Caroline Cohen

Recent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: Evidence for the functional significance of receptor subtypes

Recent research in molecular biology has demonstrated the complexity of GABAA receptors and shown that benzodiazepine (BZ-omega) receptor subtypes have a structural reality. It is therefore appropriate to ask whether the different pharmacological effects produced by benzodiazepines (anticonvulsant activity, anxiety reduction, motor incoordination, learning deficits, characteristic discriminative stimulus effects, tolerance and dependence) are associated with activity at different receptor subtypes. The present paper reviews the literature dealing with the behavioral effects of novel BZ (omega) receptor ligands relevant to the question of the functional significance of the BZ1 (omega 1) and BZ2 (omega 2) receptor subtypes. The only drugs currently available with a considerable degree of selectivity are alpidem and zolpidem. These compounds have relatively high affinity for GABAA receptors containing the alpha 1 subunit (corresponding to the BZ1 (omega 1) subtype) and very low affinity for receptors with the alpha 5 subunit (corresponding to one type of BZ2 (omega 2) receptor). Pharmacological effects observed with these, and other, less selective compounds allow several tentative conclusions to be drawn: (a) Little is known of the role of subtype selectivity in anxiolytic or amnestic effects but compounds with low intrinsic activity may reduce anxiety without giving rise to sedation or motor incoordination and BZ1 (omega 1) selective drugs appear to disrupt memory only at sedative doses; (b) Selectivity for BZ1 (omega 1) receptors may be associated with sleep-inducing activity but not with motor incoordination, suggesting that BZ2 (omega 2) receptors may be of particular importance in mechanisms of muscle relaxation; (c) The discriminative stimulus effects of different BZ (omega) receptor ligands are not identical and differences may be related to receptor selectivity; (d) Compounds with BZ1 (omega 1) selectivity and compounds with low intrinsic activity produce little or no tolerance and dependence. A wider range of selective compounds will be necessary to investigate these factors in detail and many different pharmacological profiles can be expected from drugs with selectivity and different levels of intrinsic activity.

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

Abstract There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D3 versus D2 dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01–0.1u2008mg/kg), the preferential D2 agonist, bromocriptine (1–10u2008mg/kg) and the selective D3 agonists, 7-OH-DPAT (0.003–0.1u2008mg/kg), PD 128907 (0.1–3u2008mg/kg), (+)3PPP (0.3–3u2008mg/kg), quinelorane (0.0001–0.003u2008mg/kg) and quinpirole (0.003–0.03u2008mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D3 but not D2 responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D2/D3 dopamine antagonists, haloperidol (0.1–0.4u2008mg/kg) and tiapride (10–60u2008mg/ kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission.

Effects of D1 dopamine receptor agonists on oral ethanol self-administration in rats : comparison with their efficacy to produce grooming and hyperactivity

Abstract In order to study the potential efficacy of dopamine receptor agonists in the treatment of alcohol abuse, the present study investigated the effects of several dopamine D1 receptor agonists with different intrinsic activities on ethanol self-administration in rats. In a separate experiment, the effects of two of the same compounds on saccharin self-administration were also studied. To investigate further the relationship between activity in reducing ethanol self-administration and efficacies to stimulate D1 receptors, the potencies of the agonists to reduce ethanol self-administration were compared with their potencies to produce hyperactivity and grooming, behaviors which are believed to involve stimulation of D1 receptors. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. Another group of rats was trained to self-administer a solution of saccharin (0.01% w/v) in a similar operant task. Pretreatment with full (R-6Br-APB, SKF 82958 and SKF 81297) and partial (SKF 38393 and SKF 77434) dopamine D1 receptor agonists dose-dependently decreased responding for ethanol. SKF 82958 and SKF 38393 also decreased responding for saccharin. Comparison of potencies to decrease ethanol self-administration with potencies to produce locomotor activity and grooming revealed that reduction of ethanol self-administration by D1 full agonists occurs at doses similar to those which produce grooming and locomotor activity. However, the partial agonists (and in particular, SKF 38393) reduced responding for ethanol at doses lower than those producing hyperactivity. The present results underline the involvement of D1 dopamine receptors in reward processes.

Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps

Previous research has found that drugs with affinity for ω (benzodiazepine) sites differ in their abilities to produce tolerance and dependence. The present study therefore investigated the effects of ligands of ω (BZ) sites in rats that had been rendered tolerant to a benzodiazepine. Two experiments were carried out in separate groups of rats. Behavioral changes induced by chronic infusion of triazolam (3 mg/kg/day, SC, for 14 days) via osmotic pumps were studied in animals trained on a fixed ratio 10 schedule of food presentation. Control animals were implanted with pumps containing the vehicle. Test drugs were administered IP using cumulative dosing. In one experiment triazolam decreased response rates on days 1, 2 and 3 after implantation of the pumps and tolerance developed to this depressant effect. In the other experiment, vehicle and triazolam treated rats differed in their responding during chronic infusion but differences were not statistically significant on any particular day. Flumazenil (3.0–30 mg/kg) greatly decreased rates of responding on day 11 in triazolam treated rats. This effect may represent a precipitated withdrawal syndrome. However, no withdrawal effects on operant performance were observed upon pump removal. Chronic infusion of triazolam did not affect the sensitivity of rats to alpidem on day 11 (10–100 mg/kg) whereas it abolished the stimulant effect of bretazenil (0.1–1.0 mg/kg). Chronic triazolam treatment produced tolerance to the depressant effects of triazolam (1.0–3.0 mg/kg), lorazepam (0.3–3.0 mg/kg) and zopiclone (10 mg/kg) but no tolerance to those of CL 218,872 (3.0–30 mg/kg) and zolpidem (0.3–3.0 mg/kg) when tested 3–14 days after pump removal. Differences between compounds highlighted with this model are in agreement with previous observations that these agents possess different pharmacological profiles and different potentials to induce tolerance and dependence.

