Faculty Biosketch
|
Milton S. Hershey
Medical Center
Penn State College of Medicine
P.O. Box 850,
500 University Drive
Hershey, PA 17033-2390 |
|
|
Patricia Sue Grigson,
Ph.D.
Neural and Behavioral Sciences
|
 |
Office Information
Phone: 717-531-5772
Mail Code: H181
|
|
Education |
B.S., Elizabethtown
College, 1984
M.S., Ph.D., Rutgers University, 1990
Post Doc, Penn State College of Medicine, Lab of Dr.
Norgren, 1993 |
| Primary
Area of Interest |
| We are interested in the mechanisms by which
drugs of abuse come to devalue natural rewards and, in
turn, the mechanisms by which natural rewards might come
to protect against substance abuse and addiction. |
| Research
Focus |
| 1) Significance. According to
figures provided by the National Institute on Drug Abuse,
there are 8.2 million alcoholics in America, 1.5 million
chronic users of cocaine (3.2% of 8th graders have used
cocaine at least once), 2.4 million Americans have used
heroin (87% under the age of 26), and as of 2002, 10 million
Americans have used ecstasy. Eighty-three million Americans
(37%) have tried marijuana and 57 million Americans smoke
cigarettes. These numbers, while large, are even more
astounding as it becomes increasingly evident that addiction
is not resolved following abstinence. In fact, addiction is
now recognized as a disease of chronic relapse (Leshner, 1999), costing society hundreds of
billions of dollars/year as the addict repeatedly cycles
from addiction to abstinence, withdrawal, drug-seeking,
and relapse. Along with society, the addict and his or her
family, also pay as substance abuse, dependence, and
addiction are associated with an apparent devaluation of,
and inattention to, natural rewards. According to DSM-IV,
substance abuse and dependence involve a failure to
fulfill major obligations at work, school, or home, the
giving up of important social, occupational, or
recreational activities, and continued drug use in spite
of recurrent physical, legal, social, or psychological
problems. These findings are supported by published data
(Jones et al., 1995; Nair et al., 1997; Santolaria-Fernandez
et al., 1995). Addiction, then, is a two-part problem
involving chronic relapse and the concurrent devaluation
of natural rewards. While there are a number of critical
animal models of craving and relapse (Grimm et al., 2001;
Neisewander et al., 2000; Weiss et al., 2000), there are
no recognized animal models for the study of drug-induced
devaluation of natural rewards. Thus, we have developed
such a model. Our data demonstrate that a long-standing
model of drug-induced conditioned taste aversion likely
has been misinterpreted and actually serves as an animal
model for the study of drug-induced devaluatio
(2) Intake suppression: Aversive and appetitive
conditioning. Rats suppress intake of a saccharin
conditioned stimulus (CS) when paired with either an
aversive or an appetitive unconditioned stimulus (US). In
aversive conditioning, a conditioned taste aversion (CTA)
occurs when rats suppress intake of a gustatory CS
(usually saccharin) after it has been paired with an
aversive, illness-inducing agent such as lithium chloride
(LiCl) or x-radiation (Garcia, Kimeldorf, & Koelling,
1955). In appetitive conditioning, an anticipatory
contrast effect (ACE) occurs when rats avoid intake of a
similar saccharin CS when paired with a more rewarding
sucrose US (Flaherty & Checke, 1982). This phenomenon
is referred to as an anticipatory contrast effect because
the decrease in intake of the taste cue is thought to
reflect an associative process whereby the perceived value
of the saccharin CS pales in anticipation of the
availability of the preferred sucrose US (Flaherty &
Grigson, 1988; Flaherty & Rowan, 1985).
(3) Intake suppression: Drugs of abuse. Not long after
CTAs were discovered using emetic agents, but prior to the
discovery of anticipatory contrast, drug-induced
suppression of CS intake also was found with a range of
abused substances (for reviews, see Gamzu, Vincent, &
Boff, 1985; Goudie, 1987; Hunt & Amit, 1987).
Drug-induced suppression of CS intake can be established
with morphine (Cappell, LeBlanc & Endrenyi, 1973;
Miller, Kelly, Neisewander, McCoy, & Bardo, 1990;
Sherman, Pickman, Rice, Liebeskind, & Holman, 1980),
cocaine (Glowa, Shaw, & Riley, 1994), amphetamine (Cappell
& LeBlanc, 1971), ethanol, flurazepam, and
chlordiazepoxide (Cappell et al., 1973; Lester, Nachman,
& LeMagnen, 1970; Vogel & Nathan, 1975), and with
amobarbital and phenobarbital (Vogel & Nathan, 1975).
