Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism.

We have observed that systemic administration of cannabinoid CB1 antagonists exerts antiparkinsonian effects in rats with very severe nigral lesion (>95% cell loss), but not in rats with less severe lesion (85-95% cell loss). Local injections into denervated striatum and corresponding globus pallidus reduced parkinsonian asymmetry. Infusions into lesioned substantia nigra enhanced motor asymmetries, but this effect was absent after very severe nigral lesion. At the striatal level, CB1 antagonists act enhancing dopamine D1 receptor function and reducing D2 receptor function. Striatal dopaminergic denervation did not affect cannabinoid CB1 receptor coupling to G proteins. These results suggest that (i) systemic administration of CB1 antagonists in rats with severe nigral degeneration is ineffective because striatopallidal-mediated motor effects are antagonized by nigra-mediated activity, and (ii) CB1 antagonists exert antiparkinsonian effects after very severe nigral degeneration because nigra-mediated inhibition disappears. CB1 receptor antagonists that lack psychoactive effects might be of therapeutic value in the control of very advanced stage of Parkinson's disease in humans.

Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D1 (not D2) dopamine receptors.

The periaqueductal grey (PAG) area is involved in pain modulation as well as in opiate-induced anti-nociceptive effects. The PAG possess dopamine neurons, and it is likely that this dopaminergic network participates in anti-nociception. The objective was to further study the morphology of the PAG dopaminergic network, along with its role in nociception and opiate-induced analgesia in rats, following either dopamine depletion with the toxin 6-hydroxydopamine or local injection of dopaminergic antagonists. Nociceptive responses were studied through the tail-immersion (spinal reflex) and the hot-plate tests (integrated supraspinal response), establishing a cut-off time to further minimize animal suffering. Heroin and morphine were employed as opiates. Histological data indicated that the dopaminergic network of the PAG is composed of two types of neurons: small rounded cells, and large multipolar neurons. Following dopamine depletion of the PAG, large neurons (not small ones) were selectively affected by the toxin (61.9% dopamine cell loss, 80.7% reduction of in vitro dopaminergic peak), and opiate-induced analgesia in the hot-plate test (not the tail-immersion test) was reliably attenuated in lesioned rats (P < 0.01). After infusions of dopaminergic ligands into the PAG, D(1) (not D(2)) receptor antagonism attenuated opiate-induced analgesia in a dose-dependent manner in the hot-plate test. The present study provides evidence that large neurons of the dopaminergic network of the PAG participate in supraspinal (not spinal) nociceptive responses after opiates through the involvement of D(1) dopamine receptors. This dopaminergic system should be included as another network within the PAG involved in opiate-induced anti-nociception.

Effects on turning of microinjections into basal ganglia of D(1) and D(2) dopamine receptors agonists and the cannabinoid CB(1) antagonist SR141716A in a rat Parkinson's model.

Brain cannabinoid CB(1) receptors are expressed in neural areas that contribute to movement such as basal ganglia, where they co-localize with dopamine D(1) and D(2) receptors. The objective of the present study was to further study the functional role of CB(1) receptors along with D(1) and D(2) dopamine receptors of basal ganglia by local injections of SR141716A (CB(1) receptor antagonist), SKF-38393 (D(1) agonist), and quinpirole (D(2) agonist), in a rat Parkinson's model. Turning response after amphetamine was considered as the parkinsonian variable for quantifying motor effects of drugs. The findings indicated that, after intrastriatal infusions, both D(1) or D(2) dopamine receptor agonists alone reduced turning in parkinsonian rats. At the pallidal and subthalamic levels, D(1) (not D(2)) receptor stimulation also reduced rotation. Regarding SR141716A-induced effects, CB(1) antagonism reduced motor asymmetry in parkinsonian rats after injections into striatum, globus pallidus, and to a lesser extent, subthalamic nucleus. At the level of dorsal striatum, effects of SR141716A were mediated through an opposite modulation of D(1) and D(2) dopamine receptor function. At the pallidal and subthalamic nucleus levels, motor effects after SR14716A are not associated to modulation of D(1) and D(2) receptor function.

Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function.

Modulation of the endocannabinoid system might be useful in treating Parkinson's disease. Here, we show that systemic administration of N-(4-hydroxyphenyl)-arachidonamide (AM404), a cannabinoid modulator that enhances anandamide (AEA) availability in the biophase, exerts antiparkinsonian effects in 6-hydroxydopamine-lesioned rats. Local injections of AM404 into denervated striata reduced parkinsonian motor asymmetries, these effects being associated with the reduction of D2 dopamine receptor function together with a positive modulation of 5-HT(1B) serotonin receptor function. Stimulation of striatal 5-HT(1B) receptors alone was observed to ameliorate parkinsonian deficits, supporting the fact that AM404 exerts antiparkinsonian effects likely through stimulation of striatal 5-HT(1B) serotonin receptor function. Hence, modulation of cannabinoid function leading to enhancement of AEA in the biophase might be of therapeutic value in the control of symptoms of Parkinson's disease. On the other hand, reduced levels of N-acyl-transferase (AEA precursor synthesizing enzyme), without changes in fatty acid amidohydrolase (AEA degradative enzyme), were detected in denervated striata in comparison with intact striata. This finding reveals the presence of a homeostatic striatal mechanism emerging after dopaminergic denervation likely tending to enhance low dopamine tone.

Long-chain aminoalcohol and diamine derivatives induce apoptosis through a caspase-3 dependent pathway.

A number of long chain diamines and aminoalcohols and several of their alkyl, acyl and carbamoyl derivatives, have been synthesized and evaluated for their apoptotic activities using the Jurkat cell line. Apoptosis was measured by flow cytometry and the best results were found for the aminoalcohols displaying either a free alcohol or an amine with at least, one free hydrogen atom. The apoptotic pathway was mediated by a disruption of the mitochondria transmembrane potential and caspase-3 activation, inducing DNA fragmentation at the phase G(1)/S of the cell cycle.