Cardiac postjunctional supersensitivity to β-agonists after chronic chemical sympathectomy with 6-hydroxydopamine

Summary The sensitivity to sympathomimetic amines of isolated atria removed from sham-injected and 6-hydroxydopamine-treated (6-OHDA) guinea-pigs was examined in the presence of an extraneuronal uptake blocker and an -adrenoceptor antagonist. Three weeks of pretreatment with 6-OHDA resulted in leftwards shifts of the dose-response curves for the positive chronotropic and inotropic responses of right and left atria to isoprenaline. The responses to the partial agonist salbutamol were also potentiated after 6-OHDA pretreatment, revealed as an increase in the maximum response relative to isoprenaline.The supersensitivity was post-synaptic in origin and independent of changes in disposition or metabolism, since it was observed with agonists immune to neuronal uptake and O-methylation, and in the presence of extraneuronal uptake inhibition by metanephrine. It was also specific for the -adrenoceptor, no supersensitivity to histamine being found. In the right atria, the supersensitivity was partially masked by an opposing depressant effect after 6-OHDA pretreatment which was observed with histamine.Dissociation constants (K _A) for the left atrial inotropic responses to orciprenaline were determined by use of the antagonist Ro 03-7894. Atria from 6-OHDA-pretreated animals were supersensitive to orciprenaline, but the K _A value did not differ from that after sham injection. It could therefore be concluded that the increase in sensitivity was not due to an increase in affinity for the -adrenoceptor.     

Presynaptic dopamine receptors: Insensitivity to kainic acid and the development of supersensitivity following chronic haloperidol

Summary The effects of kainic acid lesions and chronic haloperidol treatment on rat striatal dopaminergic presynaptic receptors were studied. Following the -butyrolactone-induced inhibition of dopaminergic impulse flow, and after dopa decarboxylase inhibition, dopa accumulation and its reversal by dopamine agonists was measured in vivo.³H-apomorphine (a dopamine receptor ligand with purported presynaptic specificity) was used for in vitro binding experiments. Presynaptic dopamine receptors, as assessed by both methods, were unaffected by intrastriatal kainic acid injection 5–6 days before sacrifice. Seven days after termination of chronic haloperidol treatment (28 days, 0.5 mg/kg/day s.c.) both an increased apomorphine response using the dopa accumulation method and an increase in³H-apomorphine binding were observed, indicating the development of presynaptic dopamine receptor supersensitivity.     

Evidence for a receptor supersensitivity following impairment of central serotoninergic activity in the rabbit

Summary In order to investigate whether a chronic impairment of neuronal serotoninergic transmission in the CNS could result in a receptor supersensitivity, rabbits were pretreated either with 5,6-dihydroxytryptamine (5,6-DHT) or p-chlorophenylalanine (PCPA) and then tested for their hyperthermic response to serotoninergic agonists.A previous (10 days before) intracerebroventricular injection of 5,6-DHT (75 g into each cerebral ventricle) significantly potentiated the increase in body temperature induced either by quipazine (1 mg/kg i.v.) or by 5-hydroxytryptophan (5-HTP 2 mg/kg i.v.) in combination with a MAO inhibitor (phenylethylhydrazine 10 mg/kg i.v. 16 h before). Pretreatment with PCPA (100 mg/kg s.c. four times on alternate days, the last dose 48 h before the experiment) also enhanced the hyperthermic effect of quipazine, whereas it inhibited the hyperthermic response to 5-HTP plus MAO inhibitor.These results suggest the exstence of a receptor supersensitivity following prolonged blockade of serotoninergic neuronal transmission in the CNS.Supported by C.N.R. grant n. 75.00620.04.115.2380     

Behavioral evidence for supersensitivity after chronic bromocriptine administration

Behavioral evidence for tolerance and supersensitivity during and after chronic (30 day) administration of bromocriptine (BRC) or bromocriptine + L-dopa in mice was assessed by measuring wheel running (WR) behavior during and after chronic drug administration, and apomorphine- and methylphenidate-(MP-) induced stereotyped gnawing after termination of chronic injections. In both BRC and BRC +L-dopa groups, tolerance developed fairly quickly to the depressing effect of BRC on WR seen on day 1 of drug administration. Mice receiving BRC showed significant increases in WR by week 2 of chronic drug administration, which persisted for at least two days after the termination of chronic injections. During the first week after termination of chronic injections, low doses of both apomorphine and MP induced significantly more stereotyped gnawing in BRC and BRC + L-dopa mice than in the control mice or the mice treated with L-dopa alone. This behavioral evidence for dopaminergic supersensitivity after chronic BRC administration may have relevance for the clinical use of BRC in combination with L-dopa or other dopamine agonists.     

Supersensitivity of cortical neurones of the rat to acetylcholine and L-glutamate following chronic morphine treatment

Summary The effect of microelectrophoretically applied L-glutamate and acetylcholine on discharge activity of cortical neurones was studied in naive and in morphine-tolerant/dependent rats. The thresholds for increase in discharge activity elicited by these 2 putative neurotransmitters were 3 times lower in the tolerant/dependent rats than in the naive rats, indicating the development of supersensitivity.     

