European Journal of Pharmacology, 215 (1992) 145-152
145
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 52426
Effects of drugs on behavior before and during chronic diazepam administration D.E. McMillan Department of Pharmacology and Toxicology, Collegeof Medicine, Unicersity of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, U.S.A. Received 17 October 1991, revised MS received 28 January 1992, accepted 18 February 1992
The effects of diazepam, pentobarbital, and phencyclidine (PCP) were studied on punished and unpunished responding maintained by fixed-interval schedules before and during chronic administration of diazepam. Before chronic diazepam administration, increasing doses of diazepam and PCP increased and then decreased rates of both punished and unpunished responding. Increases in punished responding were larger than increases in unpunished responding. Pentobarbital only increased punished responding, while higher doses decreased both rates of punished and unpunished responding. During chronic diazepam administration, rates of punished and unpunished responding showed further increases with all three drugs and the dose-effect curves also shifted to the right. Analysis of local rates of responding within fixed-interval components suggested that increases in low rates early in the interval were responsible for the rate increases produced by these drugs before chronic diazepam administration. During chronic diazepam administration low rates early in the interval showed greater increases after all three drugs and their ability to produce rate-increasing effects extended further into the interval. The similar effects of these drugs before and during chronic diazepam administration suggests a similar mechanism despite the widely recognized differences in their interaction with receptors. This common mechanism may relate to rate-increasing effects more than to specific effects on punished responding.
Punishment; Fixed-interval responding; Diazepam; Pentobarbital; Phencyclidine; Tolerance; (Pigeon)
1. Introduction
A number of drugs that increase punished responding have different mechanisms of action at the receptor level. For example, benzodiazepines increase punished responding under a variety of conditions (McMillan, 1975; McMillan and Leander, 1976; Sepinwall and Cook, 1978). Benzodiazepines bind to specific benzodiazepine receptors in the brain to potentiate the effects of y-aminobutyric acid (GABA) and modulate the opening of chloride ion channels (Lader, 1989), which may be the mechanism underlying the effects of these drugs on punished responding. Other drugs that increase punished responding, such as the barbiturates, also interact with the G A B A r e c e p t o r / c h l o r i d e - i o n channel, although not by binding to the G A B A component of the receptor complex (Lader, 1989). More
Correspondence to: D.E. McMillan, Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, U.S.A. Tel. 1.501.686 5510, fax 1.501.686 5521.
recently, drugs that bind to 5-HT1A receptors have been shown to increase punished responding (Witkin and Perez, 1990), and drugs that bind to phencyclidine (PCP) receptors also increase punished responding (Porter et al., 1989; McMillan et al., 1991). Increases in punished responding produced by drugs that bind specifically to different receptor populations suggests that punished responding may be under the control of several different systems in brain, but another possibility is that there is a common mechanism for these drugs at some level beyond the initial binding to the receptor, a 'final common pathway'. One way to gather some evidence to support this hypothesis would be to determine if the chronic administration of a drug that increases punished responding modifies its own effects on punished responding in the same way that it modifies the effects on punished responding of drugs from other classes. McMillan and Leander (1978) showed that chronic exposure to chlordiazepoxide in the drinking water of rats enhanced the effects of both chlordiazepoxide and pentobarbital in increasing punished responding. Chronic chlordiazepoxide exposure also shifted the d o s e - e f f e c t s curve for decreasing un-
146 punished responding to the right for both chlordiazepoxide and pentobarbital. Those results might be expected since both compounds produce effects through interactions with the G A B A r e c e p t o r / chloride-ion channel complex. The purpose of the present study was to determine in pigeons if chronic administration of diazepam, a drug that both increases punished responding and binds to benzodiazepine receptors to modulate the G A B A r e c e p t o r / c h l o r i d e - i o n channel complex, modifies the effects of pentobarbital, a drug that interacts with the G A B A r e c e p t o r / c h l o r i d e - i o n channel complex (but not by binding to benzodiazepine receptors) and the effects of phencyclidine (PCP), a drug that has not been shown to interact with benzodiazepine receptors, or the G A B A r e c e p t o r / c h l o r i d e - i o n channel complex. If chronic diazepam modified its own effects in a manner similar to the modification of the effects of pentobarbital and PCP, it would suggest a similarity in the mechanism of action of these drugs on punished responding.
