextrin (Sigma-Aldrich) in sterile water. Ketamine was purchased as a solution and diluted with saline. All other drugs were dissolved in sterile water or saline. Doses are expressed as the weight of the free base or salt as indicated above, and the pH of all solutions was adjusted between 5 and 9 with sodium hydroxide or lactic acid.
Data Analysis
The percentage of responses on the drug-associated lever (baclofen or diazepam) during the response period is plotted as a percentage of the total number of responses [percent drug lever-responding (%DR)]. The rate of lever pressing is plotted in responses per second. Data are reported as the average ± 1 S.E.M. for animals with response rates greater than or equal to 20% of their vehicle control rate. When a rat responded at a rate less than 20% of its vehicle control rate, discrimination data from that test were not included in the calculation of %DR but were included in the calculation of response rate. The control rate of responding for an individual animal was the average response rate from the 5 vehicle training days immediately preceding a test. With the exception of CGP 35348 and cocaine, drugs were studied up to doses that markedly decreased the rate of responding.
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Results |
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GHB and its metabolic precursors 1,4-BDL and GBL dose-dependently increased responding on the baclofen lever (Fig. 1, top panel; Table 2). A dose of 320 mg/kg GHB occasioned a maximum of 76.5% baclofen lever-responding. A larger dose, 560 mg/kg, markedly decreased responding. Doses of 178 and 320 mg/kg 1,4-BDL occasioned 79.6 and 89.7% drug-appropriate responding, respectively, and 320 mg/kg 1,4-BDL decreased responding to 35.0% of the vehicle control rate. At 100 mg/kg, GBL occasioned 89.4% baclofen-appropriate responding. A larger dose of 178 mg/kg markedly decreased responding. The GHB receptor antagonist NCS-382 occasioned less than 27% baclofen lever-responding up to a dose (320 mg/kg) that markedly decreased responding (Fig. 1).
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The GABAA-positive modulators diazepam, pregnanolone, and pentobarbital occasioned intermediate levels of baclofen-appropriate responding up to doses that markedly decreased the rate of responding (Tables 1 and 2). A dose of 3.2 mg/kg diazepam occasioned a maximum of 50.9% drug-appropriate responding, and a dose of 10 mg/kg pregnanolone occasioned a maximum of 53.5% baclofen lever-responding. Pentobarbital occasioned a maximum of 22.1% baclofen-appropriate responding. The direct-acting GABAA agonist muscimol occasioned less than 10% baclofen-appropriate responding up to doses that nearly eliminated responding (Table 2).
Cocaine, ketamine, and morphine were tested up to doses that significantly decreased the rate of responding (Table 2). At the largest dose where at least half of the animals responded, cocaine (10 mg/kg), ketamine (3.2 mg/kg), and morphine (3.2 mg/kg) occasioned a maximum of 16.7, 36.7, and 49.6% baclofen-appropriate responding, respectively.
Baclofen Discrimination: Antagonism Studies. The GABAB receptor antagonist CGP 35348 partially attenuated the discriminative stimulus effects of the training dose of baclofen (3.2 mg/kg) as well as the dose of GHB (200 mg/kg) that has been used as the training stimulus in previous discrimination studies (Fig. 2). The effects of each compound were decreased to less than 50% baclofen lever-responding at doses of 100 to 178 mg/kg CGP 35348. A larger dose of CGP 35348 did not further decrease baclofen lever-responding for either compound. Up to a dose of 560 mg/kg, CGP 35348 alone occasioned less than 20% baclofen-appropriate responding.
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Diazepam Discrimination: Substitution Studies. The median number of days for 10 rats to meet the training criteria with 1.0 mg/kg diazepam was 44 (range: 36–84). Diazepam dose-dependently increased responding on the drug-associated lever, with doses of 1.0 and 3.2 mg/kg occasioning more than 90% drug lever-responding (Fig. 3, top panel; Table 1). Vehicle injections occasioned less than 1% diazepam-appropriate responding (Fig. 3, V, top panel). Up to a dose of 3.2 mg/kg, diazepam did not alter the rates of lever pressing.
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The GABAA-positive modulators pregnanolone and pentobarbital dose-dependently increased diazepam-appropriate responding (Fig. 3, top panel; Table 2). A dose of 10 mg/kg pregnanolone elicited 96.7% drug-appropriate responding. Pentobarbital occasioned 88.2% diazepam-appropriate responding at this same dose. A dose of 17.8 mg/kg pentobarbital markedly decreased the rate of responding (Fig. 3, bottom panel). Pregnanolone occasioned drug-appropriate responding at doses that did not markedly reduce the rate of responding. The GABAA receptor agonist muscimol occasioned vehicle-appropriate responding nearly exclusively and was studied up to a dose that markedly decreased the rate of responding (Table 2).
