Jennifer Murray | University of Cambridge (original) (raw)

Papers by Jennifer Murray

Pharmacology Biochemistry and Behavior, 2007

The present research sought to test whether caffeine functioned as a Pavlovian cue in two ways--a... more The present research sought to test whether caffeine functioned as a Pavlovian cue in two ways--as a positive drug feature or as a conditional stimulus (CS). As a positive feature (Experiment 1), brief light presentations were followed by sucrose only on sessions in which caffeine (10 mg/kg) was administered. On intermixed saline sessions, light presentations were not followed by sucrose. The light came to control robust goal tracking (i.e., conditioned responding) only in caffeine sessions. Thus, caffeine disambiguates when the light was paired with sucrose. Decreasing the dose of caffeine decreased the conditioned responding evoked by the light (ED(50)=4.16 mg/kg). Neither nicotine nor amphetamine substituted for the caffeine feature. As a CS, caffeine (10 or 30 mg/kg, Experiments 2a and 2b, respectively) signaled intermittent access to sucrose--no light presentations. No sucrose or lights were presented on intermixed saline sessions. The caffeine CS, regardless of training dose, acquired the ability to evoke only a weak goal-tracking CR. The nature of this dissociation between caffeine as a drug feature and a CS is discussed within the context of past research finding a similar dissociation with amphetamine and chlordiazepoxide, but not with nicotine.

Biological psychiatry, 2013

Background: Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-t... more Background: Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-to-dorsal striatal shift in dopaminergic control over behavior. Although these habits readily develop as drug use continues, high impulsivity predicts loss of control over drug seeking and taking. However, whether impulsivity facilitates the transition to dorsolateral striatum (DLS) dopaminedependent cocaine-seeking habits or whether impulsivity and cocaine-induced intrastriatal shifts are additive processes is unknown.

The European journal of neuroscience, 2013

Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imag... more Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imaging studies have suggested that these features may result from deficits in prefrontal cortical structure and function, and thereby impaired top-down inhibitory control over limbic-striatal mechanisms of drug-seeking behaviour. We tested the hypothesis that selective damage to distinct subregions of the prefrontal cortex, or to the amygdala, after a short history of cocaine taking would: (i) result in compulsive cocaine seeking at a time when it would not usually be displayed; or (ii) facilitate relapse to drug seeking after abstinence. Rats with selective, bilateral excitotoxic lesions of the basolateral amygdala or anterior cingulate, prelimbic, infralimbic, orbitofrontal or anterior insular cortices were trained to self-administer cocaine under a seeking-taking chained schedule. Intermittent mild footshock punishment of the cocaine-seeking response was then introduced. No prefrontal cortical lesion affected the ability of rats to withhold their seeking responses. However, rats with lesions to the basolateral amygdala increased their cocaine-seeking responses under punishment and were impaired in their acquisition of conditioned fear. Following a 7-day abstinence period, rats were re-exposed to the drugseeking environment for assessment of relapse in the absence of punishment or cocaine. Rats with prelimbic cortex lesions showed decreased seeking responses during relapse, whereas those with anterior insular cortex lesions showed an increase. Combined, these results show that acute impairment of prefrontal cortical function does not result in compulsive cocaine seeking after a short history of self-administering cocaine, but further implicates subregions of the prefrontal cortex in relapse.

Current opinion in neurobiology, 2013

Drug addiction may be associated with a loss of executive control over maladaptive incentive habi... more Drug addiction may be associated with a loss of executive control over maladaptive incentive habits. We hypothesize that these incentive habits result from a pathological coupling of drug-influenced motivational states and a rigid stimulusresponse habit system by which drug-associated stimuli through automatic processes elicit and maintain drug seeking. Neurally, incentive habits may depend upon an interaction between the basolateral amygdala and nucleus accumbens core, together with the progressive development of a ventralto-dorsolateral striatum functional coupling through the recruitment of striato-nigro-striatal dopamine-dependent loop circuitry. Recent evidence suggests that both ventral striatal and central nucleus pathways from the amygdala may be required for the recruitment of DLS-dependent control over habitual behavior.

