Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75023/1/j.1460-9568.1999.00576.x.pd

Are cocaine-seeking “habits” necessary for the development of addiction-like behavior in rats?

Drug self-administration models of addiction typically require animals to make the same response (e.g., a lever-press or nose-poke) over and over to procure and take drugs. By their design, such procedures often produce behavior controlled by stimulus-response (S-R) habits. This has supported the notion of addiction as a “drug habit”, and has led to considerable advances in our understanding of the neurobiological basis of such behavior. However, for addicts to procure drugs, like cocaine, often requires considerable ingenuity and flexibility in seeking behavior, which, by definition, precludes the development of habits. To better model drug-seeking behavior in addicts we first developed a novel cocaine self-administration procedure (the Puzzle Self-Administration Procedure; PSAP) that required rats to solve a new puzzle every day to gain access to cocaine, which they then self-administered on an Intermittent Access (IntA) schedule. Such daily problem-solving precluded the development of S-R seeking habits. We then asked whether prolonged PSAP/IntA experience would nevertheless produce ‘symptoms of addiction’. It did, including escalation of intake, sensitized motivation for drug, continued drug use in the face of adverse consequences and very robust cue-induced reinstatement of drug-seeking, especially in a subset of ‘addiction-prone’ rats. Furthermore, drug-seeking behavior continued to require dopamine neurotransmission in the core of the nucleus accumbens (but not the dorsolateral striatum). We conclude that the development of S-R seeking habits is not necessary for the development of cocaine addiction-like behavior in rats

The role of dopamine in the accumbens core in the expression of Pavlovian‐conditioned responses

The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction‐error signal necessary for stimulus–reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se , but for attributing incentive motivational value (‘incentive salience’) to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of Pavlovian‐conditioned approach behavior – one in which the cue acquires powerful motivational properties (sign‐tracking) and another closely related one in which it does not (goal‐tracking). After acquisition of these conditioned responses (CRs), intra‐accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign‐tracking CR, but not a goal‐tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction‐like decline in behavior, but maximally impaired expression of a sign‐tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction‐error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus–reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties. Ongoing debate exists about dopamine’s exact role in reward‐related processes. We took advantage of natural individual variation in the degree to which reward cues are attributed with motivational value, and asked whether dopamine in the core of the nucleus accumbens is necessary for the performance of two forms of Pavlovian conditioned approach behavior ‐ one in which the cue acquires powerful motivational properties (sign‐tracking) and another related one in which it does not (goal‐tracking). We found that blocking dopamine transmission within the core impaired the expression of sign‐tracking responses, but not goal‐tracking responses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93510/1/j.1460-9568.2012.08217.x.pd

The psychology and neurobiology of addiction: an incentive–sensitization view

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75373/1/j.1360-0443.95.8s2.19.x.pd

Amphetamine-evoked gene expression in striatopallidal neurons: regulation by corticostriatal afferents and the ERK/MAPK signaling cascade

The environmental context in which psychostimulant drugs are experienced influences their ability to induce immediate early genes (IEGs) in the striatum. When given in the home cage amphetamine induces IEGs predominately in striatonigral neurons, but when given in a novel test environment amphetamine also induces IEGs in striatopallidal neurons. The source of the striatopetal projections that regulate the ability of amphetamine to differentially engage these two striatofugal circuits has never been described. We report that transection of corticostriatal afferents selectively blocks, whereas enhancement of cortical activity with an ampakine selectively augments, the number of amphetamine-evoked c- fos -positive striatopallidal (but not striatonigral) neurons. In addition, blockade of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling cascade preferentially inhibits the number of amphetamine-evoked c- fos -positive striatopallidal neurons. These results suggest that glutamate released from corticostriatal afferents modulates the ability of amphetamine to engage striatopallidal neurons through an ERK/MAPK signaling-dependent mechanism. We speculate that this may be one mechanism by which environmental context facilitates some forms of drug experience-dependent plasticity, such as psychomotor sensitization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66343/1/j.1471-4159.2004.02712.x.pd

Hippocampal rhythmic slow activity (RSA, theta): A critical analysis of selected studies and discussion of possible species-differences

The literature concerning the correlates of hippocampal RSA (theta) has seen a wealth of hypotheses generated from seemingly contradictory data. Two possible reasons for this are examined here. (1) An analysis of the maximum published RSA amplitudes in over 70 papers shows that there is enormous variation in how effective various research groups have been in tapping the hippocampal RSA generator zones. It is suggested that this variation is a major source of `contradictory data'. The enormous variability is probably due to the fact that the laminar structure of the hippocampus, and the location of two seemingly independent 180[deg] out-of-phase RSA generators, results in very disparate signals being recorded by electrodes of different configurations. Electrodes which are not optimally placed result in records which may provide misinformation as to whether or not the hippocampus is in the RSA `mode'. The results of studies with less than adequate records must therefore be viewed with great caution. (2) An explanation often evoked to account for much of the controversy is that of species differences. This idea is examined and it is suggested that there are probably not major species differences in that all of the species appropriately examined thus far have neural systems capable of producing both an atropine-sensitive and an atropine-resistant form of RSA. All species (with the exception of primates) also show relations of RSA to ongoing motor behavior. However, there are definitely species differences in the neural mechanisms underlying the production of atropine-sensitive, immobility-related RSA. Although all species appear to be capable of producing immobility-related RSA some do so only rarely (e.g. rats), while others do so frequently, particularly in response to sensory stimulation (e.g. rabbits, cats, guinea pigs). Therefore, the answer to the question as to whether there are species differences in the occurrence of RSA may be yes, or no, depending upon how specifically the question is posed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23247/1/0000180.pd

