Pharmacological characterization of harmaline-induced tremor activity in mice.

Harmaline-induced tremor in rodents is a model of essential tremor. We utilized a novel assay to quantify tremor activity in mice and found that tremor activity was dependent on harmaline dose. The first-line clinical essential tremor treatments propranolol, primidone and gabapentin and gamma-hydroxybutyrate (GHB) significantly attenuated harmaline-induced tremor. The anticonvulsants valproate and carbamazepine and the mood stabilizer lithium suppressed harmaline-induced tremor. The gamma-amino-butyric acid (GABA) receptor subtype A receptor agonist muscimol attenuated harmaline-induced tremor. By contrast, the GABA(B) receptor agonist R-baclofen increased tremor at the lowest dose tested, but had no effects at higher doses. Administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine or 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801) attenuated harmaline-induced tremor. The competitive NMDA antagonist D-4-[(2E)-3-phosphono-2-propenyl]-2-piperazinecarboxylic acid (d-CPPene) dose-dependently blocked harmaline-induced tremor, as did the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX). The metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) was inactive against tremor. The dopamine reuptake inhibitor GBR12909 and the dopamine D(1)/D(2) receptor agonist apomorphine attenuated harmaline-induced tremor. Follow-up studies indicated that dopamine D(2)/D(3) but not dopamine D(1) receptor activation likely mediates the effects of apomorphine and GBR12909. Administration of compounds with sedative side-effects had no effect on tremor activity. In summary, the present data confirm the pharmacological validity of harmaline-induced tremor in mice, quantified via a novel assay, as an animal model of essential tremor. Further, these data provide additional evidence for the roles of ionotropic glutamate, GABA(A) and dopamine D(2)/D(3) receptors in the neurobiology of harmaline-induced tremor.

Anxiolytic effects of lamotrigine and JZP-4 in the elevated plus maze and in the four plate conflict test.

JZP-4 is a novel with anticonvulsant, antidepressant and antimania effects in preclinical models. It has some structural similarity to the sodium channel blocker, lamotrigine, but it has both potent sodium and calcium channel blocking activity. In the current studies, JZP-4 was tested in comparison to lamotrigine in the four plate and elevated plus maze tests for anxiolytic activity. In the four plate test, treatment with JZP-4 (30 mg/kg i.p.) produced significant increases in the number of punished crossings. In contrast, lamotrigine produced an inverted U shaped response with a significant increase in punished crossings at 10 mg/kg i.p. but not at 3 or 30 mg/kg i.p. The increased number of punished crossings induced by JZP-4 was similar to that produced by alprazolam (0.3 mg/kg i.p.). In the elevated plus maze test, treatment with either JZP-4 or lamotrigine at 10 mg/kg i.p. produced significant increases in the distance traveled in the open arms. However, only JZP-4 (10 mg/kg i.p.) produced significant increase in the percent of time spend in the open arms. JZP-4, lamotrigine and diazepam did not produce significant changes in the total distance traveled. Indicating that at the doses tested these compounds did not have a sedative effect. These studies have provided preliminary evidence that JZP-4 could have anxiolytic effects in addition to the anticonvulsant, antidepressant and antimania effects reported earlier.

In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity.

JZP-4 is a potent calcium and sodium channel blocker, which is currently being evaluated in patients as an anticonvulsant and mood stabilizer. In the current studies, JZP-4 was evaluated in a variety of animal models for anticonvulsant, antimania and antidepressant activity. In the mouse and rat maximal electroshock models, JZP-4 was slightly more potent than LTG. In the mouse pentylenetetrazole induced seizures model, JZP-4 was approximately twice as potent as lamotrigine in prolonging the time to clonus. In the mouse 6-Hz model for drug resistant or refractory epilepsy, JZP-4 had potent anticonvulsant activity at all current intensities, whereas LTG was active at only the lowest current intensity. In the mouse amphetamine-chlordiazepoxide model for antimanic effects, JZP-4, but not LTG, produced dose-related and significant effects at 3 and 10 mg/kg i.p. In the rat forced swim model of antidepressant activity, JZP-4 (30 mg/kg i.p.) produced a significant reduction in immobility and an increase in climbing behavior. LTG (30 mg/kg i.p.) produced similar effects but these effects did not achieve statistical significance. The specificity of this antidepressant response was confirmed in the rat locomotor test. In this test, JZP-4 produced dose-related and significant reductions in locomotor activity, indicating that it was not a CNS stimulant. LTG produced no significant effects in the rat locomotor test. The studies have demonstrated that JZP-4 has greater potency and efficacy than LTG in models of refractory epilepsy, antidepressant activity and antimania activity. The variance between the effects of LTG and JZP-4 may be related to the greater potency at sodium channels or the additional pharmacological actions of JZP-4 on calcium channels.