House of Mind

Are you a mother? If so, research presented at SfN suggests that you are less likely to develop a drug addiction problem. Behavioral research from the Becker lab at U Michigan-Ann Arbor has shown that motherhood alters a female rat’s response to cocaine in a way that attenuates (i.e. dampens) her drug abuse liability. For example, the group found that virgin rats will not only press a lever more readily to self-administer cocaine via brain infusion, but they will also escalate (or increase their drug take) during the first week of cocaine use. In contrast, rat mothers having the maternal experience of rearing at least one litter maintain a steady level of self-administration. Moreover, virgin rats are willing to expend more energy and press the lever over 70 times to receive a single cocaine infusion, suggesting that they are willing to work harder to receive the drug even when it is challenging to obtain. 

So why do these virgin rats go crazy for cocaine? In order to answer this question, the group used microdialysis, a procedure in which a probe can be inserted into a specific brain area in order to collect extracellular fluid including neurotransmitters and metabolites, to examine cocaine-induced dopamine release in the nucleus accumbens after an injection of cocaine in virgin rats and mother rats having NO prior experience with cocaine.Using this technique, they were able to show that virgin rats release significantly more dopamine in response to cocaine than females that have had a least a litter, suggesting that the same dose of cocaine has less of an effect (i.e., is less reinforcing) female rats that have been mothers before. Thus, these data indicate that mothers are less susceptible to the effects of cocaine than virgins. 

This research was presented on October 15, 2012 by J.A. Cummings as a short talk titled: Maternal experience protects female rats against drug abuse liability. 

In short: 

• The ventral tegmental area (VTA) and the basolateral amygdala (BLA) have long been regarded as key components in the brain reward circuit.
• Chronic opiate administration switches the functional role of intra-BLA dopamine (DA) transmission from a D1-dependent substrate to a D2-dependent substrates.
• This D1/D2 opiate reward switch in the BLA can directly modulate opiate reward information from the VTA. Furthermore, the DA reward processing occurs in the nucleus accumbens shell (not core) 

Author Abstract (Lintas, et. al) : Transmission through dopamine D1 versus D2 receptors in the basolateral amygdala represents an opiate addiction switching mechanism controlling opiate memory encoding in the drug naïve versus dependent state

The basolateral nucleus of the amygdala (BLA) receives innervation from dopaminergic fibers, and dopamine (DA) D1 and D2 receptors are expressed in this region. BLA sends excitatory afferents to the nucleus accumbens (NAcc), to both shell and core regions. The NAcore and NAshell are both implicated in the processing of various associative reward stimuli. However, the precise role of D1 versus D2 receptor transmission in the processing of associative, opiate-related reward learning is not presently understood. Using a combination of in vivo single unit extracellular recording in the NAcc combined with behavioural pharmacology studies, we have identified a double dissociation in the functional role of DA D1 versus D2 receptor transmission in the BLA, as a function of opiate exposure state: thus, in previously opiate-naïve rats, blockade of intra-BLA D1, but not D2, receptor transmission blocks the rewarding effects of morphine (5mg/kg;i.p.) measured in an unbiased conditioned place preference (CPP) procedure. In direct contrast, in rats made opiate dependent and in a state of withdrawal, intra-BLA D2, but not D1 receptor blockade completely blocks opiate reward encoding. We find the same double dissociation with intra-BLA D1/D2 activation: in opiate-naïve rats, pharmacological activation of intra-BLA D1 (but not D2) receptors strongly potentiates sub-threshold morphine (0.05mg/kg;i.p.) reward encoding while activation of D2 receptors (but not D1 receptors) potentiates sub-threshold morphine reward transmission in opiate dependent/withdrawn rats. Single unit recordings performed in neurons of the NAcc shell (but not core) confirm the modulatory role of BLA D1/D2 transmission in NAcc neuronal responses to morphine (1mg/kg;i.v.). Thus, blockade of intra-BLA D1 (but not D2) transmission blocks NAcc neuronal responding to morphine in opiate naïve rats, while blockade of BLA D2 (but not D1) receptors blocks neuronal responding to morphine in opiate dependent/withdrawn rats. Our results characterize and identify a novel and unique opiate addiction switching mechanism directly in the BLA, that can control the encoding of opiate reward information (behaviourally and neuronally) as a direct function of opiate exposure state, via D1 or D2 receptor signalling.

Take home messages: 

• Corticotropin releasing factor (CRF) acts in the ventral tegmental area (VTA), a primary source of dopaminergic neurons and an integral part of the mesolimbic reward pathway, to regulate dopamine (DA) neurotransmission. 
• A large reward (large reward magnitude)  will enhance motivated behavior. 
• A large reward magnitude also enhances DA release in response to cues and rewards.
• CRF, a hormone and neurotransmitter implicated in the stress response (HPA axis), in the VTA will attenuate motivated behavior in a dose-dependent manner and this effect is not due to motor suppression. 
• CRF in the VTA attenuates phasic DA release (burst DA release as opposed to a more gradual release) specifically to rewards, not the cues related to the rewards. 
• Satiety (being full) will reduce motivated behavior (in this case the reward was food pellets) as well as DA release to rewards (but not cues). 

Author Abstract (Phillips, et. al) : Phasic dopamine release during reward and effort manipulations: Effects of corticotropin release factor. 

