Subthalamic nucleus microinjections of 5-HT2 receptor antagonists suppress stereotypy in rats.

The subthalamic nucleus (STN) is an important mediator of basal ganglia output. We studied the effects of STN microinjections of the serotonin-2 (5-HT2) antagonists clozapine, mesulergine and M100,907 on apomorphine-induced stereotypic activity in the rat. Each compound profoundly decreased the expression of stereotypic behavior, with particularly strong effects to reduce gnawing behavior. Because M100,907 does not have appreciable affinity for dopamine D1 and D2 receptors, and since all three agents are 5-HT2 antagonists, the current data suggest that basal ganglia output related to orofacial movements can be significantly modified by 5-HT2 receptors. The results suggest that antipsychotics with serotonergic properties may have direct actions on the STN that influence their potential to produce orofacial and other motor side effects.

Adenosinergic modulation of ethanol-induced motor incoordination in the rat motor cortex.

1. On going work in our laboratory has shown that adenosine modulates ethanol-induced motor incoordination (EIMI) when given systemically as well as directly into the cerebral ventricles, cerebellum and corpus striatum of the rat and/or mouse. 2. The objective of this study was to determine what effect adenosine agonists and antagonists would have within the rat motor cortex on EIMI. 3. The participation of the motor cortex in EIMI was suggested when microinfusion of the anti-ethanol compound, Ro15-4513, an inverse agonist of the benzodiazepine binding site, directly into the motor cortex significantly attenuated EIMI. Further, the adenosine agonists N6-cyclohexyladenosine (CHA) and 2-p-(2-carboxyethyl)-phenethylamino-5'-N-carboxaminoadenosine++ + hydrochloride (CGS-21680) significantly accentuated EIMI in a dose-related manner. The adenosine A1 receptor-selective agonist, CHA, appeared most potent in this modulatory effect when compared to the A2-selective agonist, CGS-21680. 4. The extent of diffusion of the adenosine drugs within the cortical tissue after their microinfusion was also checked by measuring the dispersion of microinfused [3H]CHA. The [3H]CHA dispersion study indirectly confirmed that the results of the present investigation were based on the effect of adenosine drugs within the motor cortex only. 5. Accentuation by the A1- and A2-selective adenosine agonists was significantly attenuated by the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) but not by the A2 receptor-selective antagonist 8-(3-chlorostyryl)caffeine (CSC) further suggesting modulation mainly by the A1-subtype. 6. Pretreatment of the motor cortex with pertussis toxin (PT) significantly reduced the capacity of both A1- and A2-selective adenosine agonists to accentuate EIMI suggesting the involvement of a PT-sensitive Gi/Go protein. 7. These data support earlier work which showed that adenosine modulates EIMI within the central nervous system (CNS), most likely via the A1 receptor, and moreover, extend that work by including the motor cortex as a brain area participating in the adenosinergic modulation of ethanol-induced motor impairment.

Fever and feeding in the rat: actions of intrahypothalamic interleukin-6 compared to macrophage inflammatory protein-1 beta (MIP-1 beta).

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-1 beta, induce an intense fever in the rat when they are injected directly into the anterior hypothalamic, pre-optic area (AH/POA), a region containing thermosensitive neurons. The purpose of this study was to compare the central action on body temperature (Tb) of MIP-1 beta with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Following the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor Tb continuously were inserted intraperitoneally in each of 15 male Sprague-Dawley rats. Each micro-injection was made in a site in the AH/POA in a volume of 1.0 microliter of pyrogen-free artificial CSF, recombinant murine MIP-1 beta, or recombinant human IL-6. MIP-1 beta in a dose of 25 pg evoked an intense fever characterized by a short latency, a mean maximum rise in Tb of 2.4 +/- 0.21 degrees C reached by 3.7 +/- 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/POA, IL-6 induced a dose dependent fever of similar latency and a mean maximal increase in Tb of 1.2 +/- 0.25 degrees C, 1.8 +/- 0.15 degrees C, and 2.1 +/- 0.22 degrees C and duration of 6.2 +/- 1.28 hr, 6.7 +/- 0.49 hr, and 6.8 +/- 0.65 hr when given in doses of 25, 50, and 100 ng, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Fever of unknown origin: due to C. albicans or other fungi acting on the hypothalamus?

