ABSTRACT
A significant consequence of chronic ethanol (EtOH) exposure is the development of tolerance. The present study was designed to investigate tolerance to the discriminative stimulus properties of EtOH following chronic EtOH exposure. Adult male C57BL/6J mice were trained to discriminate EtOH (1.00 g/kg; i.p.) from saline, using a food-reinforced two-lever operant task. Following acquisition and establishment of criterion discrimination performance, a series of generalization tests were conducted to generate a baseline EtOH dose-response curve with a calculated ED50 dose of 0.42 g/kg. Mice were then placed into control (air) or EtOH inhalation chambers for 64 h. In Experiment 1, discriminative stimulus generalization tests with the EtOH ED50 dose conducted 24 h following chronic EtOH (or air) exposure did not yield significantly different EtOH responding, although a trend towards reduced sensitivity to the EtOH cue (tolerance) was evident. In Experiment 2, a cumulative dosing procedure (ED50=0.37 g/kg) was employed, yielding a baseline EtOH dose-response function with a calculated ED50 dose of 0.37 g/kg. At 24 h following chronic EtOH exposure, re-determination of the EtOH dose-response curve revealed a significant shift to the right, with more than a twofold increase in the ED50 value (ED50=1.09 g/kg) compared to the control air exposure condition (ED50=0.49 g/kg). This apparent tolerance to the EtOH cue dissipated in chronic EtOH-exposed mice tested 48 h following the inhalation treatment (ED50=0.51 g/kg). These results demonstrate tolerance to the discriminative stimulus effects of EtOH in C57BL/6J mice following chronic EtOH exposure in inhalation chambers.
Subject(s)
Central Nervous System Depressants/pharmacology , Discrimination, Psychological/drug effects , Ethanol/pharmacology , Animals , Central Nervous System Depressants/administration & dosage , Central Nervous System Depressants/blood , Conditioning, Operant/drug effects , Discrimination Learning/drug effects , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Ethanol/blood , Generalization, Stimulus/drug effects , Inhalation Exposure , Male , Mice , Mice, Inbred C57BLABSTRACT
RATIONALE: Centrally active beta-1 and beta-2 adrenergic agonists produce antidepressant-like effects in several behavioral tests, suggesting that these receptors may be involved in the mediation of the effects of antidepressant drugs. OBJECTIVES: This study aimed to evaluate the ability of intra-cerebral ventricular (ICV) isoproterenol to produce discriminative stimulus effects mediated by beta adrenergic receptors, establishing a reliable model of in vivo activation of central beta adrenergic receptors. METHODS: Rats were trained to discriminate the non-selective beta adrenergic agonist isoproterenol (10 microg ICV) from artificial cerebral spinal fluid (aCSF) using a water-reinforced two-lever operant task [fixed ratio-10 schedule of reinforcement (FR10)]. For substitution and antagonism tests, drugs were administered IP. RESULTS: Following acquisition of the discrimination, ICV isoproterenol produced dose-related increases in drug-appropriate responding (ED50 = 1.14 microg). The beta-1 selective adrenergic agonist dobutamine fully substituted for isoproterenol at a dose of 0.3 mg/kg (ED50 = 0.15 mg/kg). By contrast, the beta-2 selective adrenergic agonist clenbuterol produced 20% isoproterenol-appropriate responding when administered at doses up to 0.1 mg/kg. The beta adrenergic antagonist propranolol fully antagonized the isoproterenol cue at a dose of 0.03 mg/kg (ID50 = 0.013 mg/kg). The beta-1 selective antagonist betaxolol (ID50 = 0.03 mg/kg) more potently antagonized isoproterenol's cue than did the beta-2 selective antagonist ICI 118,551 (ID50 = 0.41 mg/kg). The antidepressant desipramine (1.0 mg/kg) substituted for isoproterenol. CONCLUSIONS: These results demonstrate that the discriminative stimulus effects of isoproterenol are mediated primarily via beta-1 adrenergic receptors. This provides a functional model for activation of central beta-1 adrenergic receptors, permitting further characterization of the role of this receptor subtype in the mechanism of action of antidepressant drugs.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Discrimination, Psychological/drug effects , Isoproterenol/pharmacology , Receptors, Adrenergic, beta-1/drug effects , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Antagonists/metabolism , Animals , Binding, Competitive/drug effects , Injections, Intraventricular , Isoproterenol/administration & dosage , Male , Pindolol/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Rolipram, a selective inhibitor of type 4 cyclic AMP phosphodiesterase (PDE4), completely reversed the amnesic effects of MK-801 on working and reference memory (F[4,64] = 11.10; p <.0001 and F[4,64] = 2.53; p <.05, respectively) at doses of 0.01-0.1 mg/kg in the radial-arm maze task. Similar antagonism by rolipram of the effects of MK-801 was observed on inhibitory avoidance behavior (F[3,35] = 190.8; p <.0001). In vitro evidence suggests that an increase in cAMP concentrations may mediate the observed behavioral effects of rolipram. In the absence of PDE4 inhibition, NMDA did not increase cAMP concentrations in primary cultures of rat cerebral cortical neurons. However, when PDE4 was inhibited with rolipram, NMDA markedly elevated cAMP. These observations suggest that PDE4 is an integral component of the NMDA receptor-mediated signal transduction pathway involved in memory processes. Inhibitors of PDE4 may act on this pathway to produce their effects on memory and may represent a new class of cognitive enhancers.
