Gestational ethanol and nicotine exposure: effects on maternal behavior, oxytocin, and offspring ethanol intake in the rat.

Alcohol consumption and smoking during pregnancy is common, despite the known adverse effects of these drugs on fetal development. Though studies on the effects of each drug separately are published, little is known about the effect of concurrent use of alcohol and nicotine in humans or in preclinical models. In this report, we examined the impact of continuous gestational exposure to both ethanol via liquid diet and nicotine via an osmotic minipump on maternal behavior, offspring ethanol intake, and oxytocin levels in a rat model. Dams were tested for the onset of maternal behavior with litters of unexposed surrogate pups and then killed to examine oxytocin levels within specific brain regions. Drug-exposed offspring reared by surrogate dams were tested for ethanol intake at either adolescence or adulthood, and oxytocin levels were measured in relevant brain regions after behavioral tests. Dams exhibited minor deficits in maternal care, which were associated with lower oxytocin levels in both the ventral tegmental and medial preoptic areas compared to control dams. Prenatal exposure altered sex-specific ethanol intake, with differential effects at adolescence and adulthood. Oxytocin system changes were also apparent in the ventral tegmental and medial preoptic regions of drug-exposed adolescent and adult offspring. These results suggest that dam treatment with ethanol and nicotine can somewhat negatively affect the early rearing environment, and that prenatal exposure to both of these drugs results in drinking behavior differing from what would be expected from either drug alone. Oxytocin's possible involvement in the mediation of these effects is highlighted.

Withdrawal emotional-regulation in infant rats from genetic animal models of depression.

Children of depressed parents exhibit high rates of emotion-dysregulation, characterized by excessive withdrawal or approach strategies toward the mother in infancy. The understanding of factors affecting the establishment of these behavioral deficits is limited. The current study utilized two genetic animal models of depression, the Wistar-Kyoto (WKY) and Flinders Sensitive Line (FSL) rat strains. In addition, in order to assess the interactive effects of depressive vulnerability and exposure to early life stress, the subjects were raised either in a standard rearing condition or exposed to mild chronic-stress on postnatal days (PND) 2-9. On PND 10-11, an isolation test examined the pups' emotion-regulation. WKY pups produced less separation-induced ultrasonic vocalizations (USV) and proximity-seeking behaviors, compared to controls. In addition, WKY pups did not show the expected potentiation effect that was evident in control pups (an increase in USV and pivoting behavior after a short reunion with the dam). FSL pups exhibited less proximity-seeking behaviors compared to controls while showing levels of USV, potentiation of USV, and change in proximity-seeking behaviors that were similar to controls. No differences between the strains were found in self-grooming. The early life chronic-stress paradigm had no effect on the behaviors of the pups, indicating either stress-resilience or a limited effect of the paradigm. Overall, the results tentatively imply a tendency of the WKY and FSL pups towards withdrawal behavior instead of approach-behavior when regulating emotion, with a more pronounced pattern in WKY pups. This behavioral profile is reminiscent of avoidant attachment, a characteristic of many children of depressed parents.

Anxiety-like behaviors in pre-pubertal rats of the Flinders Sensitive Line (FSL) and Wistar-Kyoto (WKY) animal models of depression.

Animal models have been used in understanding the neuro-biological basis of depression and predicting successful treatment strategies. The current study focused on two genetic models of depression, the Flinder's Sensitive Line (FSL) and Wister-Kyoto (WKY). Our laboratory showed depressive symptomatology in pre-pubertal WKY and FSL rats, and the current study focused on the strains' anxiety-like traits. Since human depression-anxiety comorbidity is very common at young ages, it is essential to establish whether FSL and WKY pre-pubertal rats also exhibit such comorbidity. In addition, the effect of different rearing environments was studied using a mild chronic-stress condition (limiting available bedding between post-natal days 2-9). Two well-validated tests of anxiety, the open-field and elevated plus-maze, were used on 40-day-old pups. FSL pups exhibited lower anxiety-like behavior when compared to controls, in traditional open-field and plus-maze measures. A different pattern was observed in the WKY strain, which exhibited heightened anxiety-like behaviours in the FSL strain and affecting WKY's body-weight. Overall, the findings indicate differential expression of anxiety in pre-pubertal rats belonging to the 'depressed' strains, suggesting that these strains may be suitable for modelling different sub-groups of depression at young ages.

