Acoustic startle, conditioned startle potentiation and the effects of 8-OH-DPAT and buspirone in rats selectively bred for differences in 8-OH-DPAT-induced hypothermia.

HDS and LDS rats are the result of selective breeding for differences in the hypothermic effects of the 5-hydroxytryptamine-1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); HDS (high DPAT sensitivity) rats exhibit a much greater hypothermic response than do LDS (low DPAT sensitivity) rats. It is possible that this genetically-based difference in sensitivity to the hypothermic effects of the 5-HT1A agonist is associated with a change in other behaviours modulated by 5-HT neurotransmission. The present study examined the acoustic startle response, the classically conditioned enhancement of startle, and the effects of 8-OH-DPAT and buspirone treatments on these measures, in HDS and LDS rats. On four test sessions, HDS and LDS rats were exposed to 20 acoustic startle stimuli (115 dB; 40 ms in duration). For each test session, 10 trials were presented in the dark (Noise Alone trials) and 10 were presented at the end of a 3500 ms presentation of a 15 W signal light (Light + Noise trials). LDS rats exhibited greater startle amplitude than did HDS rats on Noise Alone trials. Initially, there was no difference in startle amplitude on the Light + Noise versus Noise Alone trials in either LDS or HDS rats. By the end of the first test session, however, and continuing throughout the remainder of the four test sessions, startle amplitude on the Light + Noise trials was significantly greater than in the Noise Alone trials. The magnitude of this startle-potentiated startle (SPS) effect did not differ in HDS versus LDS rats. SPS testing was continued for three additional sessions; in these sessions the effects of acute treatment with the 8-OH-DPAT (125 microg/kg, subcutaneously (s.c.)), the novel anxiolytic buspirone (4 mg/kg, intraperitoneally (i.p.)) or vehicle (distilled water) were determined. Both 8-OH-DPAT and buspirone treatment increased baseline (Noise Alone) startle amplitude in LDS rats but not in HDS rats. With respect to the conditioned enhancement of startle, buspirone reduced the SPS effect in both HDS and LDS rats, whereas 8-OH-DPAT did not change the conditioned enhancement effect in either rat line. These findings suggest that the selective breeding for differences in 8-OH-DPAT-induced hypothermia has resulted in changes in other behaviours and also changes in the response to 5-HT1A agonist treatment. Moreover, these findings are consistent with the hypotheses that: (a) 5-HT1A agonist actions underlie the buspirone-induced and 8-OH-DPAT-induced increases in Noise Alone startle amplitude; whereas (b) the buspirone-induced reduction in potentiated startle is not the result of 5-HT1A agonist actions of this compound.

Enduring effects of prenatal cocaine administration on emotional behavior in rats.

The present studies sought to determine whether prenatal cocaine administration (15 mg/kg b.i.d. between gestational ages 1-20) had enduring effects on emotional behavior of rats. Rats prenatally treated with cocaine interacted less with other rats in the social interaction test of anxiety at both 30 and 120 days of age. However, there were no differences in the elevated plus maze test of anxiety. Rats prenatally treated with cocaine were significantly more immobile in the forced-swim test at 60 and 120 days of age. In addition, animals exposed to prenatal cocaine were more sensitive to the enhancing effect of phencyclidine (2.0 mg/kg) on startle responses to an acoustic stimulus. The cocaine-treated animals tested at 50 to 60 days of age showed higher levels of prepulse inhibition, in comparison to the saline group, after vehicle pretreatment, but not after phencyclidine. Although there were gender differences in the expression of some of these behavioral tasks, there were no gender differences in the effects of cocaine. These findings indicate that when emotional behavior is altered by prenatal cocaine administration, the effects are enduring.

Attenuation of alcohol intake by extract of Hypericum perforatum (St. John's Wort) in two different strains of alcohol-preferring rats.

Extract of the common plant Hypericum perforatum L. (St John's Wort, SJW) has been used successfully for the treatment of mild to moderate depression since ancient times and has recently been studied clinically. Depression and alcoholism have some neurochemical similarities, such as low brain serotonin activities. Thus, we hypothesized that SJW extract, which contains 0.22% hypericin and 4.05% hyperforin, also may be effective in suppressing alcohol intake. To test this hypothesis, the effects of SJW extract on voluntary alcohol intake were studied in two different genetic animal models of human alcoholism: fawn-hooded (FH) and high-alcohol drinking (HAD) rats. FH and HAD rats received a single oral administration (5 ml/kg) of either vehicle or one of the five doses (100, 200, 400, 600, and 800 mg/kg) of SJW extract. The oral administration of SJW extract significantly (P < 0.0001) reduced alcohol intake in both FH and HAD rats. In a third study, FH rats did not develop tolerance to the suppressant effects of SJW on alcohol intake and preference following oral administration of (400 mg/kg) of the extract for 15 consecutive days. These promising findings suggest that SJW extract should be evaluated clinically as a potential therapeutic agent in the treatment of alcoholism.

