Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment

5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: More than 30 years of research

Neurons in the dorsomedial hypothalamus (DMH) play key roles in physiological responses to exteroceptive (“emotional”) stress in rats, including tachycardia. Tachycardia evoked from the DMH or seen...

The dorsomedial hypothalamus: a new player in thermoregulation

Drug addiction and drug abuse in Korea.

The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse.

8-OH-DPAT (2.5–10 mg/kg) and buspirone (10 mg/kg) but not 5,7DHT (200 Μg/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1–100 Μg/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.

Effect of serotoninergic drugs on stress-induced hyperthermia (SIH) in mice.

Stress-induced hyperthermia (SIH), which is seen in the last mice removed from the cage, is a novel animal model sensitive to anxiolytic drugs. SIH is antagonized by CL 218872 (25 and 50 mg/kg, os), by tracazolate (5 and 7.5 mg/kg, ip) and by 2-AP-5 (50 and 100 mg/kg, ip). At higher dose, CL 218872 (100 mg/kg, os) and tracazolate (12.5 mg/kg, ip) lose their activity.

Effect of psychotomimetics and some putative anxiolytics on stress-induced hyperthermia.

A molecule, 6-methyl-6,11-dihydro-11-[(N,N-dimethylamino) acetyl]dibenzo[c,fl-[1,2,5]thiadiazepine 5,5-dioxide, (IM/P/3/4, CAS 128377-70-8), was identified in a screening program, which had the scope of finding compounds with antidepressive potential without the common sideeffects of existing antidepressive medication. IM/P/3/4 was found active a) in antagonizing apomorphine (16 mg/kg) and reserpine-induced hypothermia in mice; b) in potentiating yohimbine-induced lethality in mice; c) in reducing immobility of rats forced to swim and of mice suspended by the tail. IM/P/3/4 does not affect a) apomorphine-induced stereotypy; b) amphetamine-induced hypermotility; c) haloperidol-induced catalepsy and water-induced grooming and d) does not induce stereotypy or alter motor activity. The compound also a) reduced the beating of rat right heart atria only at a concentration of 3 x 10-4 mol/l; b) had weak anticholinergic activity; c) antagonized electroshock-induced convulsions and d) prevented indometacin-induced duodenal ulcers. IM/P/3/4 does not have good affinity for noradrenergic, serotonergic, dopaminergic, histaminergic or muscarinic receptors and does not displace imipramine, desipramine and mianserine from their binding sites. IM/P/3/4 increases 5-hydroxyindolacetic acid content and 3H-serotonin uptake in the hypothalamus. The present results suggest that IM/P/3/4 is a potential antidepressant with reduced side effects and with a mechanism of action which is different from that of other antidepressants.

Potential antidepressant activity and enhancement of serotonin uptake of a new dibenzothiadiazepine derivative.

— The D-2 agonist LY 171555 (0.05, 0.1, 0.2 mg kg−1 s.c.) but not the D-1 agonist SK&F 38393 (5, 10, 20 mg kg−1 s.c.) reduced reserpine-induced hypothermia (RIH) in mice. This effect was antagonized by the D-2 antagonist (-)-sulpiride (50 mg kg−1 i.p.) but not by the D-1 antagonist SCH 23390 (0.1 mg kg−1 s.c). SK&F 38393 (20 and 1 mg kg−1 s.c.) did not alter the effect of LY 171555 (0.1 and 0.2 mg kg−1) on RIH, but administration of both LY 171555 (0.2 mg kg−1 s.c.) and SK&F 38393 (1 mg kg−1 s.c.) antagonized the reserpine-induced sedation.

Importance of D-2 mechanisms in the reversal of reserpine hypothermia in the mouse.

The reversal of hypothermia, induced by reserpine or by a high (16 mg) dose of apomorphine, in male Swiss mice, does not seem to utilize a common mechanism. Desipramine (20 mg kg-1 i.p., 60 min) or nortriptyline (8 mg kg-1 i.p., 60 min) increased temperature in both reserpine (2.5 mg kg-1 s.c., 18-19 h) and apomorphine (16 mg kg-1 s.c., 30 min) treated mice. In apomorphine-treated animals the effect of both drugs was reversed by the mixed dopaminergic D1- D2-antagonist haloperidol (1 mg kg-1 i.p., 90 min), the D1-receptor blocking drug SCH 23390 (0.05 mg kg-1 s.c., 30 min), the alpha 1-adrenoceptor blocking drugs prazosin (3 mg kg-1 s.c., 90 min) and phenoxybenzamine (20 mg kg-1 i.p., 65 min), the beta-adrenoceptor blocking drug (+/-)-propranolol (10 mg kg-1 i.p., 120 min), and the opioid antagonist naloxone (2 mg kg-1 i.p., 15 min). In contrast the selective D2-antagonist (+/-)-sulpiride (100 mg kg-1 i.p., 90 min), and the alpha 2-antagonist yohimbine (2 mg kg-1 i.p., 75 min), failed to effect the reversal of apomorphine hypothermia brought about by desipramine or nortriptyline. Their temperature effects in reserpinized mice were not modified by any of the antagonists tested.

G. Volterra

Papers

Effect of serotoninergic drugs on stress-induced hyperthermia (SIH) in mice.

Effect of psychotomimetics and some putative anxiolytics on stress-induced hyperthermia.

Potential antidepressant activity and enhancement of serotonin uptake of a new dibenzothiadiazepine derivative.

Importance of D-2 mechanisms in the reversal of reserpine hypothermia in the mouse.

Desipramine and nortriptyline antagonize apomorphine and reserpine hypothermia by a different mechanism.