Reward and anxiety in genetic animal models of childhood depression.

One of the most important criteria for major depressive disorder in adults and in children and adolescents as well, is the loss of interest in or pleasure from typically enjoyable experiences or activities: anhedonia. Anxiety is frequently co-morbid with depression. We examined reward and anxiety in genetic animal models of childhood depression. Two different "depressed" lines were studied: the Flinders Sensitive Line (FSL) and their controls, Sprague-Dawley (SD) rats and the Wistar Kyoto (WKY) line and their controls, Wistar rats. Recently, we found that prepubertal rats (about 35 days old) from these lines exhibited increased immobility in the swim test, and abnormal social play observed after 24-h isolation. We hypothesized that FSL and WKY prepubertal rats will further show anhedonia in two different behavioral assays: the conditioned place preference test (CPP), examining the rewarding aspect of social interaction and the saccharin preference test. Behavior in the open field paradigm and freezing behavior in the CPP apparatus were also used as measures of anxiety. WKY, but not FSL prepubertal rats, consumed less of the saccharin solution compared to their control line. FSL, and WKY prepubertal rats found social interaction to be rewarding to a similar extent as their control lines, in the CPP test. Only the WKY rats showed anxiety in behavior in the open field and freezing behavior in the CPP paradigm. The results suggest that WKY prepubertal rats are anxious and sensitive to stress-induced anhedonia, while FSL prepubertal rats exhibit none of these symptoms.

Blunted response to cocaine in the Flinders hypercholinergic animal model of depression.

The Flinders sensitive line (FSL) rat is a proposed genetic hypercholinergic animal model of human depression. Considering the strong comorbidity between depression and cocaine dependence we investigated the well-documented behavioral and molecular effects of cocaine in the FSL and their control Flinders resistant line (FRL) rats. First, we found no difference between the two lines to establish cocaine self-administration; both lines reached stable responding within 10 days of training at a fixed ratio-1 schedule of reinforcement (1.5 mg/kg/injection). However, the FSL rats exhibited reduced cocaine intake at a dose of 0.09 mg/kg/injection in a within-session dose-response curve (0.02, 0.09, 0.38, 1.5 mg/kg/injection). Second, we examined the effects of repeated cocaine administration on locomotor activity, dopamine overflow and striatal prodynorphin mRNA expression. We found the FSL rats to be low responders to novelty and to exhibit less locomotor activation after repeated cocaine administration (30 mg/kg, i.p., daily injections for 10 days) than their controls. Microdialysis sampling from the nucleus accumbens shell revealed no significant difference in the dopamine overflow between the rat lines, neither during baseline nor after cocaine stimulation. Postmortem analyses of striatal prodynorphin mRNA expression (using in situ hybridization histochemistry) revealed a differentiated response to the cocaine exposure. In contrast to control FRL rats, the FSL rats showed no typical cocaine-evoked elevation of prodynorphin mRNA levels in rostral subregions of the striatum whereas both strains expressed increased prodynorphin mRNA levels in the caudal striatum after cocaine administration. In conclusion, the FSL animal model of depression demonstrates marked blunting of the locomotor and dynorphin neuroadaptative responses to cocaine in accordance with its enhanced cholinergic sensitivity.

Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat.

