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Psychopharmacology (2002) 159:138–144DOI 10.1007/s002130100883 Luiz Carlos Schenberg · Larissa Bustamante Capucho
Ricardo Ossamu Vatanabe · Leila César Vargas
Acute effects of clomipramine and fluoxetine on dorsal periaqueductalgrey-evoked unconditioned defensive behaviours of the rat Received: 6 December 2000 / Accepted: 7 July 2001 / Published online: 22 September 2001 Springer-Verlag 2001 Abstract Rationale: Several antidepressants attenuate
Keywords Clomipramine · Fluoxetine · 5-HT · Panic ·
conditioned escape behaviours reinforced by the terminus Periaqueductal Grey · Freezing · Flight of an electrical stimulus applied to the dorsal periaque-ductal grey (DPAG). Objective: The present study exam-ined whether the antidepressant and antipanic drugs clomipramine (CLM) and fluoxetine (FLX) also attenuatethe DPAG-evoked unconditioned defensive behaviours.
Electrical stimulation of dorsal periaqueductal grey Methods: Rats with electrodes in the DPAG were matter (DPAG) has putative aversive properties because electrically stimulated in the absence of any treatment or rats readily learn to avoid or switch-off the stimulus.
30 min after injections of CLM, FLX or saline. Threshold Electrical and chemical stimulations of DPAG also produce functions of cumulative response frequencies were fitted unconditioned defensive behaviours. Thus, either a through the logistic model and compared using likelihood freezing behaviour characterised by a tense immobile ratio coincidence tests. Results: CLM produced non- display, exophthalmus, vibrissae paralysis and/or defecation linear effects on galloping, for which median thresholds and micturition, or a flight behaviour made up of (I ) were significantly increased (19±2%) or decreased trotting, galloping and jumping responses is brought (–22±2%) with 5 mg/kg and 10 mg/kg, respectively, or about by electrical or chemical stimulation of DPAG did not change with 20 mg/kg. The latter dose further (Sudré et al. 1993; Bittencourt et al. 2000; Schenberg et al. 2000; Vargas et al. 2000). Although the stimulation of the defecation output (–33±15%). FLX significantly DPAG has been formerly proposed as an anxiety model in operant procedures (Schenberg and Graeff 1978; (25±3%) with 1 mg/kg and 5 mg/kg, respectively. More- Graeff 1981), DPAG stimulation in healthy humans over, corresponding doses either decreased the maximum produces sensations, visceral responses and neurological symptoms remarkably similar to clinical panic attacks defecation. Saline was ineffective. Conclusions: While (Nashold et al. 1969). Therefore, DPAG stimulation has the attenuation of defecation and micturition by also been proposed as a model of panic attacks (Gentil 20 mg/kg CLM suggests a peripheral antimuscarinic action, 1988; Deakin and Graeff 1991). As a matter of fact, CLM non-linear effects on galloping were most likely pharmacological evidence in the rat supports the due to its differential action on monoaminergic and panic-like nature of DPAG stimulation. Thus, while the cholinergic central mechanisms. In contrast, the attenuation acute administration of drugs that are effective in panic of immobility, galloping and defecation by low doses of therapy (panicolytics) – such as the selective serotonin FLX suggests a serotonin-mediated antiaversive action.
