Robert W. Dunn

Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze

The effects of several 5-HT1A agonists and excitatory amino acid antagonists were compared to the standard benzodiazepines, diazepam and chlordiazepoxide (CDP) in two assays predictive of anxiolytic activity, the social interaction and elevated plus maze procedures. Indicative of anxiolytic effects the 5-HT1A agonists, buspirone, gepirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) all significantly increased social interaction time and open arm exploration time in the social interaction and elevated plus maze procedures, respectively. Likewise, anxiolytic activity in these assays were also produced by the competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (AP-5), 2-amino-7-phosphonoheptanoic acid (AP-7), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the non-competitive NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) while NMDA produced anxiogenic effects. Furthermore, the anxiolytic effects of these agents were of equal magnitude to the benzodiazepines. These two classes of compounds were differentiated in the yohimbine-induced seizure assay, with the NMDA antagonists dose dependently antagonizing seizures similar to the benzodiazepines while the 5-HT1A agonists were inactive. These results suggest that the 5-HT1A agonists and the NMDA antagonists may be potential non-classical anxiolytic agents with different mechanisms of action.

Selective serotonin re-uptake inhibitors decrease schedule-induced polydipsia in rats: a potential model for obsessive compulsive disorder

Schedule-induced polydipsia was used to determine the effects of selective serotonin re-uptake inhibitors on adjunctive water consumption. Polydipsia was induced in food deprived rats by exposure to a fixed time feeding schedule (FT=60 s) for 150 min per day for 22 days. Selected polydipsic rats consumed 3–4 times greater volume of water compared to food deprived control rats. Chronic administration of the selective serotonin re-uptake inhibitors fluoxetine and clomipramine (CMI) at 5 mg/kg per day and fluvoxamine at 10 mg/kg twice a day significantly decreased schedule-induced polydipsia (SIP) on day 15 and throughout the remainder of the study compared to control rats. The noradrenergic re-uptake inhibitor, desipramine (DMI), only decreased SIP behavior on day 1. The neuroleptic, haloperidol (0.03 and 0.1 mg/kg), and the benzodiazepine, diazepam (2.5 mg/kg), failed to alter SIP behavior. Since obsessive-compulsive disorder (OCD) and polydipsic behavior both involve excessive expression of a normal behavior, the polydipsia model may be relevant for the prediction of compounds useful in the treatment of OCD.

D-cycloserine attenuates scopolamine-induced learning and memory deficits in rats

The muscarinic antagonist scopolamine (SCOP; 1.0 mg/kg, ip) impaired both the acquisition of a learning task in the Morris water maze (MWM) and choice accuracy in the T-maze reinforced alternation procedure in rats. Acetylcholinesterase inhibitors (AChEIs) have been shown to attenuate these deficits. D-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, was investigated for its effects on SCOP-induced dementia in the MWM and T-maze paradigms. Combined administration of SCOP and DCS (3.0, 10.0, or 30.0 mg/kg, ip; 30 min pretreat) significantly reversed SCOP-induced deficits in the T-maze as measured by percentage correct choices. In addition, DCS (3.0 or 10.0 mg/kg, ip) significantly attenuated SCOP-induced deficits in the MWM as measured by latency to find the submerged platform. For comparison, the long-acting acetylcholinesterase inhibitor galanthamine (GAL) was tested in the T-maze (1.25, 2.5, or 5.0 mg/kg, ip) and the MWM (2.5 or 5.0 mg/kg, ip). GAL attenuated SCOP-induced deficits in both learning and memory models similar to DCS. These data suggest that the strychnine-insensitive partial glycine agonist, D-cycloserine, may be efficacious in disease states of central cholinergic hypofunction such as Alzheimers disease.

Evidence that GABA mechanisms mediate the anxiolytic action of benzodiazepines: a study with valproic acid.

Abstract Valproic acid and diazepam were tested for “anti-anxiety” activity in two animal tests known to predict the anxiolytic action of drugs. In one test, male hooded rats were trained to discriminate the “anxiomimetic” action of pentylenetetrazol from saline by responding on one of two levers for food reinforcement after pentylenetetrazol (1450 μmol/kg) injection and the other lever after saline injection. Once the pentylenetetrazol-saline discrimination was acquired, pretreatment with either diazepam (4.4–35.0 μmol/kg) or valproic acid (278–2220 μmol/kg) produced a dose-dependent antagonism of the “anxiomimetic” stimulus in this test. In the other test, male Wistar rats were trained to respond for milk reinforcement and to suppress those responses when the reinforcement was accompanied by the simultaneous delivery of foot shock. Treatment of these rats with diazepam (7–28 μmol/kg) or valproic acid (1110–2220 μmol/kg) antagonized the suppression of responding induced by the foot shock in a dose-dependent manner. In both tests, diazepam and valproic acid showed anxiolytic activity at doses which did not result in an overall suppression of responding. The demonstration of anxiolytic activity by the GABAmimetic drug, valproic acid, suggests that GABA mechanisms may mediate the anxiolytic action of benzodiazepines.