Effects of dihydropyridine Ca2+ channel blockers on the discriminative stimulus and the motor impairing effects of (±)-Bay K 8644

Functional interactions between the dihydropyridine Ca2+ channel activator, (+/-)-Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyphenyl )-pyridine-5-carboxylate), and several dihydropyridine L-type Ca2+ channel blockers were investigated on rotarod performance in mice and in rats trained to discriminate between (+/-)Bay K 8644 and saline. When administered alone, (+/-)-Bay K 8644 produced dose-dependent impairments of rotarod activity with an ED50 of 1.3 mg/kg. Pretreatment with nifedipine (10-30 mg/kg) produced dose-dependent rightward shifts of the (+/-)-Bay K 8644 dose-response curve. In contrast, pretreatment with several other dihydropyridine L-type Ca2+ channel blockers, including nicardipine, nimodipine, isradipine and nitrendipine, did not modify the (+/-)-Bay K 8644 dose-effect function. Rats learned to discriminate between (+/-)-Bay K 8644 (0.5 mg/kg) and saline in an average of 65 training sessions. In substitution tests, the Ca2+ channel activator engendered dose-related increases in the percentage of rats selecting the drug-associated lever with an ED50 of 0.19 mg/kg. Pretreatment with nifedipine (10 mg/kg) produced a rightward shift of the (+/-)-Bay K 8644 dose-response function. Pretreatment with nicardipine (2.5 mg/kg) only partially antagonised the training dose of (+/-)-Bay K 8644 whereas nimodipine (0.6-10 mg/kg) did not affect the (+/-)-Bay K 8644 discriminative stimulus. The results of the present study show that the behavioural effects of the dihydropyridine Ca2+ channel activator are differentially modified by dihydropyridine L-type Ca2+ channel blockers. These results may suggest that dihydropyridine blockers possess different intrinsic activities or act at different binding sites.

Effects of chronic treatment with triazolam on operant responding in rats.

The aims of the present study were to investigate the effect of the benzodiazepine antagonist, flumazenil, on operant responding in rats treated chronically with the short-acting hypnotic triazolam and to study the consequence of chronic triazolam treatment on the time course of effects of triazolam and zolpidem. Zolpidem is an imidazopyridine with a pharmacological and behavioral profile that differs from that of the benzodiazepine hypnotics. Rats were treated with saline or triazolam (1 or 3 mg/kg) twice daily for 5 days and were tested daily 1, 3, 5.5 or 7.5 h after injection. In addition, on the 5th day of chronic treatment all rats were injected with flumazenil (10 mg/kg) 10 min before session. The time course of effects of triazolam and zolpidem was determined after cessation of repeated saline or triazolam treatment. Tolerance to the depressant effect of 1 mg/kg of triazolam developed during long-term administration. Flumazenil decreased operant responding in rats pretreated with triazolam. The effect was statistically significant when rats had received 1 mg/kg of triazolam 3 h before the session or 3 mg/kg of triazolam 3, 5.5 or 7.5 h before the session. After cessation of chronic treatment, rats pretreated chronically with 3 mg/kg of triazolam displayed decreased sensitivity to triazolam and to 10 mg/kg but not 3 mg/kg of zolpidem. The present results indicate that chronic treatment with triazolam induces tolerance to the rate-decreasing effect of the drug and dependence as measured by flumazenil-induced disruption of operant responding. The limited degree of cross-tolerance between zolpidem and triazolam may suggest that their pharmacological mechanisms of action are distinct.

Nicotine dependence: a preventable risk factor for other diseases.

Nicotine meets all critical criteria for an addictive drug. Furthermore, there is no evidence that there would be wide-spread compulsive use of tobacco without nicotine. These findings have led to consideration of the cigarette as a contaminated vehicle for an addictive drug (nicotine). Nevertheless, nicotine itself may also be used therapeutically to reduce exposure to carcinogens and other tobacco toxins. Nicotine replacement is a useful adjunct in treating tobacco dependence. For example, nicotine replacement in the form of a polacrilex resin (chewing gum) can alleviate physically based signs and symptoms of tobacco abstinence. The fact that this form of nicotine replacement is not attractive to non-users of tobacco has opened the door to the use of nicotine in a therapeutic modality, permitting hope of eliminating tobacco dependence.