(5-HT) re-uptake inhibitors (SSRIs), fluoxetine (FLX), Finally, CLM and FLX acute effects on DPAG-evoked fluvoxamine and sertraline or the high-potency benzodi- unconditioned galloping response were strikingly azepines alprazolam and clonazepam – attenuated the similar to those reported for DPAG-evoked shuttle-box DPAG-evoked shuttle-box conditioned escape, drugs that are known to precipitate panic attacks (panicogenics) –such as yohimbine, caffeine and cholecystokinin receptor L.C. Schenberg (✉) · L.B. Capucho · R.O. Vatanabe · L.C. Vargas agonists – had a facilitatory effect (Jenck et al. 1990, Departamento de Ciências Fisiológicas – Centro Biomédico, 1995, 1996, 1998). However, the clinically effective panicolytics imipramine and clomipramine (CLM) were Av. Marechal Campos 1468 (Maruípe), 29040-090 Vitória-ES, Brazil ineffective in the DPAG-evoked shuttle-box escape e-mail: [email protected].: +55-27-33357332, Fax: +55-27-33357330 (Jenck et al. 1990). In contrast, recent studies from our laboratory showed that the administration of CLM at a time course and dose regimen (5 mg/kg and 10 mg/kg/day, Only rats that exhibited jumps with peak-to-peak intensities below 21 days) not much different from those observed in panic 55 µA were selected for drug treatments. CLM (clomipramine therapy significantly increased the thresholds of DPAG- hydrochloride, Sigma, St. Louis, Mo.) and FLX (fluoxetine hydro- evoked immobility (24%), trotting (138%), galloping chloride, Eli Lilly, São Paulo, Brazil) were dissolved in saline (75%), jumping (45%) and micturition (87%). In addition, (0.9% NaCl) and distilled water, respectively. CLM (5, 10 and the 21-day administration of FLX (1 mg/kg/day) virtually 20 mg/kg, i.p., n=28, 18 and 18, respectively) and FLX (1 mg/kgand 5 mg/kg, i.p., n=20 and 22, respectively) were administered abolished galloping without changing the remaining 30 min before the onset of stimulation sessions. Controls were responses (Vargas and Schenberg 2001).
similarly treated with saline (n=24). Drug sedative effects on There are no studies, however, evaluating the acute open-field ambulatory activity were evaluated in separate rats effects of panicolytics on unconditioned defensive (n=10 per group) similarly treated with saline, FLX (1 mg/kg and5 mg/kg) or CLM (5 mg/kg and 10 mg/kg).
behaviours produced by electrical stimulation of DPAG.
Accordingly, the present study employed the thresholdlogistic analysis (Sudré et al. 1993; Schenberg et al.
1990, 2000) to assess the acute effects of the clinically The rat behavioural output was rated according to a previously effective panicolytics CLM and FLX on DPAG-evoked made ethogram (Schenberg et al. 2000). The following responses were recorded: sleeping, resting, grooming, rearing, walking, tenseimmobility, trotting, galloping, jumping, exophthalmus (eyeballprotrusion and wide opened eyelids), defecation and micturition.
Furthermore, vibrissae paralysis (mystacioplegia) was alsoobserved during the freezing behaviour. Behaviours were recordedin a binary way, as emitted or not, irrespective of their frequency or duration in a single-stimulation trial. In order to determine theresponse threshold curves, only the “threshold responses”, i.e.
Male albino Wistar rats (200–250 g) were housed in individual those emitted with the minimally effective current, were subjected glass-walled cages with food and water ad libitum and a natural to statistical analysis. Trotting and galloping were analysed either separately or merged as the “running” response. Moreover,because defecation and micturition also occur spontaneously,unbiased fitting of their stimulus-dependent output was performed, discarding the responses emitted during 0- (sham), 5- and 10-µAstimulation trials, supposedly, due to the rat exploratory activity.
Rats were anaesthetised with 400 mg/kg (i.p.) chloral hydrate (Isofar,Rio de Janeiro, Brazil) supplemented by the s.c. infiltration ofscalp with 1% lidocaine plus 0.005% epinephrine (Cristália, São Paulo, Brazil). Thereafter, rats were fixed on a stereotaxic apparatus(David Kopf, Tujunga, Calif.) and wrapped with a cloth to avoid Drug sedative effects were assessed in separate groups by means surgical hypothermia. With the skull horizontal between bregma of a custom-built infrared-based actometer. The actometer was and lambda, the bone over the lambda was abraded with the aid of made up of an anti-burglary domestic system (Infraset, São Paulo, a drill and removed with thin forceps to expose the sinus.