2.3. Procedure The birds were trained to key peck to obtain food and then were placed under a multiple fixed-interval 200-s fixed-interval 200-s schedule of food presentation (mult FI 200 s FI 200 s). Under this schedule, in the presence of a red keylight the first peck after 200 s resulted in 4-s access to grain and in the presence of a green keylight the first keypeck after 200 s also resulted in 4-s access to grain. If no response occurred within 1 m after 200 s in the presence of either key color the schedule components alternated without food delivery. Two birds always started a session with a green keylight and the other with a red keylight. The session terminated after 10 presentations of each schedule component. After behavior had stabilized under mult FI 200 s FI 200 s, every 8th response during one of the two FI components produced electric shock (punishment component). One bird was shocked only for pecks on the green key and two birds were shocked only for pecks on the red key. All birds began the session with the non-punishment component.
2. Materials and methods
2.4. Drugs 2.1. Subjects Three male White Carneaux pigeons with no previous training, weighing approximately 560 g under a regimen of free food and water were reduced to 80% of their free-feeding weights. They were maintained at these weights throughout the experiments.
2.2. Apparatus Pigeons were implanted with electrodes around the pubis bone according to the method of Azrin (1959). Electric current (110 V AC, 60 Hz) was delivered through an adjustable resistor to a fixed resistance of about 1 000 ~Q. The range of shock intensity was varied between 2.0 and 2.4 m A through the adjustable resistor and the intensity of the shock that would give a moderate suppression of responding was determined empirically for each bird. The shock duration was 50 ms. The experimental chamber was a Model G7313 pigeon test cage (Ralph Gerbrands Co.) equipped with a response key which could be transilluminated with red or green lights. The chamber was enclosed inside a Model G7211 sound and light attenuating enclosure (Ralph Gerbrands Co.). The minimum force required to operate the key was about 0.5 N. A small relay mounted on the chamber operated whenever the key contact was opened to provide auditory feedback when a response occurred. A house light illuminated the experimental chamber during the session except during the food cycle.
Pentobarbital was used as the sodium salt, PCP as the hydrochloride, and diazepam as the free base. All dose levels refer to the drugs in these forms. Pentobarbital and PCP were dissolved in 0.9% saline and injections were given into the breast muscle in a volume of 1 m l / k g , 10 min before the beginning of the session. Saline was given as a control injection 10 rain before the session on Thursdays during the determination of the pentobarbital and PCP d o s e - e f f e c t curves. Diazepam was dissolved in its commercial solvent (Tween 80, benzyl alcohol, maleic acid, propylene glycol, sodium hydroxide and water). The commercial solvent was given as a control injection on Thursdays during the determination of the acute diazepam d o s e - e f f e c t curves. Drug injections were given on Tuesdays and Fridays. Behavior testing was conducted on Mondays and Wednesdays, but no injections were given. The entire d o s e - e f f e c t curve for each drug was determined in each bird. Two birds received an ascending dosage series of each drug and one bird received a descending series. The order of determination was always diazepam, pentobarbital, then PCP. After determination of acute dose-effect curves, diazepam was administered chronically (intramuscularly) immediately after the test session on weekdays. The dose was 5 m g / k g . Diazepam injections also were given on Saturday and Sunday at approximately 12:00 p.m., but behavioral sessions were not conducted on these days. After 4 weeks of chronic diazepam administration, the dose-effect curves for diazepam, pentobar-
147
bital and PCP were redetermined over a 6-week period with diazepam continuing to be given after each session and on weekends.
that fell more than two S.D.s. from the mean rate in each F] segment were considered to be significant.
