Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and Δ9 -tetrahydrocannabinol.

BACKGROUND AND PURPOSE: Memantine and marijuana smoking have been found to inhibit tremor in parkinsonian patients, although the observed effects were relatively weak. The tremorolytic effects of combinations of memantine and cannabinoids have not been studied. Here, we have evaluated the anti-tremor activity of memantine, Δ9 -tetrahydrocannabinol (THC) given alone and of their combination. The involvement of some neuroanatomical structures in the effects of the combination was evaluated. EXPERIMENTAL APPROACH: Haloperidol-induced tremulous jaw movements (TJMs) in rats were used as a model of parkinsonian-like tremor. To evaluate the role of central receptor systems in the drug effects, receptor ligands were administered locally into certain brain areas. KEY RESULTS: Memantine and THC alone were without effect, although co-administration of these drugs decreased the number of haloperidol-induced jaw movements. The anti-tremor activity of the combination was antagonized (a) by injections of l-glutamate into the dorsal striatum, entopeduncular nucleus, substantia nigra pars reticulata, globus pallidus, and supratrigeminal and trigeminal motor nuclei but not into the subthalamic and cuneiform nuclei; (b) by injections of CGS 21680 into the ventrolateral striatum; and (c) by injections of bicuculline into the rostral part of the parvicellular reticular nucleus. CONCLUSIONS AND IMPLICATIONS: Memantine and THC supra-additively inhibit haloperidol-induced TJMs, suggesting that co-administration of these drugs might be a new approach to the treatment of tremor. Our results identified brain areas influencing parkinsonian-like tremor in rats and can help advance the development of novel treatments for repetitive involuntary movements.

Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats.

Neural circuits involved in the development of depression are currently poorly understood. To provide insight into this issue, we evaluated the influence of seven clinically effective antidepressants on neuronal activity in thirty rat brain areas. Drugs belonging to all major groups of antidepressants (imipramine, reboxetine, fluoxetine, bupropion, mirtazapine, agomelatine, and phenelzine) were examined; since antidepressants typically require weeks of continued administration before they achieve a therapeutic effect, we administered these drugs for 21 days. The experiments were conducted with male Wistar rats. To identify the neuroanatomical targets for antidepressants, the alterations of c-Fos expression in different brain areas were measured using ELISA assay. The drugs were examined at doses sufficient to produce behavioral effect in the rat forced swim test (FST). All the drugs at the behaviorally relevant doses activated two brain areas, the lateral entorhinal cortex and dorsal subiculum of the hippocampus; none of the drugs affected the c-Fos expression in the medial orbital, prelimbic and infralimbic cortex, caudate putamen, nucleus accumbens core, bed nucleus of stria terminalis, hipothalamic paraventricular nucleus, medial amygdaloid nucleus, lateral habenula, substantia nigra pars compacta and pars reticulata, ventral tegmental area, hippocampal ventral subiculum, dorsal and ventral periaqueductal gray matters, and medial entorhinal cortex. These findings suggest that the stimulation of the lateral entorhinal cortex and hippocampal dorsal subiculum play a role in therapeutic effects of antidepressants.