Brazil) in which the time-constant circuit was modified to allow a Monopolar stainless-steel electrodes (o.d. 200 µm), insulated faster resetting. The actometer had a 360° monitoring radius and throughout except at the cross-section of the tip, were then inserted was placed 50 cm above the floor of the open field. The sensor in the right or left dorsal midbrain through a small dura incision was sensitive to a 12-cm mean displacement of the rat and filtered just by the sinus. Whenever necessary, the sinus was gently slow stretching responses, scratching, grooming and small move- pushed with the electrode itself so as to allow its penetration to the ments of the paws and head. Accordingly, records denote the aimed site. The electrode was anchored to the skull by means of a ambulatory activity only (walking and rearing). Open-field U-shaped, stainless-steel clip, three small screws and dental resin.
sessions were carried out between 0800 hours and 1500 hours in a In addition, the bone was covered with a thin layer of cyanoacrylate sound-attenuated, temperature-controlled room (23–25°C). Naive methylester glue (Super-Bond, São Paulo, Brazil) just before rats were injected (i.p) with saline, FLX or CLM and placed after pouring the dental resin to hold the pieces together. These procedures 30 min into the open field. Cumulative ambulatory scores of 10-, aided in keeping the electrodes in place for a 30-day period or so 20- and 30-min recording periods (i.e., 40, 50 and 60 min after allowing the chronic treatment with CLM and FLX reported drug injection) were subjected to statistical analysis.
elsewhere (Vargas and Schenberg 2001).
At the end of experiments, brains were sectioned in a freezing Rats were stimulated in a cylindrical Plexiglass open-field apparatus microtome (60-µm sections) and stained with neutral red. Stimulation of 60-cm wall height and diameter. The screening sessions sites were plotted on diagrams of the rat brain atlas of Paxinos and were carried out 4–10 days after surgery. The rats were connected to a constant current sine-wave stimulator and placed into theopen field, where they remained undisturbed for 15 min to getused to the environment and reduce spontaneous activity. Following this period, stepwise increasing stimuli (0–55 µA, 60 Hz,1 min, a.c.) were presented at 5-min intervals. A light cable and Behavioural items were recorded in a binary way, as emitted or mercury swivel allowed the free movement of the rat during brain not, irrespective of their frequency or duration in a single stimulation stimulation. In each trial, the intensity was increased by 5 µA until trial. Response threshold curves were obtained by logistic fitting the rat showed the jumping response. All experiments were of accumulated response frequencies. Significant regression on carried out in a sound-attenuated, temperature-controlled room stimulus intensity was assessed using Wald’s chi-square test. Drug effects were assessed according to a within-subject design. Pre- and post-drug threshold curves of each group were modelled bymeans of indicator variables and compared for either location(triggering level) or parallelism (responsiveness) using likelihood-ratio coincidence tests. Behaviour triggering level was representedby estimates of median intensity (I ±SE). Behavioural respon- siveness was represented by regression curvature (β±SE), i.e. theparameter that governs the rate of change in response probabilityas a function of stimulus change. Finally, whenever a low responseoutput precluded the logistic fitting, maximum accumulatedfrequencies (P using odds ratio (ψ) and Pearson’s χ2 analyses. A comprehensivedescription of our original approach to the threshold logistic analysisof intracranially induced behaviours can be found elsewhere(Schenberg et al. 2000).
Drug sedative effects on open-field ambulatory behaviour were evaluated using repeated-measures analysis of variance (ANOVA)followed by planned contrasts (1 d.f.) for time × group interactions.
Pairwise multiple comparisons were considered significant atBonferroni’s 5% level. All statistical analyses were performedusing the SAS software (Statistical Analysis Systems, N.C.).
Histology was performed in 96 of 130 rats. The remaining ratswere lost throughout the ensuing long-term treatment with CLMand FLX (Vargas and Schenberg 2001). Electrodes within thedorsomedial and dorsolateral columns of DPAG or just borderingit comprised 78%. The remaining electrodes were localised in thedeep collicular layers (intermediate layer 7%, deep grey/whitelayers 15%). According to the current parcellation of the PAG (P.