In the search for animal models that can replicate some features of functional dyspepsia (FD) patients, we turned our interest to the Flinders Sensitive Line (FSL) rat. Gastric motility disturbances prevalent in FD patients as well as urine corticosterone and plasma prolactin were measured following buspirone challenge. Flinders Resistant Line (FRL) rat was used as control. The results show that the FSL rats have a disturbed gastric motility, reflected as both an increased gastric accommodation rate and gastric volume during gastric distension as well as a delayed gastric emptying, the latter possibly as a consequence of the former. Lipid administration resulted in a significant increase in maximal gastric volume only in the FRL rats. Both the corticosterone response to buspirone and the 24-h urinary output of corticosterone were normal in FSL rats. Similar to FD patients, the FSL rat showed supersensitivity to buspirone in the increase in prolactin release. Although FSL rats show some features similar to a subset of FD patients, the increased gastric accommodation contrasts to the reduced accommodation often seen in FD patients. Further studies are warranted to determine the relevance of this rat strain as a model for FD.

A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function.

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean +/- SEM, pg/20 microl, was 3.0 +/- 0.4 for LDS, 3.8 +/- 0.3 for HDS and 6.4 +/- 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (+/-)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500%) as compared with LDS (248%) or RDS (243%) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900% in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line.

A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean ± SEM, pg/20 æl, was 3.0 ± 0.4 for LDS, 3.8 ± 0.3 for HDS and 6.4 ± 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (±)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500 percent) as compared with LDS (248 percent) or RDS (243 percent) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900 percent in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line

Chronic inositol treatment reduces depression-like immobility of Flinders Sensitive Line rats in the forced swim test.

Inositol, a precursor of the PIP cycle that was reported to have therapeutic effects in depressive patients and to be effective in two animal models of depression, was evaluated in the forced swim test using the genetic Flinders Sensitive Line (FSL) rats model of depression. Groups of rats were tested in a 2 x 2 design with Strain (FSL or Control) as one factor and Drug (Inositol or Placebo) as the second factor. Rats received chronic treatment (daily for 14 days) with inositol (1.2 g/kg) or placebo (1:2 glucose/mannitol solution). On day 14 rats were exposed to the forced swim test for 5 min and their behavior videotaped. Tapes were analyzed for three levels of activity: immobility, swimming, and vigorous struggle. Inositol countered the exaggerated immobility of FSL rats in the forced swim test, without affecting control animals. Data support our previous suggestion of inositol as a potential antidepressant.

Impaired release of beta-endorphin in response to serotonin in a rat model of depression.

Involvement of both the serotonergic and the endogenous opioid systems in the onset of depressive behavior has been suggested. Previously we showed that serotonin (5-hydroxytryptamine) facilitates beta-endorphin release in the nucleus accumbens (NAcc). Herein, the microdialysis method was used to assess in vivo the effects of serotonin on beta-endorphin release in a rat model of depressive behavior (the Flinders sensitive line, FSL), before and after antidepressant treatment. The basal extracellular level of beta-endorphin in the NAcc of FSL rats did not differ significantly from that in control rats. However, serotonin-induced beta-endorphin release was impaired in FSL rats. Chronic treatment (18 days) with desipramine or paroxetine did not significantly affect the extracellular levels of beta-endorphin in the NAcc of either the FSL or control rats. However, the chronic antidepressant treatment did normalize the serotonin-induced release of beta-endorphin in FSL rats, as well as their behavioral manifestation of depressive behavior. Our results show that depressive behavior may relate to an impaired effect of serotonin on beta-endorphin release in the NAcc in a rat model of depression, and suggest a possible new mode of action of antidepressant drugs.

Masculine sexual behavior features in the Flinders sensitive and resistant line rats.