Neuropsychopharmacology, Jan 1, 2012

The present study investigated the involvement of dopamine-dependent mechanisms in the anterior d... more The present study investigated the involvement of dopamine-dependent mechanisms in the anterior dorsolateral (aDLS) and posterior dorsomedial (pDMS) striatum during the early-and late-stage performance of cocaine-seeking behavior. Rats were trained to selfadminister cocaine under continuous reinforcement (fixed-ratio 1, FR1) with a 20-s light conditioned stimulus (CS) presented contingently upon each infusion. After a week, rats were challenged by a change in contingency to seek cocaine during a 15-min period uninfluenced by cocaine during which each response was reinforced by a 1-s CS presentation. Dopamine transmission blockade by intracranial infusions of a-flupenthixol only in the pDMS, but not in the aDLS, dose dependently reduced performance of cue-controlled cocaine seeking at the early stage of self-administration. One cohort of rats was then trained with increasing response requirements until completing 15 sessions under a second-order schedule [FI15(FR10:S)] so that cocaine-seeking performance became well established. At this stage, intra-aDLS, but not pDMS, a-flupenthixol infusions dose dependently reduced active lever presses. The second cohort of rats continued to self-administer cocaine under the FR1 schedule such that their drug intake was matched to the late-stage performance group. a-Flupenthixol in the pDMS, but not in the aDLS, again prevented the performance of cocaine seeking. These results show that dopamine transmission in the pDMS is required for initial performance of goal-directed cocaine seeking, and that its role is ultimately subverted and devolves instead to the aDLS only following training with high rates of cocaine-seeking behavior, supporting the theory of dynamic shifts in the striatal control over cocaine seeking between goal-directed and habitual performance.

Addictions – From Pathophysiology to Treatment, 2012

Learning & memory (Cold Spring Harbor, N.Y.), 2011

Nicotine functions as a negative feature in a Pavlovian discriminated goal-tracking task. Whether... more Nicotine functions as a negative feature in a Pavlovian discriminated goal-tracking task. Whether withholding of responding to the conditional stimulus (CS) reflects nicotine functioning as a conditioned inhibitor is unknown. Accordingly, the present research sought to determine whether nicotine trained as a negative feature passed the retardation-of-acquisition and summation tests, thus characterizing it as a pharmacological (interoceptive) conditioned inhibitor. In the retardation test, rats received either nicotine (0.4 mg/kg) or chlordiazepoxide (5 mg/kg) negative feature training in which the drug state signaled when a 15-sec light CS would not be paired with sucrose; light was paired with sucrose on intermixed saline sessions. Following acquisition of the discrimination, both groups received nicotine CS training in which sucrose was intermittently available on nicotine but not intermixed saline sessions. Acquisition of conditioned responding to the nicotine CS was slower in the nicotine negative feature group than in the chlordiazepoxide negative feature group. In the summation test, rats were assigned to either the nicotine negative feature group or a pseudoconditioning control. In this control, the light CS was paired with sucrose on half the nicotine and half the saline sessions. Both groups also received excitatory training in which a white noise CS was paired with sucrose. The summation test consisted of presenting the white noise in conjunction with nicotine. Conditioned responding evoked by the white noise was decreased in the negative feature but not the pseudoconditioning group. Combined, the results provide the first evidence that an interoceptive stimulus (nicotine) can become a conditioned inhibitor.

Exposure Therapy: New Developments, 2011

When considering human addicts, researchers often limit their definition of drug effects to those... more When considering human addicts, researchers often limit their definition of drug effects to those that are unconditioned, including the rewarding and reinforcing effects of drugs. Aspects of the surrounding environment, such as the paraphernalia required to consume the drug or the context in which the drug is consumed, come to be associated with these unconditioned stimulus (US) effects. The conditioned stimuli (CSs) now associated with the unconditioned drug effects come to evoke drug-related responses such as withdrawal, cravings, or desire-to-use when presented to an addicted individual, ultimately perpetuating drug abuse and precipitating relapse. Cue-exposure therapy targets these CSs and their conditioned responses (CRs). Notably, rodent models, and a sparse literature with humans, have extended this conceptualization of drug effects and conditioning processes to include a far more rich and complicated set of stimulus interactions. The basis for this extension is that drugs of abuse are interoceptive stimuli – and to an extent can function as any other stimulus can. In this review, we begin with animal models of self-administration and extinction of nicotine taking. We expand on these findings by discussing how the nicotine stimulus can come to control discriminated behaviors. Associations formed between nicotine and other stimuli in the exteroceptive environment can affect the control each has over a learned behavior. By expanding the conceptualization of the nicotine stimulus, we may be able to approach an explanation for the particularly poor success rates of cue-exposure therapy with smokers.