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat

Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats.B_max for specific striatal ³H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. B_max for ³H-NPA binding was elevated only after 12 months of both haloperidol and sulpiride treatment. B_max for ³H-piflutixol binding was not alfered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride.Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.     

Behavioural supersensitivity to apomorphine following cerebral dopaminergic denervation by 6-hydroxydopamine

Intraventricular injections of 6-hydroxydopamine that induce a marked and long lasting depletion of cerebral dopamine as well as noradrenaline, greatly enhanced the stimulation of locomotor activity of mice produced by the injection of apomorphine. Dose-response relationships indicated that the maximal response to apomorphine was greatly increased but that there was no apparent change in the ED50 from the response in vehicle-treated mice. 6-Hydroxydopamine treated mice were also considerably less susceptible to the cataleptic activity of pimozide and it is suggested that cerebral dopaminergic denervation may result in an increased number of available post-synaptic dopamine receptors.     

Involvement of both cholinergic and catecholaminergic pathways in the central action of methylphenidate: A study utilizing lead-exposed rats

The effects of methylphenidate (MPH) and the cholinergic agonists nicotine and oxotremorine were tested on the spontaneous multiple unit activity in the mesencephalic reticular formation of two groups of rats. In control rats i.v. MPH (1 mg/kg), nicotine (0.125 mg/kg), and oxotremorine (0.5 mg/kg) all attenuated the unit activity with latencies of less than 10 min. In another group of rats, exposed to lead acetate since birth, the extent of attenuation of unit activity induced by MPH and nicotine was reduced and the latency of effect was delayed by 45–50 min. The latency of the oxotremorine effect was not changed but the attenuation of unit activity was more pronounced in the lead-treated group. Pretreatment with spiroperidol, to inhibit the aminergic receptors, diminished the inhibitory effect of MPH in the control group but not in the lead-treated group, whereas the attenuating effect of oxotremorine was not affected in either group. These data support our previous evidence that MPH exerts its action in the central nervous system by a cholinergic pathway in addition to published catecholaminergic pathways. Furthermore, the present findings indicate that chronic leadexposure in rats results in cholinergic hypofunction and supersensitivity at central cholinergic receptor sites. This alteration of central cholinergic function may be partially attributed to the malnutrition observed in the lead-exposed animals.Part of this work was presented in abstract form (Shih et al., 1976b)     

Effects of acute morphine pretreatment on the rate-decreasing and antagonist activity of naloxone

Rats responded under a schedule in which every 30th lever press (fixed ratio 30) produced a food pellet during sessions divided into six 5-min ratio components separated by 10-min timeout (TO) periods. Cumulative doses of morphine or naloxone were administered at the start of consecutive TO periods. When given alone, morphine decreased response rates in a dose-dependent manner, abolishing responding at 10 or 17.8 mg/kg. Naloxone doses of 0.1 and 1.0 mg/kg restored rates and patterns of behavior suppressed by a dose of 17.8 mg/kg morphine; doses of 0.32 to 10 mg/kg prevented the rate-decreasing effects of cumulative morphine doses. When administered alone, naloxone initially decreased response rates at a cumulative dose of 32 to 100 mg/kg; with repeated testing and intervening morphine exposure, the required cumulative dose was decreased to 10 or 32 mg/kg. An acute 10 mg/kg morphine pretreatment, given 4 h before the session, decreased the cumulative naloxone dose required to suppress rates an additional 10- to 30-fold. This effect was time-dependent and dose-dependent, and the usual naloxone dose-response function could be recaptured 1 week after the pretreatment effect was obtained. In contrast, acute morphine pretreatment did not alter either the cumulative dose of morphine itself required to suppress rates or the naloxone dose required to reverse or prevent morphine's rate-decreasing effects.     

Chronic opioid antagonist treatment: assessment of receptor upregulation

Changes in specific brain opioid binding and opioid pharmacodynamics were determined in mice treated with the opioid antagonist naltrexone (subcutaneously implanted pellets) for 8 days. Chronic opioid antagonist treatment increased the number of binding sites (upregulation) for [³H]naloxone (+55%) and [³H][D-Ala²,D-Leu⁵]enkephalin (+41%) but did not alter the affinity of the ligands, as determined in saturation studies. Displacement studies of [³H]naloxone by morphine also indicated that there was no change in morphine's affinity. In vivo estimation of naloxone affinity (pA₂), agreed with the in vitro results indicating that chronic naltrexone treatment did not alter naloxone affinity. Chronic naltrexone treatment (0.5, 1.0, 15.0 mg pellets) increased the analgesic potency of morphine (supersensitivity) in a dose-dependent manner, up to a maximal increase in relative potency of 1.8. However, in mice tested with the naltrexone pellets still implanted, the 15 mg naltrexone pellet was able to shift the dose-response function for morphine analgesia more than 300-fold. The lowest dose naltrexone pellet (0.5 mg), produced significant antagonism of morphine analgesia, but did not produce significant supersensitivity. Thus, supersensitivity and upregulation are not proportional to the degree of antagonism of opioid effects; and supersensitivity in the mouse is related to increased binding sites and not to changes in receptor affinity as determined by in vivo and in vitro methods.