The Flinders sensitive (FSL) and resistant (FRL) lines of rats have been selectively bred for their differences in cholinergic sensitivity. The FSL rats display hypersensitive responses to agonists of muscarinic receptors. In addition, the FSL rats display behavioral alterations that support the notion that this strain could be useful as an animal model of depression. These abnormalities include increase in rapid eye movement sleep, decrease of saccharin consumption after stress, and reduced exploratory behavior in a novel open field. On the other hand, sexual behavior is a pleasure-seeking behavior that should be altered in a mood disorder characterized by anhedonia. In the present study, spontaneous masculine sexual behavior features were analyzed, both during 30-min tests as well as during a satiety test. Results showed that, compared to outbred Sprague-Dawley (SD) rats, both the FSL and the FRL rats displayed some behavioral impairment, like a marked decrease of the ejaculatory frequency. During the satiety tests, both the FSL and the FRL rats became exhausted sooner than their SD controls. In addition to considering the present results in terms of alterations in specific neurotransmitter systems, endogamy is proposed as a possible source of the behavioral alterations.

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.

Association between depressive behavior and absence of serotonin-dopamine interaction in the nucleus accumbens.

RATIONALE: Current hypotheses on the etiology of depression attribute the disorder to alterations in serotonin and norepinephrine neurotransmission. However, the relationship between these alterations and depressive behavior is poorly understood. Conversely, an interaction between the serotonergic and dopaminergic systems in the nucleus accumbens has been established. Since motivation and hedonia have been associated with dopamine release in the nucleus accumbens, we decided to test its modulation by serotonin in relation to depressive-like behavior. OBJECTIVES AND METHODS: The extracellular dopamine levels in the nucleus accumbens were studied in vivo in Flinders Sensitive Line (FSL, a rat model of depressive behavior) and control rats, before and after antidepressant treatment. Rats were chronically treated with the antidepressants desipramine (5 mg/kg/day) and paroxetine (7.5 mg/kg/day) for 18 consecutive days. As a measure of depressive behavior we used a modified swim test. The release of dopamine in response to local serotonin application was monitored using the microdialysis technique. RESULTS: Serotonin (0.5 microM) facilitated dopamine release in the nucleus accumbens of control rats. In FSL rats, basal extracellular dopamine levels in the nucleus accumbens were 40% lower than in control rats and did not increase in response to serotonin stimulation. However, chronic antidepressant treatment of the FSL rats normalized the serotonin-dopamine interaction as well as their behavioral deficiencies. CONCLUSIONS: The inability of serotonin to stimulate dopamine release in the nucleus accumbens, thereby leading to anhedonia and lack of motivation, may therefore be an essential factor in the onset of depression and a target for modulation by antidepressant drugs.

Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression.

The dopaminergic mesolimbic system has a key role in motivation and reward, and stressful stimuli appear to alter its functionality. Since stress is considered to be one of the primary factors that mediate the expression of depressive behavior, dopamine and its metabolites in the nucleus accumbens of control and Flinders Sensitive Line rats, an animal model of depression, were examined prior to and after a forced swim test. In both types of rats, the levels of dopamine metabolites markedly decreased after the forced swimming, albeit to different extents. In contrast, 60 min after the swim test, dopamine levels were elevated only in the control rats. The accumbal dopaminergic activity is discussed in relation to the behavior of 'depressed' and normal rat lines subjected to a stressful event.

Effects of sweetened ethanol solutions on ethanol self-administration and blood ethanol levels.

The enhancement of voluntary self-administration of ethanol by sucrose or saccharin was tested in conjunction with measurements of blood ethanol levels. Adult male rats were given access to both tap water and one of five solutions: 0.125% saccharin, 10% sucrose, ethanol, saccharin+ethanol, or sucrose+ethanol. The rats receiving the sucrose+ethanol solution drank consistently more ethanol (>5 g/kg/day) than did the rats receiving the saccharin+ethanol solution (<3 g/kg/day) or ethanol only (<2 g/kg/day). Both sweetened solutions produced higher ethanol consumption during these periods than ethanol alone. However, no significant differences in blood ethanol levels were found between the sucrose+ethanol and saccharin+ethanol conditions, when tested at different intervals on Day 44 or Day 45 of ethanol consumption. Following 45 days of consumption, no change in the bicuculline seizure threshold was observed in the ethanol-consuming rats compared to the controls. In a separate study using 90 naive rats, rats were gavaged with ethanol (1, 2, or 3 g/kg) containing either 10% sucrose (n=10 for each dose of ethanol), 0.125% saccharin (n=10 for each dose of ethanol), or ethanol alone (n=10 for each dose of ethanol), and blood was collected from the tip of the tail 30, 60, 180, 300, and 540 min later and analyzed for ethanol concentrations. Sucrose significantly decreased the resultant blood ethanol levels at several time points following gavage. These results indicate that sucrose can significantly alter blood ethanol levels and that chronic self-administration of a sweetened ethanol solution for 6 weeks does not produce ethanol dependence.

