Active and passive avoidance following the administration of systemic DSP4, xylamine, or p-chloroamphetamine

BEHAVIORALAND NEURALBIOLOGY43, 238-249 (1985)

Active and Passive Avoidance following the Administration of Systemic DSP4, Xylamine, or p-Chloroamphetamine T.

ARCHER,*

G.

JONSSON,t AND

S. B. Ross*

*Astra Pharmaceuticals, Research and Development Laboratories, SOdertgilje, and ~Department of Histology, Karolinska Institutet, Stockholm, Sweden Groups of rats were administered either DSP4 (50 mg/kg, ip), xylamine (50 mg/kg, ip), or p-chloroamphetamine (2 x 10 mg/kg, ip), either 2 weeks or 1 week before the testing of two-way active avoidance. DSP4 and xylamine, the selective noradrenaline (NA) neurotoxins, caused a two-way avoidance impairment but p-chloroamphetamine, the selective 5-hydroxytryptamine (5-HT) neurotoxin, did not do so. Pretreatment with desipramine (20 mg/kg, ip) blocked the avoidance impairment caused by DSP4 and xylamine treatment. Neither DSP4 nor xylamine caused any alteration of passive avoidance retention. The biochemical analyses indicated severe NA, but not 5-HT, depletions in the DSP4 and xylamine conditions and drastic 5-HT, but not NA, depletions in the p-chloroamphetamine conditions. These results confirm and extend earlier findings concerning the role of NA in avoidance behavior. © 1985AcademicPress, Inc.

Systemic administration of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) produces a sustained depletion of noradrenaline (NA) in the terminal regions of the locus coeruleus NA system in mice and rats (Jaim-Etcheverry & Zieher, 1980; Jonsson, Hallman, Ponzio, & Ross, 1981; Ross, 1976; Ross & Renyi, 1976). DSP4 also affects peripheral NA but this effect is shortlasting and the recovery seems to be complete within 15 days. N-2-Chloroethyl-N-ethyl-2-methylbenzylamine (xylamine), an irreversible inhibitor of NA uptake, is related in structure to DSP4 (Kammerer, Amini, & Cho, 1979; Dudley, Ransom, Kammerer, & Cho, 1980). Like DSP4, xylamine causes a severe long term depletion of NA in the cortex and to a lesser extent in the hypothalamus (Dudley, Butcher, Kammerer, & Cho, 1981). Both DSP4 and xylamine appear to be selective for the noradrenaline system and do not act upon dopamine neurons (Dudley et al., 198 I; Jonsson et al., 1981; Ross, 1976). Pretreatment of the rats with the NA uptake inhibitor desipramine (DMI) causes a reasonable blockade of the neurodegeneration at the NA terminals as a result of DPS4 (50 mg/kg). Consequently, we have performed a large number of experiments to examine the role of NA depletion, after DSP4 treatment, upon active and passive avoidance learning in the rats. It has 238 0163-1047/85 $3.00 Copyright© 1985by AcademicPress, Inc. All rightsof reproductionin any formreserved.

DSP4, XYLAMINE, PCA, AND AVOIDANCE

239

consistently been found that DSP4-treated rats show a long-lasting impairment of two-way active avoidance (Archer, 1982a, 1982b; Archer, 0gren, Johansson, & Ross, 1982; Archer, Jonsson, & Ross, 1984; 0gren, Archer, & Ross, 1980) but no deficit of passive avoidance (Archer, 1982a; Archer, S6derberg, Ross, & Jonsson, 1984). The purpose of this investigation was to examine whether xylamine (50 mg/kg) pretreatment would also result in the two-way avoidance deficit but not in the passive avoidance deficit, and whether or not the active avoidance deficit is reversed by prior DMI (20 mg/kg) administration. In addition, since DSP4 treatment has sometimes (Jonsson et al., 1981) but not always (Archer, 1982c) been shown to induce a 10-30% depletion of central 5-hydroxytryptamine (5HT), a secondary aim was to ascertain whether the avoidance impairment could have been due to the 5-HT loss.

