arachidonoylserotonin and capsazepine

CB(1) receptors in the amygdala have been shown to mediate learned and unlearned anxiety states, however, the role of amygdalar TRPV1 receptors remains unclear. In the present study we investigated the potential anxiolytic action of intra-basolateral amygdala (BLA) infusion of N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), and a TRPV1 antagonist. Varying doses of AA-5-HT (0-0.5 nmol) were administered into the BLA prior to elevated plus maze testing. AA-5-HT significantly increased both time spent and number of entries into the open arms. Next, to determine whether the anxiolytic effects were the result of blocking FAAH, TRPV1, or whether a combined action was required, rats were given intra-BLA infusions of either 0.25 nmol AA-5-HT, 1.0 nmol capsazepine (CZP, a TRPV1 antagonist), 0.01 μg URB597 (a selective FAAH inhibitor), or vehicle. Again, AA-5-HT increased the time spent in the open arms as well as the number of open arm entries. In contrast, CZP and URB597 did not reliably alter plus maze performance. We then investigated the effects of co-administration of CZP (1.0 or 10.0 nmol) and URB597 (0.01 or 0.1 μg). At lower doses, co-injections significantly increased both open arm entries as well as the time spent in the open arms, compared to vehicle or either compound alone. While co-administration of the higher doses had no significant effect when compared to either vehicle or CZP treatment, we did observe that open arm activity was elevated in rats receiving combined CZP-URB597 treatment compared to URB597 alone. Overall, our findings indicate that simultaneous FAAH activity and TRPV1 activation are important with respect to the expression of unconditioned fear as mediated within the BLA.

Topics: Amygdala; Analysis of Variance; Animals; Anxiety Disorders; Arachidonic Acids; Benzamides; Capsaicin; Carbamates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Exploratory Behavior; Male; Maze Learning; Rats; Rats, Sprague-Dawley; Serotonin; TRPV Cation Channels

Given that the pharmacological or genetic inactivation of fatty acid amide hydrolase (FAAH) counteracts pain and inflammation, and on the basis of the established involvement of transient receptor potential vanilloid type-1 (TRPV1) channels in inflammatory pain, we tested the capability of a dual FAAH/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT), to relieve oedema and pain in a model of acute inflammation, and compared its efficacy with that of a single FAAH inhibitor (URB597) or TRPV1 antagonist (capsazepine). Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice and the anti-inflammatory and anti-nociceptive actions of AA-5-HT were assessed at different doses, time points and treatment schedule. In addition, endocannabinoid levels were measured in paw skin and spinal cord. Systemic administration of AA-5-HT elicited dose-dependent anti-oedemigen and anti-nociceptive effects, whereas it was devoid of efficacy when given locally. When tested in a therapeutic regimen, the compound retained comparable anti-inflammatory effects. TRPV1 receptor mediated the anti-inflammatory property of AA-5-HT, whereas both CB(1) and TRPV1 receptors were involved in its anti-hyperalgesic activity. These effects were accompanied by an increase of the levels of the endocannabinoid anandamide (AEA) in both inflamed paw and spinal cord. AA-5-HT was more potent than capsazepine as anti-oedemigen and anti-hyperalgesic drug, whereas it shows an anti-oedemigen property similar to URB597, which was, however, devoid of the anti-nociceptive effect. AA-5-HT did not induce unwanted effects on locomotion and body temperature. In conclusion AA-5-HT has both anti-inflammatory and anti-hyperalgesic properties and its employment offers advantages, in terms of efficacy and lack of adverse effects, deriving from its dual activity.

Topics: Amidohydrolases; Analgesics; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Benzamides; Capsaicin; Carbamates; Carrageenan; Hyperalgesia; Inflammation; Mice; Receptor, Cannabinoid, CB1; Serotonin; TRPV Cation Channels

Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).. Because of continuously increasing evidence for a neuromodulatory role of endocannabinoids in dopamine-related pathophysiological responses, we assessed endocannabinoid signaling in DAT KO mice and evaluated the ability of endocannabinoid ligands to normalize behavioral deficits, namely spontaneous hyperlocomotion in these mice.. In DAT KO mice, we found markedly reduced anandamide levels, specifically in striatum, the dopamine nerve terminal region. Furthermore, three distinct indirect endocannabinoid agonists, the selective anandamide reuptake inhibitors AM404 and VDM11 and the fatty acid amidohydrolase inhibitor AA5HT, attenuated spontaneous hyperlocomotion in DAT KO mice. The hypolocomotor effects of AM404, VDM11, and AA5HT were significantly attenuated by co-administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine but not the selective cannabinoid type 1 (CB1)receptor antagonist AM251. Interestingly, TRPV1 binding was increased in the striatum of DAT KO mice, while CB1 receptor binding was unaffected.. These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state. Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia. In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Attention Deficit Disorder with Hyperactivity; Cannabinoid Receptor Modulators; Capsaicin; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Endocannabinoids; Mice; Mice, Knockout; Motor Activity; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Serotonin; Signal Transduction; TRPV Cation Channels