Selectively bred male rat lines differ in naïve and experienced sexual behavior.

Ejaculatory behavior is facilitated by activating 5-hydroxytryptamine(1A) (5-HT(1A)) receptors. The present study examined male sexual behavior in rat lines that were selectively bred for their different hypothermic responses to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Sexual behavior was examined in naïve and experienced HDS (high 8-OH-DPAT sensitive), LDS (low 8-OH-DPAT sensitive), and RDS (randomly bred) rats lines. In addition, the effects of 8-OH-DPAT (0.05 mg/kg) and N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl)-cyclohexane-carboxamide (WAY 100,635; 1 mg/kg) were examined. Naïve HDS animals had diminished ejaculatory behavior (as indicated by a decreased number of intromissions, mounts and ejaculations, increased ejaculation and intromission latency, and longer inter-copulatory interval), compared to the LDS and RDS groups. In addition, the post-ejaculatory interval (PEI) was longer in the HDS group. With experience, the HDS group improved its ejaculatory behavior. Experienced HDS animals had a lower number of intromissions and a longer PEI compared to the LDS group. 8-OH-DPAT facilitated ejaculatory behavior in both HDS and LDS groups. This effect was more pronounced in the LDS group. WAY 100,635 did not alter sexual behavior in either group. In summary, alteration in forebrain 5-HT(1A) receptors in HDS animals may be involved in the ability of naïve rats to achieve ejaculation. 5-HT(1A) receptors are involved in the regulation of resumption of sexual behavior after ejaculation.

A genetic rat model of cholinergic hypersensitivity: implications for chemical intolerance, chronic fatigue, and asthma.

The fact that only some individuals exposed to environmental chemicals develop chemical intolerance raises the possibility that genetic factors could be contributing factors. The present communication summarizes evidence from a genetic animal model of cholinergic supersensitivity that suggests that an abnormal cholinergic system could be one predisposing genetic factor. The Flinders Sensitive Line (FSL) rats were established by selective breeding for increased responses to an organophosphate. It was subsequently found that these FSL rats were also more sensitive to direct-acting muscarinic agonists and had elevated muscarinic receptors compared to the selectively bred parallel group, the Flinders Resistant Line (FRL) rats, or randomly bred control rats. Increased sensitivity to cholinergic agents has also been observed in several human populations, including individuals suffering from chemical intolerance. Indeed, the FSL rats exhibit certain behavioral characteristics such as abnormal sleep, activity, and appetite that are similar to those reported in these human populations. In addition, the FSL rats have been reported to exhibit increased sensitivity to a variety of other chemical agents. Peripheral tissues, such as intestinal and airway smooth muscle, appear to be more sensitive to both cholinergic agonists and an antigen, ovalbumin. Hypothermia, a centrally mediated response, is more pronounced in the FSL rats after nicotine and alcohol, as well as agents that are selective for the dopaminergic and serotonergic systems. In some cases, the increased sensitivity has been detected in the absence of any changes in the receptors with which the drugs interact (dopamine receptors), while receptor changes have been seen in other cases (nicotine receptors). Therefore, there may be multiple mechanisms underlying the multiple chemical sensitivity-chemical intolerance of the FSL rats. An elucidation of these mechanisms may provide useful clues to those involved in chemical intolerance in humans.

Conflict behavior and the effects of 8-OHDPAT treatment in rats selectively bred for differential 5-HT(1A)-induced hypothermia.