2.5. Measurement of drug effects
3. Results
Average rates of responding during the entire session were computed in responses per second from elapsed time meters and counters for both punished and unpunished responding. Thursday injection days were used as control days to determine a control mean, and a S.D. Drug effects that fell more than two S.D.s from the mean were considered to be significant. For the analysis of rate-dependent drug effects, responses were cumulated during each tenth (20 s) of the FI component for both schedule components during each session, so that average rates of punished and unpunished responding during 10 different segments of each FI component could be determined for control sessions and for drug sessions. S.D.s were calculated for the 2(1) s segments of control sessions. Drug effects
Punished responding (0.27 responses/s) occurred at approximately half the rate of unpunished responding (0.56 responses/s). During chronic diazepam administration neither the rate of unpunished nor punished responding changed significantly (points and brackets at B and D in fig. 1). Figure 1 shows dose-effect curves for diazepam, pentobarbital and PCP before and during chronic diazepam administration. Before chronic administration diazepam produced small increases in unpunished responding at 1.0 and 1.8 mg/kg. Somewhat larger increases occurred in punished responding at these doses. At the highest dose (3.0 mg/kg) the dose-effect curve turned over to form a descending leg.
UNPUNISHED
PUNISHED
DIAZEPAM
1.0o.
1.00 0,80 0.60
0,40
0,40.
0.20
0.20.
0.00
::::--:
B
a Z 0 U LIJ £~i ~_~
W
:
: ::::::
0.3
i
1.0
i
i,,,,,:
: ::::::
0.00
3.0
10.0
B
:
D
:::::::
0.3
: 1.0
:
:::::::
3.0
10.0
10
17.5
PENTOBARBITAL 1.00
~
0.80
Z o.~0Q. ~
:
D
0.80
~
0,~
o.411.
0.20. 0.00
:
:
: ::::::
B
D
:
1
:
:::::::
3
:
10
0.00
17.5
T
B
D
I
3
PHENCYCLIDINE
1.20.
1.2o,
1.00.
1.oo. -
0.80.
0.80,
0,110.
0.40. 0,20. 0,00
B
D
CONTROL
0.1
0.3
I MG//KG DOSE
3
10
B
D
CONTROL
0.1
0.3
1 MG/KG
3
10
DOSE
Fig. 1. Effects of diazepam (top row), pentobarbital (middle row) and phencyclidine (bottom row) on unpunished (first column) and punished (second column) responding before (filled points) and during (unfilled points) chronic diazepam administration. The brackets show+ 2 S.D.s around the mean control rates before (bracket at B) and during (bracket at D) chronic diazepam administration.
148
During chronic administration of diazepam, the dose-effect curve for unpunished responding shifted to the right, but the peak increase in unpunished responding was of similar magnitude to that observed before chronic diazepam administration. In contrast, during chronic diazepam administration, diazepam produced larger absolute increases in the rate of punished responding and the effects were observed across a wider range of doses. The middle frames of fig. 1 show the effects of pentobarbital before and after chronic diazepam administration. Before chronic diazepam administration, low doses of pentobarbital did not increase unpunished
responding, while doses of 10 and 13 mg/kg decreased the rate. Before chronic diazepam administration, doses of 1-10 mg/kg increased punished responding after which the curve descended with responding being eliminated after the 13 mg/kg doses. During chronic diazepam administration, doses of 3-10 mg/kg pentobarbital increased unpunished responding and the descending leg of the dose-effect curve shifted to the right. As with the diazepam doseeffect curve during chronic diazepam administration, pentobarbital increased punished responding by a larger absolute magnitude and across a wider range of doses during chronic diazepam administration. The
OIAZEPAM BEFORE
OURING 17
J/J/J/J/d;j_dsU ,_U
I.O
3.0
JJj/,/jj
fT_
56
J)_i:L,Jj_,:o:j_,:ooo.
!I'/Jii/J/./.l.tJiJ/jl, I~ lli#KG
I//llll//sdwlJ .ll
J//l/j/:/jl;/Jl 55
1.0 MG/KG
:Js/jJl./ ,l.J. /.J_,. /h/l/ JllJll.,jlJJ< 'lomt' Fig. 2. Cumulative response records for effects of diazepam before (column 1) and during (column 2) chronic post-session mazepam administration. The event pen is in the up position for the component in which responses were not punished and in the down position for the component in which responses were punished. Punishment and non-punishment components alternated. Numbers centered in the 'vehicle rows' are the individual bird identifications.