MATERIALS AND METHODS Male Sprague-Dawley rats (275-325 g, 60-70 days of age) were used in all the experiments. The rats were randomly allocated to the different treatment conditions (N = 8/group). They were placed under laboratory conditions at least 3 weeks prior to the onset of two-way active avoidance training, spontaneous activity measurements, fear conditioning and fear retention testing, and the hot-plate test. In all the experiments, rats were housed six or eight to a cage following arrival, with a 12-h light/dark cycle (lights on 6 AN) in a room thermostatically maintained at 21 _+ I°C. Food and water were freely available. All behavioral experimentation was carried out during the light phase between 8 AM-4 PM.

Apparatus Two-way active avoidance. The shuttlebox consisted of two identical compartments, each measuring 45 x 28.5 x 31.5 cm and separated by a 2-ram-thick metal wall with a 7 x 10-cm gate, and is described in detail elsewhere (Archer, Ogren, et al., 1982). Crossings were detected by photocells placed on either side of the dividing wall. Scrambled footshock was delivered through the grid floor (Model 521/c shock generators and Model 521/s shock scramblers, Campden Instruments Ltd., London, UK). Fear conditioning and retention. The shuttlebox used for two-way avoidance was adapted for studying fear conditioning and retention testing by placing an obstacle in front of the gate between the two compartments. Thus rats were confined to the fight-hand compartment of the shuttlebox where they received four inescapable shocks. For fear retention testing, the obstacle was removed and access to the nonshocked compartment allowed.

240

ARCHER, JONSSON, AND ROSS

General Procedure Signalled two-way active avoidance. Five sessions of 30 trials were presented, one on each of 5 consecutive days. At the start of session 1, each rat was placed in one compartment of the shuttlebox and allowed a 10-min period of free exploration prior to the first trials. For sessions 2-5, the free exploration period was limited to 2 min. The conditioned stimulus (CS) in all the two-way active avoidance experiments was a 10s tone (1000 Hz) which was immediately followed by the unconditioned stimulus (US), a 5-s scrambled shock (1.0 mA), if no avoidance response to the signal had been made. Avoidance responses terminated the CS, while escape responses terminated the CS-US (signal-shock) combination. The intertrial interval was constant at 40 s. Fear retention testing. Each rat was placed in the fight-hand compartment and received four inescapable shocks (1.0 mA). Twenty-four hours later, fear retention was measured as outlined previously (Archer, 1982a). Thus, each rat was placed in the same right-hand compartment in which it had previously received shocks and the barrier to the left-hand compartment was removed. The behavior of each rat was observed and rated; the latencies to locomote around the shocked compartment and to cross over to the nonshocked compartment were recorded. In Experiment 2 four groups, xylamine, DSP4, and control (x 2), respectively, were studied. Hot plate test. Rats were confined to the hot plate (a 28 x 26-cm steel sheet) by a Ptexiglas boundary (20 cm high) and the temperature of the hot plate surface was maintained at 57 _+ 0. I°C. Licking or shaking of the front paws were defined as pain responses (as described previously, Archer, Ogren et al. 1982). Pain response latencies were defined as the time from placement on the hot plate to the first display of a pain reponse. Four groups, xylamine, DSP4, and control ( x 2), were tested on the hot plate test (see Experiment 3). Biochemical Analysis Endogenous catecholamine concentrations were determined using highpressure liquid chromatography with electrochemical detection (LCEC) according to Keller, Oke, Mefford, & Adams (1980) as modified by Jonsson, Hallman, Mefford, & Adams (1980). The rats were killed by decapitation and the regional CNS dissection performed mainly according to Jonsson and Sachs (1976) and Jonsson, Hallman, & Sundstr6m (1982). The tissue was extracted with 320/zl 0.1 M perchloric acid containing 27-520 pmole of a-methyldopamine (internal standard) using a Branson B30 sonifier. After an A1203 prepurification step, the extracted catecholamines were determined by LCEC. Endogenous 5-HT was assayed using LCEC according to Ponzio & Jonsson (1979). The catecholamine and 5-HT values were expressed as nanograms/gram wet wt of the tissue, based on internal standard measurements.