Behavioural brain research, Jan 1, 2011

Previous research has shown that a nicotine conditional stimulus (CS) can compete with (i.e., ove... more Previous research has shown that a nicotine conditional stimulus (CS) can compete with (i.e., overshadow) a brief light CS. Another form of competition, blocking, has not yet been examined with the nicotine CS. Groups of rats were assigned to an element training condition. For the N+ group, during each daily 2 h element training session, there were ten intravenous nicotine infusions (0.03 mg/kg) followed 30 s later with 4 s access to sucrose. In the N− group, nicotine and sucrose presentations were explicitly unpaired. The chamber alone group (C alone) had no stimulus presentations. Element training was followed by compound training in all groups. A 30-s houselight was included during the time between the nicotine infusion and paired sucrose delivery. Non-reinforced element presentations assessed relative control of the goal tracking conditioned response (CR). The N+ group showed a higher proportion of CR control by the nicotine than the light. The opposite pattern was found in the N− and C alone groups indicating that nicotine CS controlled less of the CR than the light. Thus, excitatory conditioning with the nicotine CS blocked later conditioning to the light. This finding adds to literature examining the interaction between interoceptive drug CSs and other environmental stimuli.

Associative learning and conditioning: Human and non …, Jan 1, 2011

Addiction Biology

ABSTRACTa db_330 437..440 N-acetylcysteine (NAC) has been suggested to have therapeutic potential... more ABSTRACTa db_330 437..440 N-acetylcysteine (NAC) has been suggested to have therapeutic potential in the treatment of drug addiction through its effects on brain glutamate homeostasis. Here we show that NAC treatment resulted in dose-dependent reductions in cocaine seeking at both early and late stages of acquisition and maintenance of cocaine-seeking behavior, while confirming it had no effect on cocaine reinforcement. The results indicate that NAC is able to significantly diminish the propensity to seek cocaine early and late in the development of addiction and, taken together with previous work, indicates significant potential in relapse prevention.

European journal of pharmacology, Jan 1, 2007

Although past research has shown that the interoceptive effects of nicotine serve as a conditiona... more Although past research has shown that the interoceptive effects of nicotine serve as a conditional stimulus using sucrose as the unconditioned stimulus, very little is known about the importance of dose. Accordingly, rats were assigned to 0.1, 0.2, or 0.4 mg nicotine base/kg as the training dose. Sucrose (4-s access) was delivered 36 times on nicotine sessions; sucrose was withheld on intermixed saline sessions. The discrimination was acquired for all groups, as measured by more photobeam breaks in the dipper receptacle before the first sucrose delivery on nicotine sessions, compared with a similar interval on saline sessions. Thirty nicotine sessions without sucrose deliveries (extinction) decreased conditioned responding with the 0.4 mg/kg dose maintaining higher responding than the lower doses. After reestablishing discrimination performance, rats were tested with their training dose at various injection-to-placement intervals. Conditioned responding diminished with longer intervals; 0.4 mg/kg nicotine-evoked conditioned responding at longer intervals. Subsequent generalization testing with nicotine or saline at the 5-min training interval found that conditioned responding was evoked by lower test doses in the 0.1 mg/kg group than in the other groups. Combined, this research demonstrates that the nicotine conditional stimulus shows some variation with training dose.

Drug and alcohol …, Jan 1, 2009

Bupropion is a promising candidate medication for methamphetamine use disorder. As such, we used ... more Bupropion is a promising candidate medication for methamphetamine use disorder. As such, we used a preclinical model of drug-taking to determine the effects of bupropion on the reinforcing effects of methamphetamine (0.025, 0.05 or 0.1 mg/kg/infusion). Specificity was determined by investigating the effects of bupropion on responding maintained by sucrose. In the selfadministration study, rats were surgically prepared with indwelling jugular catheters and trained to self-administer methamphetamine under an FR5 schedule. A separate group of rats was trained to press a lever for sucrose. Once responding stabilized, rats were pretreated with bupropion (0, 10, 30 and 60 mg/kg IP) 5 min before chamber placement in a unique testing order. Following acute testing, rats were then repeatedly pretreated with 30 and 60 mg/kg bupropion. Acute treatments of bupropion dose dependently reduced drug intake for 0.025 to 0.1 mg/kg methamphetamine; sucrose deliveries were only reduced with the high bupropion dose. Repeated exposure to 60 mg/ kg bupropion before the session resulted in a consistent decrease in methamphetamine intake (0.05 and 0.1 mg/kg) and sucrose deliveries. Considered together, this pattern of findings demonstrates that bupropion decreases responding for methamphetamine, but the effects are only somewhat specific.