GABAmimetic agents display anxiolytic-like effects in the social interaction and elevated plus maze procedures

Benzodiazepine (BZD) anxiolytics, through their activation of the BZD-GABA receptor complex, display robust anxiolytic-like effects following systemic administration in both conditioned and non-conditioned behavioral procedures. The present results show that the GABAA agonists muscimol (0.5–1.0 mg/kg), THIP (2.5–10.0 mg/kg), and isoguvacine (25.0 mg/kg) as well as the GABA transaminase (GABA-T) inhibitor AOAA (aminooxyacetic acid; 5.0–20.0 mg/kg) following intraperitoneal administration exert anxiolytic-like activity of similar magnitude to that of diazepam in two nonconditioned procedures, namely the social interaction and the elevated plus maze tests. We have also extended our original findings that the anti-epileptic drug sodium valproate exerts an anxiolytic-like effect in the Geller conflict paradigm, to show this agents robust activity in the social interaction and elevated plus maze tests following systemic administration (100–400 mg/kg). These results show that GABAergic agents that facilitate GABA transmission are effective following systemic administration in non-conditioned anxiety procedures and may indicate potential therapeutic efficacy in certain anxiety states.

Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents

Anxiolytic agents disinhibit suppressed behaviors in rodents in preclinical models of anxiety such as the non-conditioned social interaction and elevated plus maze assays and the conditioned conflict Cook and Davidson procedure. The (+) and (-) enantiomers of (+/-)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966) have been resolved and revealed that R-(+)-HA-966 significantly disinhibits both non-conditioned and conditioned suppressed behavior similar to the benzodiazepine diazepam, while the S-(-) enantiomer was devoid of anxiolytic activity and only produced behavioral sedation. Furthermore, R-(+)-HA-966 lacked side-effects in rodents commonly associated with the administration of benzodiazepines such as motor incoordination and ataxia, significant interactions with ethanol, and amnesia. These data suggest that R-(+)-HA-966, an antagonist at the strychnine-insensitive glycine/NMDA receptor site, was anxioselective and lacked some of the side-effects associated with benzodiazepine anxiolytics.

Effect of valproic acid on anxiety related behaviors in the rat

Abstract Valproic acid was tested for anxiolytic activity in two behavioral tests most often used to predict anxiolytic activity in man. In one test, male hooded rats were trained to discriminate the anxiomimetic action of pentylenetetrazol by responding on one of two levers for food reinforcement after pentylenetetrazol injection and on the other lever after saline injection. Pretreatment of these rats with valproic acid (320 mg/kg) antagonized the discriminative stimulus produced by pentylenetetrazol. In the other test, male Wistar rats were trained to respond for milk reinforcement in a conflict procedure where some of the reinforced responses resulted in the simultaneous delivery of footshock. Treatment of these rats with valproic acid (320 mg/kg) antagonized the suppression of responding induced by the footshock. In both tests, valproic acid showed anxiolytic activity comparable to diazepam. These data suggest that valproic acid may be useful in treating clinical anxiety.

The effects of GABA agonists and antagonists on apomorphine-induced climbing behavior

Abstract Apomorphine administered at a dose of 1.5 mg/kg SC induces an intense climbing behavior in mice lasting for approximately 30 min. It is known that neuroleptics attenuate apomorphine climbing behavior (AC) but the influence of GABA agonists and antagonists on this behavior is unclear. The GABA agonist, muscimol, blocked AC with an ED50=0.9 mg/kg IP. Pretreatment (5 hr) with aminooxyacetic acid (50 mg/kg IP), a GABA-T inhibitor, produced a 65% inhibition of AC. The GABA antagonists, picrotoxin and bicuculline, had little effect on AC. Baclofen had no effect on AC from 0.5 to 4 mg/kg IP. Interaction studies, combining muscimol and haloperidol were conducted to evaluate the interaction between GABA-ergic and dopaminergic systems on AC. In the first studies mice were treated with haloperidol (0.04-0.15 mg/kg SC) then challenged with inactive (0.2 mg/kg IP) and active (0.4 mg/kg IP) doses of muscimol. In the second series of studies mice were treated with muscimol (0.25-1 mg/kg IP) then challenged with inactive (0.04 mg/kg SC) and active (0.08 mg/kg SC) doses of haloperidol. In all of these experiments, there was an enhanced suppression of AC. Our studies suggest that in addition to dopamine antagonists, GABA agonists are also capable of blocking AC. Our results further suggest that the effect of GABA agonists in inhibiting AC may be mediated through dopaminergic neurons.