Indeed, the only drug found not to support the reduction
in CS intake was heroin (Switzman, Hunt, & Amit, 1981)
and our recent data prove that even heroin is no exception
(Grigson, Twining, & Carelli, 2000). Thus, rats avoid
intake of a taste cue following pairings with all drugs of
abuse tested, across a range of doses (Parker, 1991), and
when administered intraperitoneally (ip), subcutaneously
(sc), intravenously (iv), and directly into the nucleus
accumbens (Bechara & van der Kooy, 1985; Cappell &
LeBlanc, 1971; Mucha & Herz, 1986; Shoaib &
Stolerman, 1995; Wise, Yokel & DeWit, 1976).
(4) Drugs of abuse: Evidence against a CTA account.
Despite the drug-induced reduction in CS intake (i.e., the
operational definition of a conditioned taste aversion),
other data suggest that these drugs are rewarding and that
the resultant reduction in CS intake is not like that
mediated by LiCl. Specifically, drugs of abuse are readily
self-administered by humans and other animals (for review,
see van Ree, 1979) and, unlike LiCl, they sustain the
development of conditioned place preferences (Bardo,
Miller, & Neisewander, 1984; Blander, Hunt, Blair,
& Amit, 1984; Katz & Gormezano, 1979; Reilly,
Grigson, & Norgren, 1993). Further, while LiCl
suppresses both instrumental and consumatory responding
(White, Sklar, & Amit, 1977), drugs of abuse
simultaneously augment instrumental performance and
suppress conditioned consumatory behavior (Wise et al.,
1976; White et al., 1977; Reicher & Holman, 1977).
Finally, Parker (1984, 1988, 1991, 1993, 1995) used the
Taste Reactivity test of Grill and Norgren (1978) to
assess the palatability of gustatory CSs and convincingly
dissociated LiCl-induced CTAs from the suppressive effects
of self-administered drugs. These findings led Parker
(1988) to conclude that "...positively reinforcing
drugs may produce a different type of CTA than do drugs
which are not positively reinforcing."
(5) Drugs of abuse: Evidence in support of the reward
comparison hypothesis. After surveying these and related
data, we developed the hypothesis that drugs of abuse do
not support CTA learning at all. To the contrary, we
proposed that the well-known rewarding properties of drugs
of abuse, rather than their aversive properties, mediate
the reduction in CS intake following taste-drug pairings
(Grigson, 1997). According to this hypothesis, the same
rewarding properties that increase self-administration of
the drug, preference for a location paired with the drug,
and running speed in a runway also mediate the reduction
in CS intake following taste-drug pairings. Specifically,
rats suppress intake of a saccharin CS following
taste-drug pairings because the perceived value of the
saccharin cue is reduced in anticipation of the
availability of the more potent rewarding properties of
the impending drug of abuse (much as it is when it
predicts access to a preferred sucrose US). In support:
(a) The reduction in CS intake that occurs with a sucrose
US, morphine and cocaine, but not LiCl, depend upon the
nature (e.g., saccharin vs. salt) of the gustatory CS (Bevins,
Delzer, & Bardo, 1996; Grigson, 1997). (b) The
suppressive effects of sucrose and morphine, but not LiCl,
increase with increasing concentrations (i.e., value) of
the saccharin CS (Ellins & Kennedy, 1995; Flaherty,
Turovsky, & Krauss, 1994; Grigson, 1997) and vary with
the length of the CS access period (Flaherty, Grigson,
Coppotelli, & Mitchell, 1996; Liu, Twining, Murty,
Salness, & Grigson, in preparation). (c) The
suppressive effects of sucrose and drugs of abuse, but to
a lesser extent LiCl, are reduced when the rats are tested
in a food- or water-deprived state (Flaherty, Grigson,
Checke, & Hnat, 1991; Gomez & Grigson, 1999;
Grigson, Lyuboslavsky, Tanase, & Wheeler, 1999). (d)
The suppressive effects of cocaine and sucrose, but not
LiCl, are greater when tested in reward sensitive Lewis,
than less sensitive Fischer 344, rats
(6) Reward Comparison: The new model. We are interested
not only in how the drug affects responding for the
natural reward, but in how the availability of the natural
reward cue might affect responding for the drug of abuse.