149
Figure 2 shows cumulative records for individual pigeons showing the effects of 1.0 and 3.0 mg/kg diazepam on unpunished and punished responding before (first column) and during (second column) chronic diazepam administration. The increases in punished responding produced by diazepam, as well the tolerance to the rate-decreasing effects of diazepam and the enhancement of the increases in punished responding during chronic diazepam administration can be seen clearly in the records from the individual birds. In fig. 3 the rate of responding has been plotted for each 20 s segment of the F1 for unpunished and punished responding before and during chronic diazcpam administration for three doses of diazepam. Before chronic diazepam administration, increases in both unpunished and punished responding occurred primarily in the early parts of the F1 when control rates of responding were low, although for bird 56, the rate-increasing effects of diazepam extended well into the FI. During chronic diazepam administration, rate-
descending leg of the pentobarbital dose-effect curve also was shifted to the right for punished responding during chronic diazepam administration. The bottom frames of fig. 1 show the effects of PCP before and during chronic diazepam. Before chronic diazepam administration, only the 0.3 mg/kg dose increased unpunished responding, while the highest dose (3.0 mg/kg) decreased unpunished responding. Before chronic diazepam administration, doses of 0.11.0 mg/kg PCP increased punished responding, while the 3.0 mg/kg dose decreased punished responding. During chronic diazepam administration, the doseeffect curve for the effects of PCP on unpunished responding was shifted upwards and to the right, with the 1.0 mg/kg dose producing the greatest increase. During chronic administration of diazepam the PCP dose-effect curve for punished responding also shifted upward and to the right, although the dose producing the greatest increase in punished responding (1.0 mg/kg) did not change.
DIAZEPAM
t "°t A
PUNISHED
UNPUNISHED DURING
BEFORE
•
BEFORE
DURING
1.4 1.6 17 1.2
o
oo
OO
.-",iS'
0.8
0 o
0.6
o, t
0
~
~
•
ot l ol , ,igll
1,41.2-
°°°
i , , ,
ooO o°~/~e
~oO°o
~oA
~°o
Ao
•
°°
0.8-
e°
o
°°o°o
'?/
o2-
.
~//
O-
J.6 o
0
°~e$ °
, , , , ,
~
o
o
:o °
"
, , , , , , , , , ,
55
1.41.21.0-
0 o°
~0
08"
•
0.6"
AO
~0
0.4" 0 O0
0.2" O"
¢t I •
O0 0
0
0
O0
~.0
12345678910
I 2345678910 123456"/'8910 20-SEC FIXED-INTERVAL SEGMENTS
1 2 3 4 5 6 78910
Fig. 3. Effects of diazepam on rates of unpunished (first two columns) and punished (last two columns) responding during 20-s fixed interval segments before (columns 1 and 3) and during (columns 2 and 4) chronic post-session diazepam administration. Solid lines show + 2 S.D.s around the control mean for the 20-s fixed-interval segments. Symbols are as follows: (e) 1 mg/kg; (zx) 1.8 m g / k g diazepam; ( o ) 3 m g / k g diazepam. Numbers inside frames in the first column are individual bird identifications.
150 PENTOBARBtTAL PUNISHED
UNPUNISHED [.6"
17
BEFORE
DURING
BEFORE
DURING
1.4" 1.2" 1.0' 0.8 0.6' 0.4' •
02
°°
O
o
i
°o°° ¢ #
z°
O9
1.4¸ 1.2¸
"-
1.0
O3 Z
0.8 ¸
o
0.6.
v,
0.4
(1_
A
&
].6 (9
°°
,,.o o
56o~~• oO
&
2.
A A
•
A
Oo °
o°O o
&o
8
0.2 ,,,,,,,,,,
oo o L6"~ 5 5 1.4-
° oo°
° o°
:.