GHB, its metabolic precursors 1,4-BDL and GBL, the putative GHB receptor antagonist NCS-382, and cocaine each occasioned less than 12% diazepam-appropriate responding. With the exception of cocaine, all of these compounds were studied up to a dose that markedly decreased the rate of responding (Table 2). Baclofen occasioned less than 4% diazepam-appropriate responding up to a dose (5.6 mg/kg) that decreased responding to 21% of control (Table 1).
Diazepam Discrimination: Antagonism Studies. The discriminative stimulus effects of diazepam were attenuated by 1.0 and 3.2 mg/kg flumazenil (Fig. 2, top right panel). The effects of the training dose of diazepam (1.0 mg/kg) were decreased from 93.0% (control conditions) to 44.9 and 27.3%, respectively, by pretreatment with 1.0 and 3.2 mg/kg flumazenil. When administered alone, flumazenil occasioned less than 34% responding on the diazepam lever (Fig. 2).
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; Mathivet et al., 1997) and may indirectly activate GABA receptors through conversion to GABA and increased synthesis of neuroactive steroids (Roth, 1970; Doherty et al., 1975; Gold and Roth, 1977; Snead et al., 1989; Barbaccia et al., 2002). Administration of GHB, like baclofen, inhibits the extracellular release of GABA and suppresses K+-stimulated [45Ca2+] uptake— effects that are blocked by the GABAB receptor antagonists phaclofen and CGP 35348 (Banerjee and Snead, 1995; Snead, 1996). Other behavioral effects of GHB, such as generalized absence seizures in rats and inhibition of gastrointestinal motility in mice, also are attenuated by GABAB antagonists (Snead, 1996; Carai et al., 2002).
GABAergic mechanisms also seem to be important in the discriminative stimulus effects of GHB (Winter, 1981). For example, the GABAB receptor agonist baclofen occasions drug-appropriate responding in rats discriminating GHB, and the GABAB receptor antagonist CGP 35348 antagonizes the discriminative stimulus effects of GHB (Colombo et al., 1998) or baclofen (Carter et al., 2003). GABAA mechanisms might also contribute to some effects of GHB. Although GHB does not bind to any known sites on the GABAA receptor complex (Serra et al., 1991), the GABAA receptor-positive modulators chlordiazepoxide (Winter, 1981), diazepam (Colombo et al., 1998), and pregnanolone (Carter et al., 2003) occasion some GHB-like responding in rats. Thus, both GABAB and GABAA mechanisms are thought to contribute to the discriminative stimulus effects of GHB. The relative contribution of GABAB and GABAA mechanisms in the discriminative stimulus effects of GHB are not well described. To that end, the current study examined GHB and related compounds in separate groups of rats discriminating either the direct-acting GABAB receptor agonist baclofen or the GABAA receptor-positive modulator diazepam. Overall, results obtained from substitution and antagonism studies indicated that each discrimination procedure was pharmacologically selective; however, GHB and its metabolic precursor 1,4-BDL occasioned drug lever-responding only in rats discriminating baclofen, indicating a greater role for GABAB mechanisms in the discriminative stimulus effects of GHB compared with GABAA mechanisms. Although the behavioral actions of another GHB precursor, GBL, are assumed to be due to its metabolic conversion to GHB, converging lines of evidence suggest that GBL has pharmacologic activity that is not identical to GHB and, therefore, not simply due to its conversion to GHB (e.g., Carter et al., 2003). Pharmacologically unrelated compounds (cocaine, ketamine, and morphine) occasioned less than 50% drug-appropriate responding in rats discriminating baclofen or diazepam (present study) and in rats discriminating GHB (Carter et al., 2003).