To address this broader issue, we incorporated drug
self-administration into the model such that each daily 5
min access period to saccharin is followed by one h to
self-administer cocaine. The results revealed large
individual differences whereby some rats avoided intake of
the saccharin cue much more than others. Moreover, we
found that greater avoidance of the taste cue was
associated with greater drug self-administration and
drug-seeking following an extended period of abstinence
(Grigson & Twining, 2002). The new model, then, can
evaluate two critical aspects of addiction that we now
know to go hand-in-hand: The first is drug-induced
devaluation of natural rewards and the second is the
propensity to ‘consume’ a drug of abuse. Finally,
while drugs of abuse can devalue natural rewards, we have
stated that natural rewards also can protect against
substance abuse and addiction. Recent data from our
laboratory shows that brief access to a sweet can delay
acquisition of cocaine self-administration (Twining &
Grigson, in preparation), protect against cue and
drug-induced relapse (Liu & Grigson, submitted), and
prevent the morphine-induced dopamine peak (typically
viewed as an index of reward) in the nucleus accumbens in
rats (Grigson & Hajnal, submitted). These data are
exciting as they begin to address the treatment potential
of competing natural rewards and the associated underlying
neural mechanisms. |
| References |
- Flaherty, C.F., Grigson, P.S., and Rowan, G.A. (1986). Chlordiazepoxide and the
determinants of negative contrast. Animal Learning and Behavior, 14, 315-321.
- Flaherty, C.F., Grigson, P.S., and Brady, A. (1987). Relative novelty of
conditioning context influences directionality of glycemic conditioning. Journal
of Experimental Psychology: Animal Behavior Processes, 13, 144-149.
- Flaherty, C.F., Grigson, P.S., and Demetrikopoulos, M.K. (1987). Effect of
clonidine on consummatory negative contrast and on novelty-induced stress.
Pharmacology Biochemistry and Behavior, 27, 659-664.
- Flaherty, C.F. and Grigson, P.S. (1988). From contrast to reinforcement: Role
of response contingency in anticipatory contrast. Journal of Experimental
Psychology: Animal Behavior Processes, 14, 165-176.
- Flaherty, C.F. and Grigson, P.S. (1989). Effect of clonidine on sucrose
intake and water intake varies as a function of dose, deprivation state and
duration of exposure. Pharmacology, Biochemistry, and Behavior, 32, 383-389.
- Grigson, P.S., Johnson, D.F., Collier, G.H., and Flaherty, C.F. (1989). The
effect of dexamethasone-21-acetate on meal size, meal frequency and
macronutrient self-selection in rats. Physiology and Behavior, 46, 211-216.
- Flaherty, C.F., Grigson, P.S., and Lind, S. (1990). Chlordiazepoxide and the
moderation of the initial response to reward reduction. Quarterly Journal of
Experimental Psychology, 42B, 87-105.
- Flaherty, C.F., Hrabinski, K., and Grigson, P.S. (1990). Effect of taste
context and ambient context changes on successive negative contrast. Animal
Learning and Behavior, 18, 261-267.
- Flaherty, C.F., Grigson, P.S., Demetrikopoulos, M.K., Weaver, M.S., Krauss,
K.L., and Rowan, G.A. (1990). Effect of serotonergic drugs on negative contrast
in consummatory behavior. Pharmacology Biochemistry and Behavior, 36, 799-806.
- Grigson, P.S. and Flaherty, C.F. (1990). The effect of chlordiazepoxide and
propranolol on glycemic conditioning in rats. Psychobiology, 18, 422-427.
- Grigson, P.S. and Flaherty, C.F. (1991). Cyproheptadine prevents the initial
occurrence of successive negative contrast. Pharmacology Biochemistry and
Behavior, 40, 433-442.
- Flaherty, C.F., Grigson, P.S., Checke, S., and Hnat, K.C. (1991). Deprivation
state and temporal horizons in anticipatory contrast. Journal of Experimental
Psychology: Animal Behavior Processes, 17, 503-518.
- Flaherty, C.F., Checke, S., Becker, H.C., Rowan, G.A., and Grigson, P.S.
(1992). Effect of chlorpromazine and halperodol on negative contrast.
Pharmacology Biochemistry and Behavior, 42, 111-117.
- Flaherty, C.F., Coppotelli, C., Grigson, P.S., Mitchell, C., and Flaherty,
J.E. (1995). Investigation of the devaluation interpretation of anticipatory
negative contrast. Journal of Experimental Psychology: Animal Behavior
Processes, 21, 229-247.
- Flaherty, C.F., Grigson, P.S., Coppotelli, C., and Mitchell, C. (1996).
Anticipatory contrast as a function of access time and spatial location. Animal
Learning & Behavior, 24, 68-81.