Recently, it was shown that cerebrospinal fluid (CSF) contaminated with the fungus Trichosporon beigelii produces an intense fever when the organism is microinjected directly into the thermosensitive region of the anterior hypothalamic preoptic area (AH/POA). The purpose of this study was to determine if the AH/POA possesses a corresponding sensitivity to another fungal organism, Candida albicans. In adult male Sprague-Dawley rats, an intracerebral cannula was implanted stereotaxically above the AH/POA and a radio transmitter for the continuous recording of body temperature (Tb) was placed in the peritoneal cavity. After recovery, one of two solutions was microinjected in the AH/POA: a pyrogen-free, filtered artificial CSF and a second cultured with C. albicans in a concentration of approximately 12 x 10(8) organisms/ml. Whereas the filtered CSF failed to evoke a significant rise in Tb, C. albicans produced a febrile response of 0.8-1.5 degrees C in the rats within 1 h after its microinjection into the AH/POA. This fever persisted typically for > or = 12 h but after 24 h Tb returned to the baseline. Histological examination of the cerebral tissue postmortem revealed focally extensive granulomatous encephalitis with disseminated inflammation throughout the parenchyma of rats given repeated microinjections of C. albicans. Since C. albicans is a highly potent pyrogen acting directly on thermosensitive neurons, it is envisaged that a massive accumulation of the organism within the brain could be responsible pathologically for the protracted fever "of unknown origin" which gives rise to clinical morbidity.

Fever produced by the fungus T. beigelii infused into the anterior hypothalamic preoptic area of the rat.

Previously it was reported that a control saline solution infused into the anterior hypothalamic, preoptic area (AH/POA) can induce an intense fever from an unknown source. To avoid such fevers, cerebral dialysis has been proposed as an alternative procedure, although in nearly all experiments on the febrile response, a nonpyrogenic solution is injected, not dialyzed, directly into the AH/POA. The purpose of this study was to determine the: a) possible conditions whereby a control solution can cause an experimental fever; b) putative organisms which may comprise the source of a centrally induced fever; and c) procedures whereby such fevers can be avoided. In twelve adult male Sprague-Dawley rats, an intracerebral cannula for microinjections and a Minimitter temperature transmitter were implanted within the AH/POA and intraperitoneal cavity, respectively. Following recovery, the thermoreactivity of each site in the AH/POA was verified by a microinjection of norepinephrine which typically lowers body temperature (Tb) by 0.5-1.0 degrees C. Two artificial cerebrospinal fluid (CSF) test solutions were used: one exposed to the ambient conditions of the laboratory, and a second prepared under pathogen-free conditions, including filtration, to exclude biological contaminants. A rise in temperature of 0.8-1.0 degrees C within 1.0 h after microinjection, which increased to as high as 3.5 degrees C within 4 h, typically was produced by the contaminated artificial CSF solution. The filtered CSF did not evoke a consistent or reliable rise in Tb of the rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Age dependent development of ethanol drinking in rats after inhibition of aldehyde dehydrogenase.

The purpose of this experiment was to determine the temporal characteristics associated with the age-related development of volitional consumption of ethanol induced by the pharmacological inhibition of aldehyde dehydrogenase (AlDH). To induce preference for ethanol, the AlDH inhibitor, cyanamide, was administered to male Sprague-Dawley rats which were 30 days of age. Cyanamide (n = 8) was injected subcutaneously twice daily in a dose of 10 mg/kg over a period of 3 days while the control group (n = 6) received the saline vehicle solution according to the same schedule. Then at 50, 70, 90, and 110 days of age, both groups of rats were given a standard 11-day test of preference for water versus ethanol offered in concentrations ranging from 3% through 30%. The results showed that at 70 days of age the preference for ethanol increased above the level of the 50-day test in terms of absolute g/kg intakes and proportion of ethanol to water consumed over the lower range of 3% through 15% concentrations. During the tests at 90 and 110 days of age, the cyanamide-treated rats further increased their preference for ethanol significantly over the levels at the 70-day test in terms of both g/kg and proportional intakes. The pattern of drinking of ethanol offered in the higher concentrations of 25% and 30% was unrelated to the age of the rats and the overall intakes were significantly higher than those of the lower concentrations. These findings demonstrate that the enzymatic inhibition of AlDH systematically acts in a delayed fashion to shift the pattern of preference for ethanol which is contingent on the maturation of the animal. In this instance, the volitional intake of ethanol in the cyanamide-treated rats reached its maximal level by 90-110 days of age. It is proposed that an endocrine mechanism involved in gonadal maturation may function in the intense shift in alcohol drinking.