Blockade of MK-801 induced ipsiversive turning in 6-OHDA lesioned rats by alpha 1-adrenoceptor antagonists.

Previously the ipsiversive turning response elicited by MK-801 in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra has been shown to be reduced by the alpha 1-receptor antagonist, prazosin. In these experiments the effects of additional alpha 1-adrenoceptor antagonists were examined to verify the involvement of alpha 1-adrenoceptors in the elucidation of the ipsiversive turning response elicited by MK-801. Both aceperone and azapetine did significantly reduce the ipsiversive turning evoked by MK-801. In contrast, neither agent produced a statistically significant reduction in the contraversive turning evoked by the direct acting dopamine agonist, apomorphine. In addition, aceperone also produced a weak but dose-related inhibition of amphetamine-induced ipsiversive rotation, whereas azapetine partially reduced amphetamine-induced turning a non-dose related manner. These data suggest alpha 1-adrenoceptors may be partially involved in the ipsiversive turning response caused by MK-801 and to a lesser extent by amphetamine. This theory was further supported by the finding that reduction of endogenous norepinephrine levels, via administration of the dopamine-beta-hydroxylase inhibitor FLA-63, markedly reduced the turning evoked by MK-801 and to a lesser degree that produced by amphetamine.

Action of selected serotonin antagonists on hyperthermia evoked by intracerebrally injected beta-endorphin.

Methergoline, an antagonist of cerebral serotonin receptors, has been shown to significantly reduce the rise in rectal temperature (Tre) produced by the intracerebral microinjection of beta-endorphin. In this study the role of serotonin in the increase in Tre elicited by beta-endorphin was further examined using three additional serotonin antagonists. beta-Endorphin was administered twice to rats using a crossover design in which half of the animals were first pretreated with the vehicle solution and half with the antagonist. Serotonin antagonists used were: methergoline, methysergide, cinanserin and cyproheptadine. Although methergoline did cause a marked reduction in the beta-endorphin-induced rise in Tre, neither methysergide, nor cinanserin, nor cyproheptadine produced a marked reduction in the hyperthermia. Since methergoline also interacts with the dopamine receptor, the effect of a dopamine antagonist, haloperidol, on the endorphin-evoked response was also examined. Haloperidol failed to attenuate the rise in Tre. The reason for the apparent discrepancy in the action of these serotonin antagonists is unclear. Further research may reveal distinct subpopulations of serotonin receptors at which these antagonists exert differential effects.

Hypothermia elicited by the intracerebral microinjection of neurotensin.

Changes in rectal temperature were measured after the intracerebral microinjection of neurotensin (2.5 micrograms/0.5 microliters) at 135 sites in the rat. At 63 of the 135 microinjection sites, the tridecapeptide produced a rapid onset of hypothermia ranging in magnitude from 0.8 to 2.3 degrees C below the baseline rectal temperature. The drop in rectal temperature persisted for 2-4 hours following the microinjection. The greatest concentrations of neurotensin-sensitive sites were found in the medial preoptic region of the hypothalamus and in the periaqueductal gray area, both of which contain relatively large amounts of endogenous neurotensin. Other active sites were found in the ventral thalamus, the dorsomedial hypothalamus, and in the diagonal band of Broca. At no injection site did neurotensin evoke an increase in rectal temperature. These data support the proposition that neurotensin may act endogenously to mediate heat-loss mechanisms in the rat. The data provide further evidence indicating a potent neuromodulatory role for neurotensin.

Stereospecific antidopaminergic and anticholinergic actions of the enantiomers of (+/-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine (CTC), a derivative of cyproheptadine.

(+/-)-CTC, a cyproheptadine derivative, possesses both antidopaminergic and anticholinergic activities which can be resolved, respectively, into its component (-)- and (+)-enantiomers. Both in vivo (antagonism of apomorphine-induced stereotypy, elevation of striatal homovanillic acid) and in vitro (inhibition of [3H]haloperidol binding), (-)-CTC was less active than haloperidol but more potent or equipotent compared to chlorpromazine. (+)-CTC was a more potent anticholinergic agent in vitro (inhibition of [3H]quinuclidinyl benzilate binding) than either thioridazine or clozapine, whereas in vivo (antagonism of the lethal action of physostigmine) the three compounds were similar. Comparison of the racemate with (-)-CTC in several in vivo test procedures to determine the influence of intrinsic anticholinergic activity showed that the presence of the anticholinergic (+)-enantiomer had little effect on the ability of (-)-CTC to antagonize apomorphine or elevate striatal homovanillic acid, whereas the activity of (-)-CTC was reduced in tests for postural asymmetry, avoidance and catalepsy. Stereoselectivity was also observed in terms of the alpha adrenergic blocking activity of CTC (inhibition of [3H]WB 4101 binding) which resides exclusively in the (-)-enantiomer. The ratios of (+)-CTC and (-)-CTC in terms of their anti-alpha adrenergic/antidopaminergic properties were large, suggesting a low propensity for the elicitation of orthostatic hypotension and sedation.

Effect on core temperature of restraint after peripherally and centrally injected morphine in the Sprague-Dawley rat.

The changes in core temperature (Tc) evoked by morphine in the Sprague-Dawley rate were altered by restraining the rat. The Tc of the free-moving rat rose after the IP (5, 15, 30, 60 mg/kg) or intracerebral injections (10, 20, 50 micrograms) of morphine. In the restrained rate, however, identical doses of morphine evoked either a hyperthermia of lesser magnitude than in the free-moving rat or a drop in Tc. These findings reemphasize the importance of restraint in determinating the action of morphine on Tc and extend the finding to the Sprague-Dawley rat.

Contralateral turning evoked by the intranigral microinjection of muscimol and other GABA agonists.

Contraversive turning was evoked by the microinjection of GABAergic agents into the substantia nigra (SN) of the rat. Muscimol, the most potent GABA agonist, evoked contralateral turning when injected into the SN in doses of 0.005, 0.05, 0.5 and 5 microgram, whereas 0.5 microgram of muscimol applied at extranigral sites produced no turning. A shorter lived contraversive turning response was evoked by the intranigral micro-injection of imidazole acetic acid (10 or 50 microgram), ethanolamine-O-sulphate (25 or 50 microgram), or GABA (50 microgram). No increase in GABA-induced turning was produced by local pretreatment with pipecolic acid (5 microgram). When injected into the SN, neither picrotoxin, in doses of 0.1, 0.5, 1.0 or 2.0 microgram, nor bicuculline methiodide (Bm), in doses of 0.1 or 0.2 microgram, elicited a significant amount of turning. Picrotoxin, however, partially blocked the turning evoked by the intranigral injection of muscimol, both via the i.p. and intranigral routes of administration whereas Bm did not. In addition, haloperidol (1 mg/kg i.p.) antagonized the muscimol-induced turning. Hence, we feel GABA mimetic substances injected within the SN might evoke contralateral turning via activation of a heretofore undescribed neural system arising from the SN or by activating the ipsilateral dopaminergic neurons projecting from the SN.

Synthesis and stereospecific antipsychotic activity of (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.

The synthesis and resolution of 3-iodocyproheptadine [(+/-)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine [(+/-)-5b] are described. The resulting atropisomers undergo reaction with trifluoromethylthiocopper to give optically active products without extensive racemization. In this manner, optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] have been prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The four compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity was found to reside solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b has significant peripheral anticholinergic activity.