Dynamic Measurements of Cerebral Pentose Phosphate Pathway Activity In Vivo Using [1,6- 13 C 2 ,6,6- 2 H 2 ] Glucose and Microdialysis

Cerebral pentose phosphate pathway (PPP) activity has been linked to NADPH-dependent anabolic pathways, turnover of neurotransmitters, and protection from oxidative stress. Research on this potentially important pathway has been hampered, however, because measurement of regional cerebral PPP activity in vivo has not been possible. Our efforts to address this need focused on the use of a novel isotopically substituted glucose molecule, [1,6- 13 C 2 ,6,6- 2 H 2 ]glucose, in conjunction with microdialysis techniques, to measure cerebral PPP activity in vivo, in freely moving rats. Metabolism of [1,6- 13 C 2 ,6,6- 2 H 2 ]glucose through glycolysis produces [3- 13 C]lactate and [3- 13 C,3,3- 2 H 2 ]lactate, whereas metabolism through the PPP produces [3- 13 C,3,3- 2 H 2 ]lactate and unlabeled lactate. The ratios of these lactate isotopomers can be quantified using gas chromatography/mass spectrometry (GC/MS) for calculation of PPP activity, which is reported as the percentage of glucose metabolized to lactate that passed through the PPP. Following addition of [1,6- 13 C 2 ,6,6- 2 H 2 ]glucose to the perfusate, labeled lactate was easily detectable in dialysate using GC/MS. Basal forebrain and intracerebral 9L glioma PPP values (mean ± SD) were 3.5 ± 0.4 (n = 4) and 6.2 ± 0.9% (n = 4), respectively. Furthermore, PPP activity could be stimulated in vivo by addition of phenazine methosulfate, an artificial electron acceptor for NADPH, to the perfusion stream. These results show that the activity of the PPP can now be measured dynamically and regionally in the brains of conscious animals in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65845/1/j.1471-4159.1995.64031336.x.pd

Sensitization to systemic amphetamine produces an enhanced locomotor response to a subsequent intra-accumbens amphetamine challenge in rats

Repeated amphetamine (AMPH) administration into the nucleus accumbens does not enhance (sensitize) the locomotor activity produced by a subsequent systemic AMPH challenge. We report here, however, that pretreatment with systemic injections of AMPH does produce a significant enhancement in the locomotor stimulant effects produced by intra-accumbens AMPH given 21 days after the last pretreatment injection of AMPH. These data support the hypothesis that neural adaptations in dopamine (DA) terminal fields are sufficient for the expression of AMPH sensitization, although an action on DA cell bodies may be required for the induction of AMPH sensitization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46336/1/213_2005_Article_BF02244569.pd

Withdrawal from morphine or amphetamine: different effects on dopamine in the ventral-medial striatum studied with microdialysis

The effect of withdrawal from chronic morphine or amphetamine treatment on dopamine (DA) neurotransmission in the ventral-medial striatum was studied by use of in vivo microdialysis. There was no effect of 24 h of amphetamine withdrawal on the basal concentration of DA in the ventral-medial striatum. Spontaneous morphine withdrawal (24 h) was associated with a significant decrease in the basal concentration of DA in dialysate, but following morphine replacement and naloxone-precipitated withdrawal variations in withdrawal symptoms were not related to variations in the concentration of DA in dialysate. It is suggested that: (1) the correlation between the extracellular concentration of DA in the ventral-medial striatum and the symptoms of morphine withdrawal may not be indicative of a necessary, causal relationship; and (2) a decrease in the extracellular concentration of DA in the ventral-medial striatum is not a common feature of drug withdrawal syndromes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31444/1/0000364.pd

Morphine alters the structure of neurons in the nucleus accumbens and neocortex of rats

Rats were given repeated injections of 10 mg/kg of morphine and were then left undisturbed for 24–25 days before their brains were processed for Golgi-Cox staining. Prior exposure to morphine decreased the complexity of dendritic branching and the number of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal cortex. It is suggested that some of the long-term behavioral consequences of repeated exposure to morphine may be due to its ability to reorganize patterns of synaptic connectivity in the forebrain. Synapse 33:160–162, 1999. © 1999 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34985/1/6_ftp.pd