Behavioural …, Jan 1, 2006

Behavioural pharmacology, Jan 1, 2007

Previous studies have shown that the interoceptive nicotine conditional stimulus (CS) functions s... more Previous studies have shown that the interoceptive nicotine conditional stimulus (CS) functions similarly to exteroceptive CSs such as lights or environments. For instance, the appetitive conditioned response (CR) evoked when nicotine is repeatedly paired with sucrose presentations (the unconditioned stimulus; US) is sensitive to changes in training dose (CS salience) and the contiguity between the CS effects and sucrose. The current study was conducted to extend this research by examining the possible role of US intensity in CR acquisition and maintenance. Rats were trained using one of four sucrose concentrations: 0, 4, 16, or 32% (w/v). On nicotine sessions (0.4 mg base/kg), rats received 36 deliveries (4 s each) of their assigned concentration intermittently throughout the session; sucrose was withheld on saline sessions. In all groups, an appetitive goal-tracking CR was acquired at a similar rate. However, the asymptotic CR level varied with sucrose concentration. The magnitude of the CR was increased in rats trained with higher sucrose US concentrations. These findings are consistent with previous Pavlovian conditioning research, and extend the conditions under which the nicotine state functions as an interoceptive conditional stimulus.

ACS Chemical Neuroscience, Jan 1, 2010

… Biochemistry and Behavior, Jan 1, 2007

The present research sought to test whether caffeine functioned as a Pavlovian cue in two ways-as... more The present research sought to test whether caffeine functioned as a Pavlovian cue in two ways-as a positive drug feature or as a conditional stimulus (CS). As a positive feature (Experiment 1), brief light presentations were followed by sucrose only on sessions in which caffeine (10 mg/ kg) was administered. On intermixed saline sessions, light presentations were not followed by sucrose. The light came to control robust goal tracking (i.e., conditioned responding) only in caffeine sessions. Thus, caffeine disambiguates when the light was paired with sucrose. Decreasing the dose of caffeine decreased the conditioned responding evoked by the light (ED 50 = 4.16 mg/kg). Neither nicotine nor amphetamine substituted for the caffeine feature. As a CS, caffeine (10 or 30 mg/kg, Experiments 2a and 2b, respectively) signaled intermittent access to sucrose-no light presentations. No sucrose or lights were presented on intermixed saline sessions. The caffeine CS, regardless of training dose, acquired the ability to evoke only a weak goal-tracking CR. The nature of this dissociation between caffeine as a drug feature and a CS is discussed within the context of past research finding a similar dissociation with amphetamine and chlordiazepoxide, but not with nicotine.

Vaccine, Jan 1, 2009

Vaccines to methamphetamine (meth) were designed by covalently attaching a meth hapten (METH) to ... more Vaccines to methamphetamine (meth) were designed by covalently attaching a meth hapten (METH) to peptide constructs that contained a conformationally biased, response-selective molecular adjuvant, YSFKPMPLaR (EP54). Rats immunized with EP54-containing meth vaccines generated serum antibody titers to authentic meth, an immune outcome that altered meth self-administration. Immunization increased meth self-administration suggesting pharmacokinetic antagonism. The ability of immune sera to bind a METH-modified target protein dramatically decreased during and shortly after the meth selfadministration assay, suggesting effective sequestration of free meth. However, the binding ability of immune sera to the METH-modified target protein was recovered 34 days after meth-free clearance time.

Behavioral neuroscience, Jan 1, 2009

Recent research examining Pavlovian appetitive conditioning has extended the associative properti... more Recent research examining Pavlovian appetitive conditioning has extended the associative properties of nicotine from the unconditioned stimulus or reward to include the role of a conditional stimulus (CS), capable of acquiring the ability to evoke a conditioned response. To date, published research has used presession extravascular injections to examine nicotine as a contextual CS in that appetitive Pavlovian drug discrimination task. Two studies in the current research examined whether a nicotine CS can function discretely, multiple times within a session using passive iv infusions. In Experiment 1, rats readily acquired a discrimination in conditioned responding between nicotine and saline infusions when nicotine was selectively paired with sucrose presentations. In Experiment 2, rats were either trained with nicotine paired with sucrose or explicitly unpaired with sucrose. The results showed that rats trained with explicitly unpaired nicotine and sucrose did not increase dipper entries after the infusions. Nicotine was required to be reliably paired with sucrose for control of conditioned responding to develop. Implications of these findings are discussed in relation to tobacco addiction, learning theory, and pharmacology.