The Role of Dopamine Receptors in the Neurobehavioral Syndrome Provoked by Activation of L-Type Calcium Channels in Rodents

Abstract

In rodents, activation of L-type calcium channels with ±BayK 8644 causes an unusual behavioral syndrome that includes dystonia and self-biting. Prior studies have linked both of these behaviors to dysfunction of dopaminergic transmission in the striatum. The current studies were designed to further elucidate the relationship between ±BayK 8644 and dopaminergic transmission in the expression of the behavioral syndrome. The drug does not appear to release presynaptic dopamine stores, since microdialysis of the striatum revealed dopamine release was unaltered by ±BayK 8644. In addition, the behaviors were preserved or even exaggerated in mice or rats with virtually complete dopamine depletion. On the other hand, pretreatment of mice with D₃ or D_1/5 dopamine receptor antagonists attenuated the behavioral effects of ±BayK 8644, while pretreatment with D₂ or D₄ antagonists had no effect. In D₃ receptor knockout mice, ±BayK 8644 elicited both dystonia and self-biting, but these behaviors were less severe than in matched controls. In D₁ receptor knockout mice, behavioral responses to ±BayK 8644 appeared exaggerated. These results argue that the behavioral effects of ±BayK 8644 are not mediated by a presynaptic influence. Instead, the behaviors appear to result from a postsynaptic activation of the drug, which does not require but can be modified by D₃ or D_1/5 receptors.

L‐type calcium channels and psychiatric disorders: A brief review

“…This report follows previous evidence which demonstrated the protective actions of LTCC blockers against neuroleptic-induced movement disorders [Barrow and Childs, 1986;Falk et al, 1988;Cates et al, 1993;Bishnoi et al, 2008]. Moreover, BayK 8644, provokes a dystonia-like motor dysfunction in mice [Jinnah et al, 2000;Kasim et al, 2006]. However, it should also be noted that negative findings have been published in clinical trials of calcium-channel antagonists for tardive dyskinesia [Loonen et al, 1992;Soares and McGrath, 2000].…”

“…However, the protective action of calcium-channel antagonists on psychostimulant-related behavioral effects and abuse liability could be limited to DHPs derivatives [Pani et al, 1990]. Contrasting evidences (e.g., a facilitating effect on cocaine reward) come from an experiment of direct injection of diltiazem into the nucleus accumbens [Chartoff et al, 2006]. Finally, findings from cocaine studies could not be completely extended to amphetamine-induced responses [Ansah et al, 1993].…”

Decreased striatal dopamine receptor binding in primary focal dystonia: A D2 or D3 defect?

“…Although the main focus has been on D2 receptor, D3 receptors have not received much attention given with the low level of their expression in the striatum. Interestingly, an L‐type calcium channel agonist provoked dystonia in mice via affecting the D3 and possibly D1‐like receptors, while D2 receptor did not seem to play a role 64. Indeed, D3 receptor could be a major contributor to dopaminergic synaptic modulations.…”

D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD

“…Briefly , concentric microdialysis probes were constructed as described (Kasim et al, 2006). Mice were anesthetized with Avertin and a microdialysis probe was implanted in the striatum (+0.6 AP, +1.7 ML, 4.5 DV).…”