DSP4, XYLAMINE, PCA, AND AVOIDANCE

241

Statistical treatment of behavioral data. As a result of the unequal group sizes obtained in all the experiments, nonparametric statistics (Siegel, 1956) were used to analyze the data. In the 30-trial five-session experiments (1 and 2), large within-group variations resulted in no overall significant effects (Kruskal-Wallis ANOVA). However, in view of the strong a priori evidence indicating impaired acquisition performance by DSP4treated rats (e.g., Archer, 1982a; Archer, Ogren et at., 1982; ()gren et al., 1980) and the strong trend of the experiments, combined MannWhitney U-test comparisons, by which the NA-neurotoxin-treated groups were compared with all other groups, were carried out. It will be noted that more than one control group was compared to the neurotoxin groups in the experiments: a pharmacological control (DMI plus DSP4, DMI plus xylamine) and a saline control. EXPERIMENT 1

Xylamine (N-2-chloroethyl-N-ethyl-2-methylbenzylamine) is related structurally to DSP4(N-2-chloroethyl-N-ethyl-2-bromobenzylamine) and causes drastic depletions of NA (Dudley et al., 1981). The purpose of this experiment was to investigate whether xylamine injected two weeks before the onset of two-way avoidance acquisition, causes the same impairment as DSP4 has repeatedly been shown to do. Materials and Methods Experiment 1A. Forty male Sprague-Dawley rats were injected ip with either DSP4 (50 mg/kg dissolved in saline), DMI (20 mg/kg) injected 30 rain prior to the DSP4 injection, xylamine (50 mg/kg dissolved in saline), DMI (20 mg/kg dissolved in saline) injected 30 rain prior to the xylamine injection, or saline (0.9%, 5 ml/kg) 2 weeks before the onset of two-way active avoidance training. Three days after the final avoidance session all the rats were decapitated and the postdecapitation reflex (PDR) of the rats was noted. Brain regions from the xylamine and saline groups only were rapidly dissected out and stored at -70°C until analysis. One rat in the DMI plus xylamine group died, so for this group only, n = 7. Experiment lB. The 23 male Sprague-Dawley rats were randomly assigned to three groups (N = 8, except for DMI + xylamine group where N = 7) that were treated as follows: xylamine (50 mg/kg ip) 2 weeks before the first avoidance session, DMI (20 mg/kg) injected 30 min prior to xylamine (50 mg/kg), or distilled water (5 ml/kg, control). The two-way avoidance procedure was maintained as in Experiment IA. Five 30-trial sessions on each of 5 consecutive days were presented. Three days after the final session, all the animals were decapitated and the PDRs of these animals were measured.

242

ARCHER, JONSSON, AND ROSS

Results and Discussion Experiment 1A. DSP4- and xylamine-treated rats showed an impairment of two-way avoidance acquisition performance in comparison with the DMI plus DSP4, DMI plus xylamine, and control rats. Figure 1 presents the percentage CARs by the DSP4, DMI plus DSP4, xylamine, DMI plus xylamine, and control groups during sessions 1-5. Kruskal-Wallis ANOVA was significant for sessions 4 and 5. Session 4: H = 14.6, NDF = 4; session 5: H = 16.7, NDF = 4. Mann-Whitney U test showed the following pattern of differences for sessions 4 and 5:DSP4 < control, DMI plus DSP4, and, xylamine < DMI plus xylamine, control. This result confirms our previous findings of an avoidance deficit in the shuttlebox following DSP4 treatment (Archer, Ogren, et al., 1982) and extends those data to the related NA neurotoxin, xylamine. It is of some interest to note that as with the DMI plus DSP4, the DMI plus xylamine condition resulted in a notable blockade of the two-way avoidance impairment. Xylamine caused notable NA depletions in brain regions (see Table 1). Experiment lB. The rats treated with xylamine (50 mg/kg) showed a notably worse avoidance acquisition performance than did the DMI plus xylamine-treated and the control rats, which confirms the findings of Experiment 1A. Figure 1B presents the median percentage CAR performed 100 A o , . . . . ~ CONTROL

