Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5HT1, 5HT2 and 5HT3 receptors

The effects of serotonin receptor antagonists with differential selectivity for the various classes of 5HT receptors (5HT₁, 5HT₂ and 5HT₃) were tested for their effects on the response to aversive brain stimulation. Electrical stimulation was administered to the dorsal part of the periaqueductal gray matter (PAG), one of the main cerebral structures subserving negative reinforcement. Stimulation frequency thresholds for escape responses were recorded before and following administration of the compounds. Ketanserin (0.32–32 mg/kg IP), trazodone (1.0–22 mg/kg), pirenperone (0.032–1.0 mg/kg) and spiperone (0.1–0.2 mg/kg) dose-dependently increased stimulation frequency thresholds necessary to induce escape responses. Opposite effects were observed with mianserin (0.01–32 mg/kg) and metergoline (0.032–10 mg/kg) which decreased threshold for escape. ICS 205-930 (0.01–10 mg/kg), MDL 72222 (0.1 22 mg/kg) and GR 38032 F (0.1–10 mg/kg) did not affect the stimulation frequency threshold for escape. Prazosin (0.1–2.2 mg/kg) did not specifically affect aversive brain stimulation. Haloperidol (0.02–1.0 mg/kg) increased the frequency threshold for escape responses but with some motoric side effects. These data show that the various types of 5HT receptors differentially contribute to the control of central aversive systems in rats. It is suggested that blockade of 5HT₂ receptors suppresses the central aversive system, whereas blockade of some 5HT₁ receptors enhances aversion and overcomes the 5HT₂-mediated suppression. Blockade of 5HT₃ receptors has no effects. Dopamine receptor blockade further contributes to the suppression of the central aversive system. The relevance of these findings to some pathophysiological mechanisms of anxiety and depressive disorders is discussed.     

Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT<Subscript>1A</Subscript> and 5-HT<Subscript>2A</Subscript> receptors in the rat dorsal periaqueductal gray

RATIONALE: Serotonin in the dorsal periaqueductal gray (DPAG) through the activation of 5-HT(1A) and 5-HT(2A) receptors inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with antipanic drugs that nonselectively or selectively blocks the reuptake of serotonin (e.g., imipramine and fluoxetine, respectively) enhances the inhibitory effect on escape caused by intra-DPAG injection of 5-HT(1A) and 5-HT(2A) receptor agonists. It has been proposed that these compounds exert their effect on panic by facilitating 5-HT-mediated neurotransmission in the DPAG. OBJECTIVES: The objective of this study was to investigate whether facilitation of 5-HT neurotransmission in the DPAG is also observed after treatment with alprazolam, a pharmacologically distinct antipanic drug that acts primarily as a high potency benzodiazepine receptor agonist. MATERIALS AND METHODS: Male Wistar rats, subchronically (3-6 days) or chronically (14-17 days) treated with alprazolam (2 and 4 mg/kg, i.p.) were intra-DPAG injected with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI), and midazolam, respectively, 5-HT(1A), 5-HT(2A/2C), and benzodiazepine receptor agonists. The intensity of electrical current that needed to be applied to the DPAG to evoke escape behavior was measured before and after the microinjection of these agonists. RESULTS: Intra-DPAG injection of the 5-HT agonists and midazolam increased the escape threshold in all groups of animals tested, indicating a panicolytic-like effect. The inhibitory effect of 8-OH-DPAT and DOI, but not midazolam, was significantly higher in animals receiving long-, but not short-term treatment with alprazolam. CONCLUSIONS: Alprazolam as antidepressants compounds facilitates 5-HT(1A)- and 5-HT(2A)-receptor-mediated neurotransmission in the DPAG, implicating this effect in the mode of action of different classes of antipanic drugs.     

Effects of fluoxetine and buspirone on the panicolytic-like response induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

Rationale Administration of 5-hydroxytryptamine (5-HT)_1A and 5-HT_2A receptor agonists into the dorsal periaqueductal gray (DPAG) inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with the antipanic compound imipramine enhances the DPAG 5-HT_1A- and 5-HT_2A-receptor-mediated inhibition of escape, implicating these receptors in the mode of action of panicolytic drugs. Objectives In the present study, we investigated whether the inhibitory effect on escape elicited by the intra-DPAG injection of 5-HT_1A and 5-HT_2A receptor agonists is also enhanced after treatment with fluoxetine, another widely used antipanic drug. The effects of fluoxetine were compared to those of buspirone, an anxiolytic drug without major effect on panic disorder. Methods Male Wistar rats, subchronically (3–6 days) or chronically (21–24 days) treated with fluoxetine (10 mg/kg i.p.) or chronically treated with buspirone (0.3 mg/kg i.p.), were intra-DPAG injected with 5-HT (20 nmol), the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 8 nmol) or the preferential 5-HT_2A receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI; 16 nmol). The intensity of electrical current that applied to the DPAG-evoked escape behavior was measured before and after the microinjection of these agonists. Results The electrical current necessary to produce escape was increased after the microinjection of the three 5-HT receptor agonists in all groups of animals tested. However, this panicolytic-like effect was significantly higher in animals receiving long-term treatment with fluoxetine. Conclusions The results suggest that facilitation of the 5-HT_1A- and 5-HT_2A-receptor-mediated inhibition of DPAG neuronal activity is implicated in the beneficial effect of antidepressants in panic disorder.     