Carrive, personal communication), most sites were distributedthroughout the intermediate (53) and caudal (29) DPAG or adjoiningdeep collicular layer (bregma AP coordinates: –6.04 mm to–7.3 mm). Moreover, seven electrodes were localised in the rostralDPAG (–5.8 mm; Fig. 1). Stimulation of these sites yielded signifi- Fig. 1 Brain sites in which stimulation during pre-drug sessions
cant regressions for defensive responses only. Pooled pre-drug elicited the jumping response with intensities below 55 µA (60 Hz, sessions (n=130) showed the following threshold hierarchy: 1 min, a.c.). Plates represent the coronal sections of the rat brain immobility < exophthalmus < jumping < trotting < galloping < atlas of Paxinos and Watson (1986). Numbers are the rostro- micturition < defecation (Table 1). Distribution of sites within the caudal coordinates in relation to bregma (mm). Clomipramine DPAG and deep collicular layers did not differ among drug groups (filled inverted triangle), fluoxetine (filled circle) and saline (open Table 1 Rat defensive profile of dorsal periaqueductal gray
CLM produced non-linear effects on galloping, for which the stimulation in pooled pre-drug sessions (n=130). I thresholds were either increased (∆I =19±1.8%, χ2=7.5, d.f.=1, (the estimate of triggering level, i.e. the intensity in which a given P<0.006), decreased (∆I =–22±2.1%, χ2=6.1, d.f.=1, P<0.01) or response has the higher frequency), β curvature parameter (the did not change with 5, 10 and 20 mg/kg, respectively (Fig. 2).
estimate of responsiveness, i.e. the rate of change in response Thresholds of micturition were increased by 20 mg/kg CLM probability in function of stimulus change), P (∆I =38±1.1%, χ2=3.6, d.f.=1, P<0.05). This dose also reduced response output (the estimate of stimulus efficacy, i.e. the maximum the maximum output of defecation. Indeed, the defecation pre- accumulated frequency). Responses were sorted according to their drug probability was six times higher than that of rats treated with 20 mg/kg CLM (ψ=6.4±5.6, χ2=4.9, d.f.=1, P<0.02). Immobility,exophthalmus, trotting, running and jumping responses did not FLX produced significant increases in the thresholds of immobility (∆I =22±2.1%, χ2=9.4, d.f.=1, P<0.002) and galloping (∆I =25±2.6%, χ2=12.0, d.f.=1, P<0.0005) with 1 mg/kg and 5 mg/kg, respectively (Fig. 3). Defecation was also attenuated by 1 mg/kg and 5 mg/kg FLX which caused a fivefold decrease inoutput probability (ψ=4.8±4.2, χ2=3.6, d.f.=1, P<0.05) or asignificant increase in I P<0.03), respectively. No changes were observed in exophthalmus,trotting, running, micturition and jumping responses.
Fig. 2 Acute effects of
clomipramine (CLM 5, 10 and
20 mg/kg, i.p.) and saline (SAL
0.9% NaCl, i.p.) on the thresh-
olds and maximum output of
galloping, defecation and
micturition evoked by electrical
stimulation of dorsal periaque-
ductal grey. Sigmoidal curves
represent the best-fitting logistic
function of accumulated response
frequencies. Line-plus-symbol
graphs represent data that did
not achieve a significant logistic
fitting (r responders, n number
of stimulated rats). Dashed
curves (–-) and asterisks (*),
P<0.05, represent curve location
and maximum output signifi-
cantly different from pre-drug
controls, respectively (likelihood
ratio coincident tests and
maximum output Pearson’s χ2
as appropriate)
(10 mg/kg) facilitation of galloping may be associated with theintensification of anxiety and panic attacks seen in treatment onset Whatever the regression parameter (I , β, P (Ramos et al. 1993). The neurochemical mechanisms underlying of saline did not change any DPAG-evoked defensive behaviour.
this “first-dose effect” remain obscure. However, besides their5-HT and noradrenaline reuptake inhibitory actions, tricyclic anti-depressants have long been known for their muscarinic blocking activity and respective side effects, such as constipation, urinaryretention, blurred vision and dry mouth (Atkinson and Ladinsky Compared with pre-drug controls, CLM-, FLX- and saline-treated 1971; Richelson and Divinetz-Romero 1977; Snyder and Yamamura rats showed a reduced open-field activity in drug sessions carried 1977; Blackwell et al. 1978; Cusack et al. 1994). Moreover, rather out the day after (Fig. 4). Nevertheless, while the open-field activity than peripherally, imipramine seems to exert its anti-enuretic of rats treated with 5 mg/kg CLM or 1 mg/kg and 5 mg/kg FLX effect via a supraspinal antimuscarinic action (Sohn and Kim did not differ from saline-treated ones, 10 mg/kg CLM significantly 1997). Thus, CLM non-linear effects on galloping were most reduced the ambulatory activity at 20-min and 30-min recording probably due to drug or metabolite differential effects on serotonergic, adrenergic and cholinergic synapses. Indeed, it has long been reported that scopolamine has a pro-aversive effect, further decreasing the operant lever pressing which was suppressedby punishment (Miczek 1973).