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FIG. IA. Median percentage CARs by rats administered either DSP4 (50 mg/kg, ip), DMI (20 mg/kg, ip) plus DSP4, xylamine (50 mg/kg, ip), DMI (20 mg/kg, ip) plus xylamine, or saline (control) 2 weeks before CAR acquisition testing. The quartiles for each group for each session were:

Session Group DSP4 DMI + DSP4 Xylamine DMI + xylamine Control

1

2

13.0 17.0 10.5 6.5 14.5

17.5 29.0 19.5 11.0 10.5

3 25.0 33.5 20.5 17.0 15.0

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243

DSP4, X Y L A M t N E , PCA, A N D A V O I D A N C E

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Fie. lB. Median percentage C A R s by rats administered either xylamine (50 mg/kg, ip), DMI (20 mg/kg, ip) plus xylamine, or saline (control) 2 weeks before C A R acquisition testing. T h e quartiles for each group for each session were: Session Group

1

1

Xylamine DMI + xylamine Saline

14.0 18.5 16.5

15.5 l l.0 19.0

3 21.5 23.0 20.5

4

5

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22.5 31.5 32.0

by the xylamine, DMI + xylamine, and control groups during sessions 1-5. Kruskal-Wallis ANOVAs performed for each session's CAR data indicated no significant effects. This was most probably due to the very high within-group variation. However, combined Mann-Whitney U tests, by which the NA-depletion condition (xylamine, n = 8) was compared with the control condition (DMI + xylamine + control, n = 15), indicated significant differences ( U = 23, NI = 8, N2 = 15, p < .02) for the session-5 data. The comparisons for the individual groups were as follows: TABLE 1 Effects of Xylamine (50 mg/kg) on Cortical Catecholamine Levels Frontal

Xylamine NA DA Saline NA DA

Occipital

ng/g

%

ng/g

197-+53 121-+10 760 + 66 101±10

26 121

12-+4 7-+2 590 ± 42 71-+2

Entorhinal %

ng/g

2 106±27 41 108+-26 698 +-45 95-+6

Cerebellum

Spinal cord

%

ng/g

%

ng/g

%

15 114

25-+6 6-+3 436 ± 72 7-+2

6 83

69-+4 31-+1 712 ± 38 39-+3

10 81

Note. Values are e x p r e s s e d as m e a n _+ SE of six to eight determinations. Xylamine (50 mg/kg) was injected 15 d a y s before avoidance and 18 days before sacrifice.