1.21.0" 0.8-
o
&
°°
ooO,
n
n Aa
A A
0.6-
o o°
° o
•
o: °°
0.4-
L
O.Z" O"
[~4gg~'ggb 20-SEC
FIXED-INTERVAL
SEGMENTS
Fig. 4. Effects of pentobarbital on rates of unpunished (first two columns) and punished (last two columns) responding during 20-s fixed-interval segments before (columns I and 3) and during (columns 2 and 4) chronic post-session diazepam administration. Solid lines show +_2 S.D.s around the mean control rates for the 20-s fixed-interval segments. Symbols are as follows: (o) 3 mg/kg pentobarbital: ( zx) 5.6 mg/kg pentobarbital: (
145
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 52426
Effects of drugs on behavior before and during chronic diazepam administration D.E. McMillan Department of Pharmacology and Toxicology, Collegeof Medicine, Unicersity of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, U.S.A. Received 17 October 1991, revised MS received 28 January 1992, accepted 18 February 1992
The effects of diazepam, pentobarbital, and phencyclidine (PCP) were studied on punished and unpunished responding maintained by fixed-interval schedules before and during chronic administration of diazepam. Before chronic diazepam administration, increasing doses of diazepam and PCP increased and then decreased rates of both punished and unpunished responding. Increases in punished responding were larger than increases in unpunished responding. Pentobarbital only increased punished responding, while higher doses decreased both rates of punished and unpunished responding. During chronic diazepam administration, rates of punished and unpunished responding showed further increases with all three drugs and the dose-effect curves also shifted to the right. Analysis of local rates of responding within fixed-interval components suggested that increases in low rates early in the interval were responsible for the rate increases produced by these drugs before chronic diazepam administration. During chronic diazepam administration low rates early in the interval showed greater increases after all three drugs and their ability to produce rate-increasing effects extended further into the interval. The similar effects of these drugs before and during chronic diazepam administration suggests a similar mechanism despite the widely recognized differences in their interaction with receptors. This common mechanism may relate to rate-increasing effects more than to specific effects on punished responding.
Punishment; Fixed-interval responding; Diazepam; Pentobarbital; Phencyclidine; Tolerance; (Pigeon)
1. Introduction
A number of drugs that increase punished responding have different mechanisms of action at the receptor level. For example, benzodiazepines increase punished responding under a variety of conditions (McMillan, 1975; McMillan and Leander, 1976; Sepinwall and Cook, 1978). Benzodiazepines bind to specific benzodiazepine receptors in the brain to potentiate the effects of y-aminobutyric acid (GABA) and modulate the opening of chloride ion channels (Lader, 1989), which may be the mechanism underlying the effects of these drugs on punished responding. Other drugs that increase punished responding, such as the barbiturates, also interact with the G A B A r e c e p t o r / c h l o r i d e - i o n channel, although not by binding to the G A B A component of the receptor complex (Lader, 1989). More
Correspondence to: D.E. McMillan, Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, U.S.A. Tel. 1.501.686 5510, fax 1.501.686 5521.
recently, drugs that bind to 5-HT1A receptors have been shown to increase punished responding (Witkin and Perez, 1990), and drugs that bind to phencyclidine (PCP) receptors also increase punished responding (Porter et al., 1989; McMillan et al., 1991). Increases in punished responding produced by drugs that bind specifically to different receptor populations suggests that punished responding may be under the control of several different systems in brain, but another possibility is that there is a common mechanism for these drugs at some level beyond the initial binding to the receptor, a 'final common pathway'. One way to gather some evidence to support this hypothesis would be to determine if the chronic administration of a drug that increases punished responding modifies its own effects on punished responding in the same way that it modifies the effects on punished responding of drugs from other classes. McMillan and Leander (1978) showed that chronic exposure to chlordiazepoxide in the drinking water of rats enhanced the effects of both chlordiazepoxide and pentobarbital in increasing punished responding. Chronic chlordiazepoxide exposure also shifted the d o s e - e f f e c t s curve for decreasing un-
146 punished responding to the right for both chlordiazepoxide and pentobarbital. Those results might be expected since both compounds produce effects through interactions with the G A B A r e c e p t o r / chloride-ion channel complex. The purpose of the present study was to determine in pigeons if chronic administration of diazepam, a drug that both increases punished responding and binds to benzodiazepine receptors to modulate the G A B A r e c e p t o r / c h l o r i d e - i o n channel complex, modifies the effects of pentobarbital, a drug that interacts with the G A B A r e c e p t o r / c h l o r i d e - i o n channel complex (but not by binding to benzodiazepine receptors) and the effects of phencyclidine (PCP), a drug that has not been shown to interact with benzodiazepine receptors, or the G A B A r e c e p t o r / c h l o r i d e - i o n channel complex. If chronic diazepam modified its own effects in a manner similar to the modification of the effects of pentobarbital and PCP, it would suggest a similarity in the mechanism of action of these drugs on punished responding.