In contrast to the complete absence of effects of saline, FLX caused modest but significant attenuation of DPAG-evoked defensivebehaviours. The attenuation of galloping by a non-sedative dose of Compared with chronically treated rats (Vargas and Schenberg FLX (5 mg/kg) supports the 5-HT inhibitory modulation of flight.
2001), the acute administration of CLM produced fewer and lesser Indeed, iontophoretic application of 5-HT predominantly inhibited effects on DPAG-evoked defensive behaviours. Hence, while single neuron activity in the dorsolateral and lateral sectors of galloping was attenuated by a non-sedative dose of CLM PAG (Lovick 1994). Moreover, these inhibitory actions were (5 mg/kg), this response was facilitated following the administration potentiated by the iontophoretic application of a SSRI panicolytic, of a manifestly depressant dose (10 mg/kg). Accordingly, CLM paroxetine, supporting the FLX inhibitory modulation of PAG attenuation of galloping did not correlate with its sedative properties, (Lovick 1994). Because galloping was attenuated to a much greater supporting a specific anti-aversive action instead. However, CLM extent following a 21-day administration of 1 mg/kg/day FLX Fig. 4 Fluoxetine (FLX 1 mg/kg and 5 mg/kg, i.p.) and clomipramine
(CLM 5 mg/kg and 10 mg/kg, i.p.) acute effects on open-field
exploratory activity. Pre-drug sessions were performed the day
Fig. 3 Acute effects of fluoxetine (FLX 1 mg/kg and 5 mg/kg, i.p.)
before drug testing. Activity was recorded 10, 20 and 30 min after and saline (SAL 0.9% NaCl, i.p.) on the thresholds and maximum session onset. *P<0.05, significantly different from saline-treated output of immobility, galloping and defecation evoked by electrical rats (repeated-measures analysis of variance followed by planned stimulation of dorsal periaqueductal grey. Sigmoidal curves contrasts for time × group interactions) represent the best-fitting logistic function of accumulated responsefrequencies. Line-plus-symbol graphs represent data that did notachieve a significant logistic fitting (r responders, n number of It is worth noting that exogenous 5-HT sensitises normal peristalsis stimulated rats). Dashed curves (---) and asterisks (*), P<0.05, and facilitates stress- and corticotropin releasing factor (CRF)- represent curve location and maximum output significantly different from pre-drug controls, respectively (likelihood ratio coincident 1992, 1998; Sanger et al. 1998). Accordingly, 5-HT has been tests and maximum output Pearson’s χ2 as appropriate) proposed as a key sensitising agent in the aetiology of irritablebowel syndrome, a functional gastrointestinal disorder (Sanger1996). In addition, central 5-HT (Vargas and Schenberg 2001), both short- and long-term mechanisms normal peristalsis (Croci et al. 1995). Consequently, FLX attenuation seem to be involved in FLX inhibitory effects on galloping.
of DPAG-evoked defecation was most probably a specific anti- Alternatively, galloping attenuation could have been a by-product aversive action at DPAG properly or its efferent pathways. Indeed, of a facilitation of freezing brought about by the enhancement of recent transneuronal track tracing studies with pseudorabies virus 5-HT transmission in the “behavioural inhibition system” (Gray suggested that colonic motility is chiefly controlled by Barrington’s 1991). Yet, instead of a facilitation, immobility was attenuated or nucleus, formerly considered solely as a micturition centre, but did not change after acute administration of 1 mg/kg and 5 mg/kg also by the lateral PAG and spinally projecting locus coeruleus FLX, respectively. Therefore, 5-HT seems to inhibit both freezing CRF neurons (Monnikes et al. 1994; Valentino et al. 2000). In and flight behaviours. Immobility attenuation, however, wanes turn, the PAG is known to project to Barrington’s nucleus and following the chronic administration of FLX (Vargas and Schenberg locus coeruleus rostromedial dendrites (Valentino et al. 1994; 2001). Finally, attenuation of galloping but not immobility Luppi et al. 1995; Blok and Holstege 1996). These data give neuro- following the administration of 5 mg/kg FLX suggests a complex anatomical support to the elicitation of defecation and micturition interplay of DPAG-evoked somatic defensive behaviours. Apparently, by electrical and chemical stimulation of PAG (Schenberg et al.