244

ARCHER, JONSSON, AND ROSS

xylamine versus DMI plus xylamine (U = 13, NI = 8, N2 = 7, p < .05); and xylamine versus control (U = 16, N1 = 8, p = .052). EXPERIMENT 2 DSP4 treatment causes a depletion of 5-HT concentrations, that varies between 10 and 40% in those areas, e.g., cortex and hippocampus, which are most affected by the neurotoxin (c.f., Archer, 0gren, et al., 1982; Jonsson et al., 1981). The uptake of 14C-5-HT is not diminished while considerable decreases in SH-NA uptake are obtained. In view of the small, but consistent, 5-HT depletions produced by DSP4, it is of relevance to ascertain whether this depletion can account for the avoidance impairments obtained. Thus, in Experiment 2 treatment of groups with long-term PCA treatment (2 x l0 mg/kg 1 week before testing) which causes a selective depletion of 5-HT (Fuller et al., 1975; Harvey et al., 1975; Harvey & McMaster 1976; Ross 1976) and offers a reliable test of the possible effects of 5-HT depletion upon two-way avoidance acquisition performance was performed. Material and Methods The 32 male Sprague-Dawley rats were randomly assigned to four groups (n = 8) that were treated as follows: DSP4 (50 mg/kg ip) was injected 2 weeks before and saline 1 week before avoidance session 1, DSP4 (50 mg/kg ip) 2 weeks before and PCA (2 x 10 mg/kg) 7 and 6 days before, distilled water 2 weeks before PCA (2 x 10 mg/kg) 7 and 6 days before, distilled water 2 weeks before PCA (2 x l0 mg/kg) 7 and 6 days before, and finally distilled water 2 weeks before and saline 1 week before the onset of active avoidance training. The two-way avoidance procedure was maintained as in the previous experiment. Five 30-trial sessions on each of 5 consecutive days were presented. Two rats died in the DSP4 + PCA group so for this group n = 6 only. Three days after the final session, all the rats were decapitated and the PDRs of these animals were measured. In a separate biochemical experiment rats were treated in identical groups: DSP4 + Sal, DSP4 + PCA, Sal + PCA, and saline, but were sacrificed 10 months after treatment. Cortical regions were dissected out according to Jonsson and Sachs (1976) and stored at -70°C until analysis. Results and Discussion The trend of the data clearly indicate that there was a performance impairment shown by the DSP4 condition in comparison with the 5-HT depletion and control conditions. Figure 2 presents the median percentage CARs performed by the DSP4 plus PCA, DSP4 plus saline, distilled water plus PCA, and distilled water plus saline groups during sessions I-5. Kruskal-Wallis ANOVAS performed on the CAR data from each

245

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0 SESSION N U M B E R FIG. 2. Median percentage CARs by rats administered either DSP4 (50 mg/kg, ip) plus PCA (2 x 10 mg/kg, ip), DSP4 (50 mg/kg, ip) plus saline (5 ml/kg), distilled water plus PCA (2 x 10 mg/kg, ip), or distilled water plus saline before CAR acquisition testing. The quartiles for each group for each session were: Session Group DSP4 + DSP4 + DW a + DW a +

PCA saline saline saline

1

2

20.0 17.0 31.5 22.0

10.5 23.5 32.5 28.5

3 13.5 21.5 39.0 34.0

4

5

19.0 16.5 20.5 16.5

18.5 14.0 23.5 14.0

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session did not indicate any significant effects, once again resulting from large within-group variation. Combined Mann-Whitney U tests, by which the NA depletion condition (DSP4 plus PCA + DSP4 plus Sal) was compared with the non-NA depletion condition (DW plus Sal + DW plus PCA), indicated significant differences for the sessions 4 and 5 data (U > 61, NI = 14, N2 = 16, p < .05). Postdecapitation ratings (cf. Archer et al., 1984) confirmed the blockade of PDR for DSP4 and DS£4 + PCA-treated rats. In the separate biochemical analysis, DSP4 (50 mg/kg) treatment in the DSP4 + Sal and DSP4 + PCA groups caused notable NA depletions in the occipital cortex (21 and 41% of control values), but had no effect (DSP4 + Sal group) upon 5-HT concentrations in the parietal cortex (see Table 2). PCA (2 × 10 mg/kg) treatment in the PCA + Sal and DSP4 + PCA groups had only a small effect upon NA but caused a severe depletion of 5-HT in the parietal cortex (11 and 7% control values). PCA may have a small effect on DA concentrations but since the region is DA-poor no satisfactory conclusion can be drawn. EXPERIMENT 3 The purpose of this experiment was to test the effects of xylamine (50 mg/kg) upon fear conditioning and retention testing. It has been shown

246

ARCHER, JONSSON, AND ROSS

TABLE 2 Effects of DSP4 (50 mg/kg) and p-Chloroamphetarnine (2 x 10 mg/kg) on Cortical Amine Levels in a Separate Biochemical Experiment Occipital cortex