One mechanism by which GHB might act at GABA receptors is through its metabolic conversion to GABA; however, the direct-acting GABAA receptor agonist muscimol fails to substitute for GHB in drug discrimination assays (Winter, 1981; Carter et al., 2003), suggesting that conversion to GABA and resulting direct effects on GABAA receptors is not a likely mechanism of action for GHB in drug discrimination assays. The finding that GHB shares discriminative stimulus effects with GABAA receptor-positive modulators and not with direct-acting GABAA receptor agonists is consistent with previous studies showing qualitative differences between direct-acting GABAA agonists and GABAA receptor-positive modulators. For example, neither muscimol nor baclofen substituted for pentobarbital in rats (Grech and Balster, 1993), and neither baclofen nor the GABAA-positive modulators pentobarbital and midazolam reliably substituted for muscimol (Grech and Balster, 1997). Similarly, rats discriminating diazepam do not respond on the drug lever after administration of muscimol, baclofen, or GHB. Thus, direct agonism at GABAA receptors does not seem to be important for the discriminative stimulus effects of GHB in rats.
A second mechanism by which GHB might act at GABAA receptors is indirectly through GABAB receptor-stimulated increases in neurosteroid synthesis (Barbaccia et al., 2002). Thus, GHB-like responding observed after administration of GABAA receptor-positive modulators such as diazepam, chlordiazepoxide, and pregnanolone (Winter, 1981; Colombo et al., 1998; Carter et al., 2003) could be related to GHB-stimulated increases in neurosteroids that can positively modulate GABAA receptor function. It is well known that GHB can bind to GABAB receptors. This binding might explain the GHB-like effects obtained with both GABAB receptor agonists and GABAA receptor-positive modulators under some conditions.
There is mounting evidence for multiple subtypes of GABAB receptors in the brain and spinal cord (for reviews, see Bonanno and Raiteri, 1993; Bowery et al., 2002). Several studies have reported a differential sensitivity of GABAB autoreceptors that modulate the release of GABA and heteroreceptors that regulate the release of glutamate, somatostatin, or cholecystokinin to different GABAB receptor antagonists (Bonanno and Raiteri, 1992; Fassio et al., 1994; Gemignani et al., 1994). Electrophysiological studies have also shown differential sensitivity of pre- and postsynaptic GABAB receptors to different GABAB receptor antagonists (Seabrook et al., 1990; Lambert and Wilson, 1993; Yamada et al., 1999). It is possible, therefore, that different GABAB receptor subtypes contribute differentially to the behavioral actions of GHB, baclofen, and related compounds and that less-than-complete antagonism of baclofen in the current study is due to actions of these compounds at CGP 35348-insensitive GABAB receptors or at non-GABAergic receptors. Given the mounting evidence for GABAB receptor subtypes, the ongoing synthesis of novel selective ligands for GABAB receptors, and the well documented pharmacological selectivity of drug discrimination procedures, further study of animals trained to discriminate selective GABAB receptor ligands will likely yield important new insights into the heterogeneity of GABAB receptors and the mechanisms of action of novel GABAB receptor agonists, antagonists, and allosteric modulators.
In the current studies, rats were trained to discriminate baclofen or diazepam from vehicle to make direct comparisons regarding the relative contribution of each mechanism of action to the discriminative stimulus effects of GHB. Similar to rats that discriminate GHB, rats that discriminate baclofen respond greater than 75% on the drug-appropriate lever following administration of baclofen, GHB, or 1,4-BDL, whereas the same subjects responded less than 51% on the baclofen lever after administration of diazepam (Table 1). Conversely, in rats discriminating diazepam, neither GHB nor baclofen occasioned greater than 4% diazepam-appropriate responding, whereas diazepam, pregnanolone, and pentobarbital occasioned greater than 88% drug-appropriate responding. These data clearly suggest a less prominent role for GABAA mechanisms in the discriminative stimulus effects of GHB compared with GABAB mechanisms.
GHB and related compounds continue to be abused, although the effects of these compounds are different from previously characterized drugs of abuse. A rapidly growing literature, including data obtained in this newly developed drug discrimination procedure with baclofen, strongly implicates GABAB mechanisms in the behavioral actions of GHB. That baclofen is not abused (like GHB) could be due to differential effects of these compounds at GABAB receptor subtypes, to different mechanisms (direct versus modulation) of action at the same GABAB receptors, to actions on non-GABAergic systems, or to nonpharmacologic factors (availability) that can dramatically influence recreational drug use.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: GHB, -hydroxybutyrate; NCS-382, (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulene-6-ylidene ethanoic acid; CGP 35348, (3-aminopropyl)(diethoxymethyl) phosphinic acid; FR, fixed ratio; GBL, -butyrolactone; 1,4-BDL, 1,4-butanediol; %DR, percent drug lever-responding.
Address correspondence to: Dr. Charles P. France, Department of Pharmacology, Mail Code 7764, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: france{at}uthscsa.edu
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