The high DPAT sensitivity (HDS) and low DPAT sensitivity (LDS) rat lines are the result of selective breeding for differences in the hypothermic response to acute treatment with the 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetralin (8-OHDPAT). The HDS rats exhibit a much greater hypothermic response than do the LDS rats. The present study examined conflict anxiety-like behavior and the effects of acute challenges with 8-OHDPAT and phenobarbital (PhB) on conflict behavior in HDS and LDS rats. Water-restricted (24-h deprivation) HDS and LDS rats were trained to drink from a tube that was occasionally electrified. The 5-s bouts of drinking tube electrification occurred on a fixed interval (FI) 30-s schedule and were signaled by the presence of a tone. Under this schedule, responding is suppressed approximately 10-fold during the tone-on periods compared to the no-tone periods. After two weeks of training in this repeated measures drink suppression conflict paradigm, the effects of acute challenges with 8-OHDPAT (30-500 microg/kg, SC, +10 min) or PhB (20 mg/kg, IP, +10 min) were determined. In control (i.e. , non-drug) conflict test sessions, rats of the HDS line accepted significantly fewer shocks than did rats of the LDS line. Acute treatment with 8-OHDPAT resulted in a modest increase in punished responding (maximum increase: +30-40 shocks/session) in both lines at doses of 60 and 125 microg/kg. Higher doses produced significant general behavioral disruption and substantial reductions in water intake (unpunished responding) in both HDS and LDS rats. Neither the increase in shocks received nor the decrease in water intake produced by these 8-OHDPAT challenges differed between HDS and LDS rats. In both lines, acute PhB treatment resulted in a more dramatic increase in punished responding than did 8-OHDPAT (+55-65 shocks/session) and an increase in water intake. The effects of PhB also did not differ between HDS and LDS rats. These data suggest that the HDS and LDS rats exhibit differences in baseline anxiety-like behavior in the conflict task, but do not differ in their response to acute challenges with PhB or 8-OHDPAT.

Expression and function of striatal nAChRs differ in the flinders sensitive (FSL) and resistant (FRL) rat lines.

Rats of Flinders Sensitive (FSL) and Flinders Resistant lines (FRL) differ in their susceptibility to physiological and associated behavioral responses elicited by nicotine. In the present study, we measured dopamine (DA) content in striatal dialysates to investigate the sensitivity of FSL and FRL rats to nicotine delivered locally through a microdialysis probe placed in the striatum. We also measured the expression density of striatal high-affinity nicotinic acetylcholine receptors (nAChRs), and that of mRNAs encoding for alpha3, alpha4, alpha7 and beta2 nAChR subunits in both lines. The DA content of dialysates was measured before and after a 1-min perfusion of nicotine (6, 10 or 20 nmoles/min) and the resulting DA increase was taken as a measure of the alkaloid's intrinsic activity for nAChRs involved in the release of DA. The nicotine-induced increase of striatal DA release was greater in FSL than in FRL rats for all concentrations of nicotine, suggesting that the intrinsic activity of nicotine was greater in the FSL than in the FRL rats. This was further supported by our finding that the density of high-affinity nAChRs in the striatum of FSL rats was 44% greater than in the FRL rats, whereas affinity (K(D)) was virtually the same in the two lines of rats. Also the expression of mRNAs encoding for alpha(4), alpha(7), and beta(2) subunits in the striatum was greater in FSL than in FRL rats (attomol/microg total RNA, alpha(4):98+/-10 vs. 77+/-7; alpha(7):279+/-16 vs. 184+/-16; beta(2):310+/-19 vs. 201+/-12). We hypothesize that the difference in nicotine-induced DA release in the striatum of FSL and FRL rats depends on the difference in nAChR subunit expression in the striatum between the two lines. The Flinders rats could be used as a model for nicotine self-administration studies to evaluate the susceptibilities of FSL and FRL rats to nicotine dependence.

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.