Parietal cortex

ng/g

%

ng/g

%

DSP4 + Sal

NA DA 5-HT

136---36 6.9 --- 1 --

21 69 --

--228± 10

--101

DSP4 + PCA

NA DA 5-HT

199±58 5.1 ± 1 --

41 51 --

--25±4

--11

Sal + PCA

NA DA 5-HT

388 ± 18 5.0± 5 --

79 50 --

--16±2

--7

Saline

NA DA 5-HT

494 ~ 53 10 ± 2 --

----

--226 _+20

----

Note. Values are expressed as mean _+ SE of six to eight determinations. DSP4 (50 mg/ kg) and PCA (2 x 10 mg/kg) were injected in a similar manner as for the avoidance test and the animals were sacrificed 10 months later.

a l r e a d y t h a t D S P 4 h a s , if a n y t h i n g , a slight e n h a n c i n g e f f e c t u p o n f e a r r e t e n t i o n ( A r c h e r , 1982a).

Materials and Methods T h e 32 m a l e S p r a g u e - D a w l e y r a t s w e r e r a n d o m l y a s s i g n e d to f o u r g r o u p s (n = 8) t h a t w e r e t r e a t e d as f o l l o w s : D S P 4 (50 mg/kg) a n d x y l a m i n e (50 m g / k g ) w e r e i n j e c t e d 2 w e e k s b e f o r e F C ; t w o g r o u p s w e r e a d m i n i s t e r e d s a l i n e at t h e s a m e t i m e . T h e F C a n d r e t e n t i o n t e s t i n g p r o c e d u r e w a s c a r r i e d o u t as o u t l i n e d a b o v e .

Results and Discussion N e i t h e r D S P 4 (50 m g / k g ) n o r x y l a m i n e (50 m g / k g ) c a u s e d s i g n i f i c a n t effects upon fear retention. Figure 3 presents the median latencies to locomote and cross over by the DSP4, xylamine, and control groups. N o significant d i f f e r e n c e s b e t w e e n t h e g r o u p s w e r e o b t a i n e d as e s t i m a t e d by the Mann-Whitney U t e s t s . N o e f f e c t s o f x y l a m i n e (50 m g / k g ) u p o n p a i n s e n s i t i v i t y in t h e h o t p l a t e t e s t w e r e o b t a i n e d . Pain r e s p o n s e l a t e n c i e s w e r e a s f o l l o w s : x y l a m i n e = 15.8; c o n t r o l = 17.1 s. P o s t d e c a p i t a t i o n c o n v u l s i o n r a t i n g s i n d i c a t e d r e l i a b l e N A l o s s as w e h a v e i l l u s t r a t e d p r e v i o u s l y ( A r c h e r , C o t i c , & J f i r b e , 1982; A r c h e r et al. 1984).

247

DSP4, XYLAMINE, PCA, AND AVOIDANCE

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F1o. 3. Median latencies to locomote and crossover by rats administered either DSP4 (50 mg/kg, ip), xylamine (50 mg/kg, ip), or saline (control) 2 weeks before FC and retention testing. The quartiles for each group for each session were:

Latency to locomote Latency to cross over

Xylamine

Control

DSP4

Control

161 96

158 163

137 147

155 171

DISCUSSION

The experiments presented above compared the effects of NA depletion, as a result of DSP4 on xylamine treatment, with that of 5-HT depletion, as a result of PCA treatments, upon two-way active avoidance acquisition. The data may be summarized as follows: (1) Both DSP4 and xylamine (50 mg/kg) caused a small acquisition impairment. The significance of the effects seems assured on the basis of the a priori considerations mentioned. (2) Xylamine produced severe depletions of NA in several brain regions while DA was relatively unaffected. (3) DMI pretreatment blocked the avoidance impairment produced by xylamine (50 mg/kg). In addition, neither DSP4 nor xylamine treatment produced any effect upon the passive avoidance task (fear conditioning and retention testing). These results are in accordance with those of several previous studies (Archer, 1982a; Archer, Jonsson, et al., 1984; Archer, S6derberg et al., 1984; 0gren et al., 1980) in demonstrating the two-way avoidance deficit of the DSP4 rats. The pattern of NA depletion following xylamine treatment has been suggested to be similar to that of DSP4 (Dudley et al., 1981); the present findings, therefore, seem to be in agreement with what could be predicted from their investigation. The relevance of demonstrating a two-way active avoidance deficit with xylamine is its confirmation of a noted pharmacological function and the correlation of that function to neurochemical evidence. In the second experiment, PCA was shown to cause a drastic depletion of 5-HT (90% depletion) yet the two-way avoidance impairment was