galloping attenuation with the higher dose of FLX shifted the 1990, 2000; Sudré et al. 1993; Bittencourt et al. 2000; Vargas et al.
defensive repertoire towards immobility and trotting, compensating 2000; Vargas and Schenberg 2001). Further, 5-HT inhibits the an eventual attenuation of the latter responses. As a matter of fact, PAG and locus coeruleus neuron activity, supporting the FLX a similar interplay of galloping and trotting was also observed inhibitory modulation of DPAG-evoked defecation (Shiekhattar following the chronic treatment with FLX (Vargas and Schenberg and Aston-Jones 1993; Lovick 1994). More importantly, given the 2001). In any event, FLX seems to downgrade the defensive high co-morbidity of panic disorder and irritable bowel syndrome repertoire from flight to freezing and thence to non-defensive (Lydiard et al. 1994; Lydiard and Falsetti 1999), FLX attenuation of DPAG-evoked defecation is likely to underlie the reported Remarkably, whereas the attenuation of defecation and micturi- effectiveness of antipanic agents on concomitant panic and irritable tion by 20 mg/kg CLM could be due to a peripheral cholinergic bowel disorders (Lydiard et al. 1986).
blockade, DPAG-evoked defecation was also attenuated by FLX, Antidepressant effects confirmed previous studies with DPAG- which is devoid of any antimuscarinic action (Cusack et al. 1994).
evoked shuttle-box escape behaviour. In particular, while the shuttle- box escape was attenuated by SSRIs, FLX (10–32 mg/kg), sertraline tasks such as bar-pressing or shuttle-box escape. Finally, the threshold (1–10 mg/kg) and fluvoxamine (10–22 mg/kg), no threshold logistic analysis detected effects of CLM and FLX doses within the changes were observed following 10-mg/kg and 22-mg/kg doses true clinical range. In this regard, it should be stressed that the of the non-selective tricyclic antidepressants imipramine and CLM thresholds of jumping of the present study were lower than those of (Jenck et al. 1990). Likewise, in the present study, while galloping trotting and galloping. The stringent criterion employed in rat was attenuated by a non-sedative dose of FLX (5 mg/kg), it was screening for drug treatments, i.e. selection of rats that jumped with facilitated or did not change in the same dose range of CLM that less than 55 µA, most probably biased the sample defensive profile failed in attenuating the DPAG-evoked shuttle-box escape.
towards the high-threshold, drug-resistant jumping behaviour.
Notably, CLM had no effects on running (merging of trotting and Indeed, immobility, trotting, galloping and jumping are usually galloping), the behaviour most likely recorded in the shuttle-box elicited with increasing stimuli when rats are pooled on either a escape paradigm. The striking similarity of antidepressant actions plain neuroanatomical basis (Bittencourt et al. 2000) or through a on innate and shuttle-box escape behaviours thus supports the more flexible criterion, i.e. presentation of any flight response, such unconditioned nature of the latter behaviour. Consequently, as trotting, galloping or jumping, with less than 50 µA (Sudré et al.
instead of a “conditioning”, DPAG-evoked shuttle-box escape 1993). Thus, the rather stringent criterion of rat selection should be would be more akin to a stimulus titration procedure.
considered in the appraisal of present drug effects.