2.3. Procedure The birds were trained to key peck to obtain food and then were placed under a multiple fixed-interval 200-s fixed-interval 200-s schedule of food presentation (mult FI 200 s FI 200 s). Under this schedule, in the presence of a red keylight the first peck after 200 s resulted in 4-s access to grain and in the presence of a green keylight the first keypeck after 200 s also resulted in 4-s access to grain. If no response occurred within 1 m after 200 s in the presence of either key color the schedule components alternated without food delivery. Two birds always started a session with a green keylight and the other with a red keylight. The session terminated after 10 presentations of each schedule component. After behavior had stabilized under mult FI 200 s FI 200 s, every 8th response during one of the two FI components produced electric shock (punishment component). One bird was shocked only for pecks on the green key and two birds were shocked only for pecks on the red key. All birds began the session with the non-punishment component.
2. Materials and methods
2.4. Drugs 2.1. Subjects Three male White Carneaux pigeons with no previous training, weighing approximately 560 g under a regimen of free food and water were reduced to 80% of their free-feeding weights. They were maintained at these weights throughout the experiments.
2.2. Apparatus Pigeons were implanted with electrodes around the pubis bone according to the method of Azrin (1959). Electric current (110 V AC, 60 Hz) was delivered through an adjustable resistor to a fixed resistance of about 1 000 ~Q. The range of shock intensity was varied between 2.0 and 2.4 m A through the adjustable resistor and the intensity of the shock that would give a moderate suppression of responding was determined empirically for each bird. The shock duration was 50 ms. The experimental chamber was a Model G7313 pigeon test cage (Ralph Gerbrands Co.) equipped with a response key which could be transilluminated with red or green lights. The chamber was enclosed inside a Model G7211 sound and light attenuating enclosure (Ralph Gerbrands Co.). The minimum force required to operate the key was about 0.5 N. A small relay mounted on the chamber operated whenever the key contact was opened to provide auditory feedback when a response occurred. A house light illuminated the experimental chamber during the session except during the food cycle.
Pentobarbital was used as the sodium salt, PCP as the hydrochloride, and diazepam as the free base. All dose levels refer to the drugs in these forms. Pentobarbital and PCP were dissolved in 0.9% saline and injections were given into the breast muscle in a volume of 1 m l / k g , 10 min before the beginning of the session. Saline was given as a control injection 10 rain before the session on Thursdays during the determination of the pentobarbital and PCP d o s e - e f f e c t curves. Diazepam was dissolved in its commercial solvent (Tween 80, benzyl alcohol, maleic acid, propylene glycol, sodium hydroxide and water). The commercial solvent was given as a control injection on Thursdays during the determination of the acute diazepam d o s e - e f f e c t curves. Drug injections were given on Tuesdays and Fridays. Behavior testing was conducted on Mondays and Wednesdays, but no injections were given. The entire d o s e - e f f e c t curve for each drug was determined in each bird. Two birds received an ascending dosage series of each drug and one bird received a descending series. The order of determination was always diazepam, pentobarbital, then PCP. After determination of acute dose-effect curves, diazepam was administered chronically (intramuscularly) immediately after the test session on weekdays. The dose was 5 m g / k g . Diazepam injections also were given on Saturday and Sunday at approximately 12:00 p.m., but behavioral sessions were not conducted on these days. After 4 weeks of chronic diazepam administration, the dose-effect curves for diazepam, pentobar-
147
bital and PCP were redetermined over a 6-week period with diazepam continuing to be given after each session and on weekends.
that fell more than two S.D.s. from the mean rate in each F] segment were considered to be significant.