Ontogeny of muscarinic cholinergic supersensitivity in the Flinders Sensitive Line rat.

The present study examined the ontogeny of muscarinic sensitivity in the Flinders Sensitive Line (FSL) rat, a model for human depression that was selectively bred for increased cholinergic function. In most cases, the FSL rats were more sensitive to the muscarinic agonists, oxotremorine and oxotremorine-M. early postnatally [13 days postpartum (P13)], suggesting that muscarinic supersensitivity is an inherent characteristic of FSL rats. The emergence of increased sensitivity to muscarinic agonists in FSL rats did not correlate with either the emergence of subsensitivity to the muscarinic antagonist, scopolamine, at P60 or with increased muscarinic (M1 or M2) receptor density. Relative to FRL rats, FSL rats did not exhibit increases in muscarinic receptor binding until P32 in the striatum and hippocampus and P120 in the hypothalamus. These results are consistent with the suggestions that (a) muscarinic supersensitivity, which appears early in development, may be associated with depressive disorders, and (b) the differences in muscarinic sensitivity early postnatally cannot be accounted for by an increase in the number of muscarinic receptors, per se.

Suppression of alcohol intake after administration of the Chinese herbal medicine, NPI-028, and its derivatives.

The Chinese herbal medicine, NPI-028, has been used for centuries in China to counteract alcohol intoxication. The present study used a number of different experimental conditions to determine whether NPI-028 and its derivatives might selectively influence alcohol intake in rodents that naturally exhibit high alcohol intakes. It was determined that intraperitoneal (i.p.) injections of NPI-028 (0.5, 0.75, and 1.0 g/kg) suppressed alcohol intake by up to 30% in both alcohol-preferring P and Fawn-Hooded (FH) rats during a continuous access schedule. These injections did not significantly affect food or water intakes, nor did the highest dose of NPI-028 (1 g/kg) alter blood ethanol levels after an i.p. injection of 2.5 g/kg of ethanol. In P rats, it was found that NPI-028 was orally active with the dose of 1.5 g/kg having a greater effect on ethanol intake than the 1.0 g/kg dose; once again, food and water intakes were not significantly altered. In FH rats maintained on a limited access schedule (1 hr/day), alcohol intake was completely abolished by 1.5 g/kg of NPI-028. Chronic i.p. administration of NPI-028 (0.75 g/kg) for four consecutive days in FH rats maintained on a continuous access schedule did not lead to any diminution of its alcohol-suppressant effects. Thus, NPI-028 has significant effects on alcohol intake without much effect on water and food intake, and tolerance does not readily develop to these effects. The i.p. administration of a partially purified extract (NPI-031) of NPI-028, obtained by countercurrent chromatography, also dose-dependently suppressed ethanol intake in FH rats, but the highest dose 200 mg/kg) also significantly decreased food intake. Finally, the i.p. administration of puerarin (NPI-31G), an isoflavone isolated from NPI-031 by countercurrent chromatography, significantly reduced ethanol intake in FH rats without affecting food or water intake. Therefore, NPI-028 and one of its pure components, NPI-031G, selectively reduced ethanol intake in alcohol-preferring rats.

Effects of bright light on responsiveness to a muscarinic agonist in rats selectively bred for endogenously increased cholinergic function.

The Flinders Sensitive Line (FSL) was derived from the Sprague-Dawley rat by selectively breeding those animals exhibiting a high level of sensitivity to an anticholinesterase. The Flinders Resistant Line (FRL) was simultaneously developed as a control line. These lines exhibit nonoverlapping distributions of their thermic responsiveness to oxotremorine. Bright light prevents the development of supersensitivity to oxotremorine occurring as a result of forced stress or treatment with a muscarinic receptor antagonist in the rat. The authors now report that treatment with bright light during the regular photoperiod (i.e., a time that does not produce a phase-shift or free-running) differentially affects the hypothermic response and activity-suppressing effect of oxotremorine in both the FSL and FRL. Both lines exhibit decreased hypothermia without reduction in motor activity in response to oxotremorine following 6 days of treatment with bright light. The magnitude of blunting of the hypothermic response was greater in the FSL than the FRL. These findings suggest that (1) studies of the effects of bright light are contingent on the end point one measures and (2) the capacity of this treatment to blunt the hypothermic response to a muscarinic agonist is greater in an animal model with endogenously hyperactive muscarinic cholinergic systems.

Selective antagonistic effects of exposure to bright light on the hypothermic action of ethanol.

Flinders Sensitive and Resistant Lines of rats, which are differentially sensitive to the hypothermic effects of both muscarinic agonists and ethanol, were exposed to full spectrum artificial bright light for eight days, because exposure to bright light has been shown to blunt hypothermic responses to muscarinic agonists. There was a selective blunting of the hypothermic effects of ethanol, but no significant change in the intoxicating effects of ethanol, as measured by evaluation of the righting reflex. The selective effect of exposure to bright light on the hypothermic actions of ethanol suggests that bright light may be modifying the function of only a limited number of brain regions, including the hypothalamus.