The neurochemistry of DPAG-evoked innate behaviours and In conclusion, in contrast to the CLM non-linear effects on their complex interplay remains unclear. Indeed, most studies on galloping, FLX attenuation of immobility and galloping with this issue were carried out with the shuttle-box escape procedure non-sedative doses suggests a 5-HT antiaversive action similar to and provide information on running responses only. However, as that reported for FLX and other SSRIs on DPAG-evoked shuttle-box far as the 5-HT transmission is concerned, it is noteworthy that escape behaviour. Moreover, while the attenuation of defecation intra-periaqueductal injection of both 5-HT and the SSRI zimelidine and micturition by the higher dose of CLM suggests a peripheral produced antiaversive effects (Schütz et al. 1985). Administration antimuscarinic effect, FLX attenuation of defecation supports a of 5-HT receptor agonists and antagonists yielded, however, conflicting results. Therefore, while the systemic injection of thesedrugs suggested a pro-aversive role of both 5-HT Acknowledgements This work was supported by research grants
receptor subtypes, the local injection of corresponding drugs led to from AFIP, CNPq, FACITEC and FINEP. L.C. Schenberg, L.C.
opposite results (Jenck et al. 1989; Nogueira and Graeff 1995).
Vargas and L.B. Capucho were recipients of Research, Master Thus, either the loss of drug specificity at high concentrations Degree and Undergraduate CNPq fellowships, respectively. The attained by intracerebral injections or the different sites of action authors wish to thank Eli Lilly do Brasil Ltd. (São Paulo, SP) for of systemically and locally injected drugs could underlie these conflicting data. Indeed, DPAG-evoked unconditioned flightin the open-field was either enhanced or attenuated by the5-HT selective agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT), depending on the route of administration, systemic or local, respectively (Beckett and Mardsen 1997).
It is also noteworthy that the predator-elicited flight behaviour Atkinson J, Ladinsky H (1972) A quantitative study of the was potentiated by acute administration of imipramine (5, 10 and anticholinergic action of several tricyclic antidepressants on 15 mg/kg), which either reduced the avoidance distance or the rat isolated fundal strip. Br J Pharmacol 45:519–524 increased the flight speed (Griebel et al. 1995, 1996; Blanchard et Beckett S, Marsden CA (1997) The effect of central and systemic al. 1997). A similar effect on galloping was observed in the present study after the administration of a 10-mg/kg dose of CLM, which receptor antagonist WAY100635 on periaqueductal both reduced the triggering level and increased the responsiveness grey-induced defence behaviour. J Psychopharmacol 11:35–40 (parameters akin to “avoidance distance” and “flight speed”, Bittencourt AS, Carobrez AP, Schenberg LC (2000) Intrinsic respectively). However, in contrast to the present data, the predator- properties of lateral and dorsolateral columns of periaqueductal elicited flight behaviour was facilitated by 5 mg/kg and 10 mg/kg FLX (Griebel et al. 1996; Blanchard et al. 1997). Therefore, albeit Blackwell B, Stefopoulos A, Enders P, Kuzma R, Adolphe A similar, the substrates of DPAG-evoked and predator-elicited (1978) Anticholinergic activity of two tricyclic antidepressants.
flight behaviours seem not to be identical. However, in contrast to the lack of effects of the higher doses of CLM (>10 mg/kg) in Blanchard RJ, Griebel G, Henrie JA, Blanchard DC (1997) both DPAG-evoked innate and shuttle-box escape behaviours, Differentiation of anxiolytic and panicolytic drugs by effects CLM (15 mg/kg) attenuated the bar-pressing decremental escape on rat and mouse defense test batteries. Neurosci Biobehav in which rats learn to titrate the intensity of DPAG stimulation (Kiser et al. 1978). Decremental escape was further potentiated by Blok BF, Holstege G (1996) The neuronal control of micturition para-chlorophenylalanine and depressed by 5-hydroxytryptophan, and its relation to the emotional motor system. In: Holstege G, supporting the 5-HT mediation of CLM attenuating effects (Kiser Bandler R, Saper CB (eds) The emotional motor system.
and Lebovitz 1975; Kiser et al. 1978). Therefore, CLM differential effects on DPAG-evoked, predator-elicited and bar-pressing Croci T, Landi M, Bianchetti A, Manara L (1995) Drug-induced escape behaviours suggest the involvement of multiple 5-HT defaecation in rats: role of central 5-HT1A receptors. Br J systems controlling these responses.
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