- Norgren, R. and Grigson, P.S. The role of the central gustatory system in
learned taste aversions. In: Perception, Memory, and Emotion: Frontiers in
Neuroscience, T. Ono, B. McNaughton, S. Molotchnikoff, E. Rolls, and H. Nishijo,
Eds. Pergamon Press, New York, pp. 479-497, 1996.
- Grigson, P.S., Shimura, T., and Norgren, R. (1997). Brainstem lesions and
gustatory function: III. The role of the nucleus of the solitary tract and the
parabrachial nucleus in the retention of a conditioned taste aversion in rats.
Behavioral Neuroscience, 111, 180-187.
- Grigson, P.S., Spector, A.C., and Norgren, R. (1993) Microstructural analysis of
successive negative contrast in free-feeding and deprived rats. Physiology &
Behavior, 54: 909-916.
Reilly, S., Grigson, P.S., and Norgren, R. (1993) Parabrachial nucleus lesions
and conditioned taste aversion: Evidence supporting an associative deficit.
Behavioral Neuroscience, 107: 1005-1017.
Grigson, P.S., Spector, A.C., and Norgren, R. (1994) Lesions of the pontine
parabrachial nuclei eliminate successive negative contrast effects in rats.
Behavioral Neuroscience, 108, 714-723,
Norgren, R. and Grigson, P.S. The role of the central gustatory system in
learned taste aversion. In: Perception, Memory, and Emotion; Frontier in
Neuroscience, T. Ono, B. McNaughton, S. Molotshnikoff, E. Rolls, and H. Nishijo
(Eds.). Elseview, Tokyo, 1996. Shimura, T., Grigson, P.S., and Norgren, R.
(1997). Brainstem lesions and gustatory function: I. The role of the nucleus of
the solitary tract during a brief intake test in rats. Behavioral Neuroscience,
111, 155-168.
Grigson, P.S., Shimura, T., and Norgren, R. (1997). Brainstem lesions and
gustatory function: II. The role of the nucleus of the solitary tract in Na+
appetite, conditioned taste aversion, and conditioned odor aversion in rats.
Behavioral Neuroscience, 111, 169-179.
Grigson, P.S., Shimura, T., and Norgren, R. (1997). Brainstem lesions and
gustatory function: III. The role of the nucleus of the solitary tract and the
parabrachial nucleus in retention of a conditioned taste aversion in rats.
Behavioral Neuroscience, 111, 180-187.
- Grigson, P.S. Conditioned taste aversions and drugs of abuse: A
reinterpretation. (1997). Behavioral Neuroscience, 111, 129-136.
- Scalera, G.,
Grigson, P.S., and Norgren, R. (1997). Gustatory functions, sodium appetite, and
conditioned taste aversion survive excitotoxic lesions of the thalamic taste
area. Behavioral Neuroscience, 111, 633-645.
- Grigson, P.S., Kaplan, J.M., Roitman, M.F., Grill, H.J., and Norgren, R. (1997).
Reward comparison in chronic decerebrate rats. American Journal of Physiology:
Regulatory, Integrative and Comparative Physiology, 273, R479-R486.
- Grigson, P.S., Reilly, S., Shimura, T., and Norgren, R. (1998). Ibotenic acid
lesions of the parabrachial nucleus and conditioned taste aversion: Further
Evidence for an associative deficit. Behavioral Neuroscience, 112,
160-171.
- Grigson, P.S., Reilly, S., Scalera, G., and Norgren, R. (1998). The parabrachial
nucleus is essential for acquisition of a conditioned odor aversion in rats.
Behavioral Neuroscience, 112, 1104-1113.
- Gomez, F., and Grigson, P.S. (1999). The suppressive effects of LiCl, sucrose,
and drugs of abuse are modulated by sucrose concentration in food-deprived rats.
Physiology & Behavior, 67, 351-357.
- Grigson, P.S., Lyuboslavsky, P., Tanase, D., & Wheeler, R.A. (1999). Water
deprivation prevents morphine-, but not LiCl-induced, suppression of sucrose
intake. Physiology & Behavior, 67, 277-286.
- Grigson, P.S., and Freet, C.S. (2000). The suppressive effects of sucrose and
cocaine, but not LiCl, are greater in Lewis than in Fischer rats: Evidence for
the reward comparison hypothesis. Behavioral Neuroscience, 114, 353-363.
- Grigson, P.S., Lyuboslavsky, P., & Tanase, D. (2000). Bilateral lesions of
the gustatory thalamus disrupt morphine-, but not LiCl-induced intake
suppression in rats: Evidence against the conditioned taste aversion account.
Brain Research, 858, 327-337.