The effort an individual is willing to exert to obtain a reward is dependent upon one’s motivational state as well as the value of the reward. Contemporary theories of dopamine function suggest that dopamine release, particularly in the striatum, is involved with enabling high-effort behaviors. Motivated behaviors can be influenced by stressful stimuli and stress-released neuropeptides such as corticotropin-releasing factor (CRF). The behavioral effects of stress on motivation could involve the midbrain dopamine system as (i) stress increases dopamine levels, (ii) CRF is released into the midbrain during stress, and (iii) CRF increases the firing rate and potentiates glutamate receptor current in dopamine neurons. Thus, we hypothesized that CRF in the VTA will elevate phasic dopamine release and increase the effort exerted to obtain a reward. However, before addressing this pharmacological question it was important to first determine how natural manipulations of motivational state and reward magnitude influence phasic dopamine release during high-effort behaviors.

We utilized fast-scan cyclic voltammetry to examine phasic striatal dopamine release to rewards and reward-predictive cues in rats performing an operant task under a progressive ratio (PR) reinforcement schedule for natural reinforcers. In separate sessions, we assessed behavior and dopamine release in rats under different motivational states (food-deprived or free-fed) or working for rewards of different magnitudes. The cumulative number of rewards earned scaled with the reward size in a given PR session. Interestingly, we found that motivational state and reward size robustly scaled reward-evoked dopamine release, while cue-evoked dopamine release was less sensitive to these manipulations. After establishing the effect of natural manipulations, we next examined how CRF injections into the midbrain affected behavior and dopamine release during PR sessions. Contrary to our hypothesis, CRF injected into the midbrain lowered the breakpoint in PR sessions. Furthermore, CRF injections attenuated reward-evoked dopamine release but did not affect cue-evoked dopamine release. Together, these results suggest that CRF modulates motivated behavior by affecting either dopamine neurons responsive to reward delivery and/or inputs to the midbrain representing the delivery of rewards.

1. Effect of sex and dose in selecting food or cocaine (Ballis): Male rats will administer cocaine more, but females will choose cocaine more often when given the choice between food and cocaine. However, ovariectomized females will not choose cocaine over food. Therefore, as a result of ovarian hormones, female rats place a higher value on cocaine and food relative to males. I always suspected that our female condition renders us susceptible.

2. Effect of binge drinking during adolescence on anxiety related behavior in adulthood (Karanikas): Binge drinking during an overnight period or a 2-week period has a relatively small effect on anxiety and locomotor activity in adulthood. 

3. Examination of addictive behavior in rats selectively bred for response to novelty (Flagel): These high-responding (HR) animals are the model for an addictive personality and exhibit: increased locomotor activity, increased risk-taking behavior, increased susceptibility to be controlled by reward-related cues, increased impulsivity, increased aggression, and dopamine (DA) system hypersensitivity. 

4. Dissociation of attention and emotion-related neural activity in the nuclei of the primate amygdala (Mosher): The centromedial nuclei of the amygdala are involved in allocating attention to stimuli (task-related) while the basolateral nuclei are involved primarily in evaluation emotional significance of stimuli (stimulus-selective). 

• Experimental use: Usually represents a benign category that marks the initiation of use. This kind of use is limited to few exposures, no development of a regular pattern of use, and relatively no substance-related harm or consequences. Experimental use is usually sparked by a curiosity to experience and usually takes places in social situations. Ex. Being curious about cigarettes and having a couple of puffs. 
• Occasional use: Another relatively benign category. Social or recreational substance use falls into this category. Substance use typically infrequent and irregular and in modest consumption. This one is tricky because it is common for a patient to report irregular use even when a pattern is starting to develop. Ex. Drinking limited to social situations.
• Regular use: Use becomes more frequent and patterned as people shift from occasional to regular use. Some people move so quickly that they hardly notice when the transition into regular use occurs. Once the person becomes habituated, a regular pattern emerges. However, regularity of use may or may not be an indicator that loss of control has happened. The reinforcing properties of a drug become seductive once a person reliably achieves desirable changes in mood and feelings after administering the drug. Ex. Drinking/smoking almost every day. 
• Circumstantial use: This category includes various patterns in which the substance is used to produce specific types of effects deemed desirable to enhance an experience or to better cope with certain situations. Ex. Taking Adderall for a late night cram session before a big test. 
• Binge: An episodic pattern in which large quantities of alcohol/drugs are consumed intensively in a marathon-like fashion during a single episode of use. Binges maybe punctuated with long period of abstinence or little/no craving.  Ex. Blowing through many lines of cocaine through one night. 
• Abuse: Individual manifests significant substance-related problems repeatedly in important areas of functioning (health, legal, social). Many people who show signs of abuse do not progress to substance dependence. Ex. Using drugs even when you’re on probation, despite being advised of the consequences of pissing a positive. 
• Dependence: The most troubling category as evidenced with a preoccupation with obtaining and using the drug, an inability to control consumption in a dependable manner, impairment in psychosocial functioning, and continued use despite adverse consequences. Ex. A mom that had her kids taken away because of her drug use wants them back, but is unable to stop using.

Taken from Treating Alcohol and Drug Problems in Psychotherapy Practice: Doing What Works by Arnold M. Washton and J.E. Zweben. Part of my psychology of addiction reads.