248

ARCHER, JONSSON, AND ROSS

observed only in the groups treated with DSP4 (DSP4 + Sal and DSP4 + PCA). DSP4 treatment did not cause any decrease in the 5-HT concentrations of the parietal cortex. The relevance of this experiment is for indicating that our previously demonstrated two-way avoidance acquisition deficits could not have been confounded by the variable loss of 5-HT (20-40%) obtained after DSP4 administration. Taken together, these results offer further evidence implicating central NA involvement in the acquisition of the two-way avoidance task. However, the impairment induced by DSP4 and xylamine is generally not reflected by any deficit following the dorsal bundle 6-hydroxydopamine lesion (e.g., Mason & Fibiger, 1979). This is to be expected since these two lesions produce a very different pattern of NA depletion and, perhaps more importantly, the nonselective cytotoxic damage produced by 6-hydroxydopamine lesions (Hodge & Butcher, 1980; Sievers, Klemm, Jenner, Baumgarten, & Berry, 1980) is not shown following DSP4 on xylamine administration (Dudley et al., 1981). Thus, these compounds appear to have much potential as selective pharmacological tools for the investigation of the functions of noradrenergic systems.

ACKNOWLEDGMENT We thank Dr. Arthur K. Cho, University of California, Los Angeles, for the generous gift of xylamine.

REFERENCES Archer, T. (1982a). DSP4-(N-2-Chloroethyl-N-ethyl-2-bromobenzylamine), a new noradrenaline neurotoxin, and stimulus conditions affecting acquisition of two-way active avoidance. Journal of Comparative and Physiological Psychology, 96, 476-490. Archer, T. (1982b). The role of noradrenaline in learned behaviors: studies using DSP4. Scandinavian Journal of Psychology (Suppl. 1), 61-71. Archer, T. (1982c). Serotonin and fear retention in the rat. Journal of Comparative and Physiological Psychology, 96, 491-516. Archer, T., Cotic, T., & Jfirbe, T. U. C. (1982). Attenuation of the context effect and lack of unconditioned stimulus preexposure effect in taste-aversion learning following treatment with DSP4, the selective noradrenaline neurotoxin. Behavioral and Neural Biology, 35, 159-173. Archer, T., Jonsson, G., & Ross, S. B. (1984). A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurons in the CNS of the rat. British Journal of Pharmacology, 82, 249-257. Archer, T., Ogren, S.-O., Johansson, G., & Ross, S. B. (1982). DSP4-induced two-way active avoidance impairment: Involvement of central and not peripheral noradrenaline depletion. Psychopharmacology, 76, 303-309. Archer, T., S/~derberg, U., Ross, S. B., & Jonsson, G. (1984). The role of olfactory bulbectomy and DSP4 treatment in avoidance learning in the rat. Behavioral Neuroscience, 98, 496-505. Dudley, M. W., Butcher, L. L., Kammerer, R. G., & Cho, A. K. (1981). The actions of Xylamine on central noradrenergic neurons. The Journal of Pharmacology and Experimental Therapeutics, 271, 834-840. Dudley, M. W., Ransom, R. W., Kammerer, R. C., & Cho, A. K. (1980). The interaction of Xylamine with the adrenergic neuron. Federal Proceedings, 39, 857.

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