- Gomez, F., Leo, N.A., & Grigson, P.S. (2000). Morphine-induced suppression
of saccharin intake is correlated with elevated corticosterone levels. Brain
Research, 863, 52-58.
- Gigson, P.S., Twining, R.C., & Carelli, R.M. (2000). Heroin-induced
suppression of saccharin intake in water-deprived and water-replete rats.
Pharmacology, Biochemistry, & Behavior, 66, 603-608.
- Grigson, P.S. (2000). Drugs of abuse and reward comparison: A brief review.
Appetite, 35, 89-91.
- Flahagan-Cato, L.M., Grigson, P.S., & King, J.L. (2001). Estrogen-induced
suppression of intake is not mediated by taste aversion in female rats.
Physiology & Behavior, 72, 549-558 .
- Grigson, P.S., Wheeler, R.A., Wheeler, D.S., & Ballard, S.M. (2001). Chronic
morphine treatment exaggerates the suppressive effects of sucrose and cocaine,
but not lithium chloride, in Sprague-Dawley rats. Behavioral Neuroscience, 115,
403-416.
- Grigson, P.S., Cornelius, K., & Wheeler, D.S. (2001). The suppressive
effects of intraperitoneal cocaine are augmented when evaluated in nondeprived
rats. Pharmacology Biochemistry & Behavior, 69, 117-123.
- Sclafani, A., Azzara, A.V., & Touzani, K. (2001). Parabrachial nucleus
lesions block taste and attenuate flavor preference and aversion conditioning in
rats. Behavioral Neuroscience, 115, 920-933.
- Grigson, P.S. (2002). Introduction: Like Drugs for Chocolate: Separate rewards
modulated by common mechanisms? Physiology & Behavior, 76, 345-346.
- Grigson, P.S. (2002). Discussion: Like Drugs for Chocolate: Separate rewards
modulated by common mechanisms? Physiology & Behavior, 76, 389-395.
- Grigson, P.S. & Twining, R.C. (2002). Cocaine-induced suppression of
saccharin intake: A model of drug-induced devaluation of natural rewards.
Behavioral Neuroscience, 116, 321-333.
- Jones, B.C., Wheeler, D.S., Beard, J.L., & Grigson, P.S. (2002). Iron
deficiency in rats decreases acquisition of and supresses responding for
cocaine. Pharmacology, Biochemistry & Behavior, 73, 813-819.
- Norgren, R., Grigson, P.S., Hajnal, A., & Lundy, R.F.Jr. Motivational
Modulatin of Taste. In: Cognition and Emotion in the Brain. International
Congress Series, 1250, 319-334.
- T. Ono, G. Matsumoto, R.R. Llinas, A. Berthoz, R. Norgren, H. Nishijo, and R.
Tamura (Eds). Elsevier Science, Amsterdam, 2003. Smith, M.E., Norgren, R., &
Grigson, P.S. A mixed design reveals that glucose moieties facilitate extinction
of a conditioned taste aversion in rats. Learning and Behavior, in press. Schroy,
P.L., Wheeler, R.A., Davidson, C., Scalera, G., Twining, R.C., & Grigson,
P.S. The role of the gustatory thalamus in the anticipation and comparison of
rewards over time in rats. AJP, in press.
- Schroy, P.L., Wheeler, R.A., Davidson, C., Scalera, G., Twining, R.C., &
Grigson, P.S. (2005). Role of gustatory thalamus in anticipation and comparison
of rewards over time in rats. Am J Physiol Regul Integr Comp Physiol, 288:
R966-R980.
- Liu, C. & Grigson, P.S. Brief Access to Sweets Protect Against Relapse to
Cocaine-Seeking. Brain Research, In press.
- Wheeler, R.A., Roitman, M.F., Grigson, P.S., & Carelli, R.M. Single neurons
in the nucleus accumbens track relative reward. Submitted.
- Twining, R.C., Hajnal, A., Bruno, K., Hess, E.J., Han, L., & Grigson, P.S.
Lesions of the ventral tegmental area have no effect on reward comparison,
disrupt drug-induced appetite stimulating effects, and augment latent inhibition
in rats. Submitted.
- Wheeler, R.C., Sublette, N.A., & Grigson, P.S. Fischer 344 and Lewis rats
exhibit similar concentration-response functions for sweet, sour, and bitter
stimuli, but not for salt or a trigeminal stimulus in a brief lick test.
Submitted.
- Liu, C., & Grigson, P.S. mu-Opioid Receptor Agonist DAMGO-Induced Suppression
of Saccharin Intake in Lewis and Fischer Rats. Submitted.
|
| |
|