2.5. Measurement of drug effects
3. Results
Average rates of responding during the entire session were computed in responses per second from elapsed time meters and counters for both punished and unpunished responding. Thursday injection days were used as control days to determine a control mean, and a S.D. Drug effects that fell more than two S.D.s from the mean were considered to be significant. For the analysis of rate-dependent drug effects, responses were cumulated during each tenth (20 s) of the FI component for both schedule components during each session, so that average rates of punished and unpunished responding during 10 different segments of each FI component could be determined for control sessions and for drug sessions. S.D.s were calculated for the 2(1) s segments of control sessions. Drug effects
Punished responding (0.27 responses/s) occurred at approximately half the rate of unpunished responding (0.56 responses/s). During chronic diazepam administration neither the rate of unpunished nor punished responding changed significantly (points and brackets at B and D in fig. 1). Figure 1 shows dose-effect curves for diazepam, pentobarbital and PCP before and during chronic diazepam administration. Before chronic administration diazepam produced small increases in unpunished responding at 1.0 and 1.8 mg/kg. Somewhat larger increases occurred in punished responding at these doses. At the highest dose (3.0 mg/kg) the dose-effect curve turned over to form a descending leg.
UNPUNISHED
PUNISHED
DIAZEPAM
1.0o.
1.00 0,80 0.60
0,40
0,40.
0.20
0.20.
0.00
::::--:
B
a Z 0 U LIJ £~i ~_~
W
:
: ::::::
0.3
i
1.0
i
i,,,,,:
: ::::::
0.00
3.0
10.0
B
:
D
:::::::
0.3
: 1.0
:
:::::::
3.0
10.0
10
17.5
PENTOBARBITAL 1.00
~
0.80
Z o.~0Q. ~
:
D
0.80
~
0,~
o.411.
0.20. 0.00
:
:
: ::::::
B
D
:
1
:
:::::::
3
:
10
0.00
17.5
T
B
D
I
3
PHENCYCLIDINE
1.20.
1.2o,
1.00.
1.oo. -
0.80.
0.80,
0,110.
0.40. 0,20. 0,00
B
D
CONTROL
0.1
0.3
I MG//KG DOSE
3
10
B
D
CONTROL
0.1
0.3
1 MG/KG
3
10
DOSE
Fig. 1. Effects of diazepam (top row), pentobarbital (middle row) and phencyclidine (bottom row) on unpunished (first column) and punished (second column) responding before (filled points) and during (unfilled points) chronic diazepam administration. The brackets show+ 2 S.D.s around the mean control rates before (bracket at B) and during (bracket at D) chronic diazepam administration.
148
During chronic administration of diazepam, the dose-effect curve for unpunished responding shifted to the right, but the peak increase in unpunished responding was of similar magnitude to that observed before chronic diazepam administration. In contrast, during chronic diazepam administration, diazepam produced larger absolute increases in the rate of punished responding and the effects were observed across a wider range of doses. The middle frames of fig. 1 show the effects of pentobarbital before and after chronic diazepam administration. Before chronic diazepam administration, low doses of pentobarbital did not increase unpunished
responding, while doses of 10 and 13 mg/kg decreased the rate. Before chronic diazepam administration, doses of 1-10 mg/kg increased punished responding after which the curve descended with responding being eliminated after the 13 mg/kg doses. During chronic diazepam administration, doses of 3-10 mg/kg pentobarbital increased unpunished responding and the descending leg of the dose-effect curve shifted to the right. As with the diazepam doseeffect curve during chronic diazepam administration, pentobarbital increased punished responding by a larger absolute magnitude and across a wider range of doses during chronic diazepam administration. The
OIAZEPAM BEFORE
OURING 17
J/J/J/J/d;j_dsU ,_U
I.O
3.0
JJj/,/jj
fT_
56
J)_i:L,Jj_,:o:j_,:ooo.
!I'/Jii/J/./.l.tJiJ/jl, I~ lli#KG
I//llll//sdwlJ .ll
J//l/j/:/jl;/Jl 55
1.0 MG/KG
:Js/jJl./ ,l.J. /.J_,. /h/l/ JllJll.,jlJJ< 'lomt' Fig. 2. Cumulative response records for effects of diazepam before (column 1) and during (column 2) chronic post-session mazepam administration. The event pen is in the up position for the component in which responses were not punished and in the down position for the component in which responses were punished. Punishment and non-punishment components alternated. Numbers centered in the 'vehicle rows' are the individual bird identifications.