5-HT<Subscript>1A</Subscript> and 5-HT<Subscript>2A</Subscript> receptors in the rat dorsal periaqueductal gray mediate the antipanic-like effect induced by the stimulation of serotonergic neurons in the dorsal raphe nucleus

Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucleus (DRN) to the dorsal periaqueductal gray (DPAG) is implicated in the regulation of escape, a behavior that has been related to panic. Objectives: We further evaluated this hypothesis by investigating whether intra-DRN injection of the 5-HT_1A receptor antagonist WAY-100635 changes the escape response of rats submitted to the elevated T-maze. This test also measures inhibitory avoidance, which has been associated with generalized anxiety disorder. We also investigated whether the 5-HT_1A and 5-HT_2A receptors in the DPAG mediate the behavioral consequences induced by the injection of WAY-100635 into the DRN. Results: Intra-DRN injection of WAY-100635 facilitated inhibitory avoidance, while impairing escape. The same effect was obtained after intra-DRN injection of the glutamate receptor agonist kainic acid. Preadministration of WAY-100635 into the DPAG counteracted the effect induced by intra-DRN injection of WAY-100635 and of kainic acid on escape, but not on inhibitory avoidance. Preadministration of the preferential 5-HT_2A receptor antagonist ketanserin into the DPAG abolished the effects of intra-DRN injection of WAY-100635 on both elevated T-maze tasks. Conclusion: The results are indicative that 5-HT_1A autoreceptors in the DRN are under tonic inhibitory influence by endogenous 5-HT. The effects of 5-HT release in the DPAG after intra-DRN injection of WAY-100635 and kainic acid on inhibitory avoidance and escape involve different 5-HT receptor subtypes. Whereas 5-HT_2A receptors in the DPAG seem to mediate the effect of 5-HT on both behaviors, 5-HT_1A receptors are only involved in the regulation of escape.     

The selective serotonin reuptake inhibitor paroxetine is effective in more generalized and in less generalized social anxiety disorder

RATIONALE: The DSM-IV includes the specifier "generalized" to refer to social anxiety disorder (social phobia) patients if the fears include "most social situations". The focus on interventions such as the selective serotonin reuptake inhibitors (SSRIs) for generalized social anxiety disorder arguably runs the risk that inadequate treatment will be provided to patients with the non-generalized or discrete subtypes. There are, however, few data to address whether more generalized and less generalized subgroups of social anxiety disorder differ in response to medication. OBJECTIVE: To compare response of more generalized and less generalized social anxiety disorder to pharmacotherapy. METHODS: Data from three randomized placebo-controlled double-blind multicenter trials of the SSRI paroxetine in social anxiety disorder were pooled. Response on the Clinical Global Impression Global Improvement item was analyzed using logistic regression, and change in total Liebowitz Social Anxiety Score was analyzed using analysis of variance, with both models incorporating treatment (paroxetine vs placebo), subgroup (more generalized vs less generalized), demographic, and clinical variables. RESULTS: The prevalence of more generalized social anxiety disorder was higher in females than in males. However, there was no significant difference in terms of age or clinical characteristics (duration of condition, baseline pulse, mean arterial blood pressure). At treatment endpoint there were significant treatment effects (for paroxetine vs placebo), but no significant subgroup effects (for more generalized vs less generalized). CONCLUSIONS: Although the current database is limited insofar as few patients with discrete social anxiety disorder would have been included, it is helpful in addressing the value of medication for patients lying on the spectrum from generalized to non-generalized and discrete social anxiety disorder. Paroxetine was effective in both more generalized and in less generalized social anxiety disorder.     

New perspectives in glutamate and anxiety

Anxiety and stress-related disorders, namely posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (ODC), social and specific phobias, and panic disorder, are a major public health issue.A growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response and anxiety-related disorders. The glutamatergic system mediates the acquisition and extinction of fear-conditioning. Thus, new drugs targeting glutamatergic neurotransmission may be promising candidates for new pharmacological treatments. In particular, N-methyl-d-aspartate receptors (NMDAR) antagonists (AP5, AP7, CGP37849, CGP39551, LY235959, NPC17742, and MK-801), NMDAR partial agonists (DCS, ACPC), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) antagonists (topiramate), and several allosteric modulators targeting metabotropic glutamate receptors (mGluRs) mGluR1, mGluR2/3, and mGluR5, have shown anxiolytic-like effects in several animal and human studies.Several studies have suggested that polyamines (agmatine, putrescine, spermidine, and spermine) may be involved in the neurobiological mechanisms underlying stress-response and anxiety-related disorders. This could mainly be attributed to their ability to modulate ionotropic glutamate receptors, especially NR2B subunits.The aim of this review is to establish that glutamate neurotransmission and polyaminergic system play a fundamental role in the onset of anxiety-related disorders. This may open the way for new drugs that may help to treat these conditions.