PubMed · 9415187
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P M Rowe. 1995. How do antidepressants work?. https://doi.org/10.1016/s1357-4310(95)90551-0
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Serotoninergic and noradrenergic drugs have been shown to initiate and/or modulate locomotion in cats after spinal cord transection and in patients suffering from spinal cord injuries. To establish a firmer basis for locomotor pharmacotherapy, the distribution of alpha1- and alpha2-noradrenergic and serotonin1A (5-HT1A) receptors was examined in the spinal cord of control cats and of from animals with spinal cord transection at T13 some weeks or months previously. In control cats, the highest levels of alpha1-noradrenergic receptors, labeled with [3H]prazosin, were found in laminae II, IX, and X. The alpha2-noradrenergic receptors, labeled with [3H]idazoxan, were found mainly in laminae II, III, and X, with moderate densities in lamina IX. After spinal transection, both receptors did not change in segments above the lesion. At 15 and 30 days after spinal transection, binding significantly increased in laminae II, III, IV, and X for alpha2 and in laminae I, II, III, and IX for alpha1 receptors in lumbar segments. For longer survival times, binding densities returned to near control values. The 5-HT1A receptors, labeled with [3H] 8-hydroxy-dipropylaminotetralin, were found mainly in laminae I-IV and X. After spinal transection, binding significantly increased only in laminae II, III, and X of lumbar segments at 15 and 30 days. Thereafter, binding returned to control values. The pronounced upregulation of different monoaminergic receptors observed in the lumbar region in the first month after spinal transection suggests that these receptors may be important during the period when cats normally recover functions such as locomotion of the hindlimbs.
Although the initiation of inflammatory pain (hyperalgesia) has been demonstrated to require the cAMP second messenger signaling cascade, whether this mechanism and/or other mechanisms underlie the continued maintenance of the induced hyperalgesia is unknown. We report that injection of adenylyl cyclase inhibitors before but not after injection of direct-acting hyperalgesic agents (prostaglandin E2 and purine and serotonin receptor agonists) resulted in reduction in hyperalgesia, evaluated by the Randall-Selitto paw-withdrawal test. In contrast, injection of protein kinase A (PKA) inhibitors either before or after these hyperalgesic agents resulted in reduced hyperalgesia, suggesting that hyperalgesia after its activation was maintained by persistent PKA activity but not by adenylyl cyclase activity. To evaluate further the role of PKA activity in the maintenance of hyperalgesia, we injected the catalytic subunit of PKA (PKACS) that resulted in hyperalgesia similar in magnitude to that induced by the direct-acting hyperalgesic agents but much longer in duration (>48 vs 2 hr). Injection of WIPTIDE (a PKA inhibitor) at 24 hr after PKACS reduced hyperalgesia, suggesting that PKACS hyperalgesia is not independently maintained by steps downstream from PKA. In summary, our results indicate that, once established, inflammatory mediator-induced hyperalgesia is no longer maintained by adenylyl cyclase activity but rather is dependent on ongoing PKA activity. An understanding of the mechanism maintaining hyperalgesia may provide important insight into targets for the treatment of persistent pain.
Modulation of the sexual behavior of male rats by the anxiolytic buspirone (S-20499) and its analog gepirone were compared to the effects of 8-OH-DPAT (or DPAT, a selective 5-HT1A reference agonist), and BMY-7378 (a selective 5-HT1A partial agonist). Long-Evans rats were used; modulation of copulatory behavior and alteration of penile reflexes were examined. Modulation of copulatory behavior was assessed by three indices: frequency and length of intromission, and latency of ejaculation. DPAT, at doses of 1-8 mg/kg, reduced these three indices in a time dependent manner such that the effects peaked at 45 min and normalized at 90 min. The dose-effect relationship (assessed 45 min after DPAT injection) is bell-shaped with an ED50 approximately 1 mg/kg on the ascending limb of the curve. The effects of buspirone (2 mg/kg) and gepirone (2 mg/kg) on copulatory behavior were indistinguishable from control. BMY-7378 alone and in combination with these other 5-HT1A agonists reduced copulatory behavior, though not statistically significant. Penile reflexes, including number of erections, cups and flips, were inhibited by these agents: DPAT>buspirone>gepirone (inactive at 2 mg/kg). Furthermore, the latency period to erection was at least doubled by DPAT (2 mg/kg). Buspirone and gepirone, however, reduced the latency period to erection. BMY-7378 inhibited penile reflexes when administered alone and even more in combination with DPAT or buspirone. Two butyrophenone analogs, spiperone (a 5-HT1A and dopamine D2 antagonist) and haloperidol (a D2 antagonist), were also tested for their interaction with DPAT. Both of these drugs (at 0.25 mg/kg, 60 min after administration) reduced all indices of penile reflexes and copulation. Furthermore, in combination with DPAT (2 mg/kg, 45 min), the effects were synergistic such that sexual activity came nearly to a standstill. These opposing effects on putatively brain originated copulatory behavior and spinal mediated penile reflexes indicate that the effects of buspirone and DPAT on sexual behavior in the male rat may be possible at different parts of the central nervous system. If a tentative shared target site by DPAT and buspirone is the 5-HT1A receptor, than the same 5-HT receptor sub-type at different locations (brain, raphe nuclei, spinal cord and autonomic ganglia) may modulate rat sexual behavior in opposing ways.