149
Figure 2 shows cumulative records for individual pigeons showing the effects of 1.0 and 3.0 mg/kg diazepam on unpunished and punished responding before (first column) and during (second column) chronic diazepam administration. The increases in punished responding produced by diazepam, as well the tolerance to the rate-decreasing effects of diazepam and the enhancement of the increases in punished responding during chronic diazepam administration can be seen clearly in the records from the individual birds. In fig. 3 the rate of responding has been plotted for each 20 s segment of the F1 for unpunished and punished responding before and during chronic diazcpam administration for three doses of diazepam. Before chronic diazepam administration, increases in both unpunished and punished responding occurred primarily in the early parts of the F1 when control rates of responding were low, although for bird 56, the rate-increasing effects of diazepam extended well into the FI. During chronic diazepam administration, rate-
descending leg of the pentobarbital dose-effect curve also was shifted to the right for punished responding during chronic diazepam administration. The bottom frames of fig. 1 show the effects of PCP before and during chronic diazepam. Before chronic diazepam administration, only the 0.3 mg/kg dose increased unpunished responding, while the highest dose (3.0 mg/kg) decreased unpunished responding. Before chronic diazepam administration, doses of 0.11.0 mg/kg PCP increased punished responding, while the 3.0 mg/kg dose decreased punished responding. During chronic diazepam administration, the doseeffect curve for the effects of PCP on unpunished responding was shifted upwards and to the right, with the 1.0 mg/kg dose producing the greatest increase. During chronic administration of diazepam the PCP dose-effect curve for punished responding also shifted upward and to the right, although the dose producing the greatest increase in punished responding (1.0 mg/kg) did not change.
DIAZEPAM
t "°t A
PUNISHED
UNPUNISHED DURING
BEFORE
•
BEFORE
DURING
1.4 1.6 17 1.2
o
oo
OO
.-",iS'
0.8
0 o
0.6
o, t
0
~
~
•
ot l ol , ,igll
1,41.2-
°°°
i , , ,
ooO o°~/~e
~oO°o
~oA
~°o
Ao
•
°°
0.8-
e°
o
°°o°o
'?/
o2-
.
~//
O-
J.6 o
0
°~e$ °
, , , , ,
~
o
o
:o °
"
, , , , , , , , , ,
55
1.41.21.0-
0 o°
~0
08"
•
0.6"
AO
~0
0.4" 0 O0
0.2" O"
¢t I •
O0 0
0
0
O0
~.0
12345678910
I 2345678910 123456"/'8910 20-SEC FIXED-INTERVAL SEGMENTS
1 2 3 4 5 6 78910
Fig. 3. Effects of diazepam on rates of unpunished (first two columns) and punished (last two columns) responding during 20-s fixed interval segments before (columns 1 and 3) and during (columns 2 and 4) chronic post-session diazepam administration. Solid lines show + 2 S.D.s around the control mean for the 20-s fixed-interval segments. Symbols are as follows: (e) 1 mg/kg; (zx) 1.8 m g / k g diazepam; ( o ) 3 m g / k g diazepam. Numbers inside frames in the first column are individual bird identifications.
150 PENTOBARBtTAL PUNISHED
UNPUNISHED [.6"
17
BEFORE
DURING
BEFORE
DURING
1.4" 1.2" 1.0' 0.8 0.6' 0.4' •
02
°°
O
o
i
°o°° ¢ #
z°
O9
1.4¸ 1.2¸
"-
1.0
O3 Z
0.8 ¸
o
0.6.
v,
0.4
(1_
A
&
].6 (9
°°
,,.o o
56o~~• oO
&
2.
A A
•
A
Oo °
o°O o
&o
8
0.2 ,,,,,,,,,,
oo o L6"~ 5 5 1.4-
° oo°
° o°
:.
1.21.0" 0.8-
o
&
°°
ooO,
n
n Aa
A A
0.6-
o o°
° o
•
o: °°
0.4-
L
O.Z" O"
[~4gg~'ggb 20-SEC
FIXED-INTERVAL
SEGMENTS
Fig. 4. Effects of pentobarbital on rates of unpunished (first two columns) and punished (last two columns) responding during 20-s fixed-interval segments before (columns I and 3) and during (columns 2 and 4) chronic post-session diazepam administration. Solid lines show +_2 S.D.s around the mean control rates for the 20-s fixed-interval segments. Symbols are as follows: (o) 3 mg/kg pentobarbital: ( zx) 5.6 mg/kg pentobarbital: (
