NIDA Program Project Grant on Drug Addiction at UT Southwestern

Overview of Drug Abuse and Addiction

According to the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Press, 2000), drug addiction is referred to as “substance dependence,” the essential characteristic of which is a compulsive pattern of drug-seeking and drug-taking behavior that continues despite adverse consequences of drug use. Addiction, however, is by far the preferable term, because dependence—a pharmacologic term—describes just one of many types of adaptations to drug exposure that comprise addiction. Dependence refers to drug-induced adaptations that compensate for drug exposure and lead to an array of withdrawal symptoms when drug use ceases. Withdrawal symptoms vary based on the substance, but usually involve a significant negative emotional state (dysphoria), and in some cases profound somatic (physical) abnormalities. Tolerance refers to drug-induced adaptations that lead to diminishing effects of a constant drug dose. Sensitization, or reverse tolerance, is caused by drug-induced adaptations that enhance drug responsiveness with repeated drug exposure. Many drugs cause both tolerance and sensitization, with some drug effects decreasing over time while others increase.

The complex syndrome of addiction is believed to be caused by a compilation of these types of pharmacologic adaptations to repeated drug exposure that occur in many brain regions important for the regulation of reward, motivation, and emotional (or affective) state.

Acute Mechanisms of Drug Action

Drugs of abuse produce their effects on brain function and behavior by interacting with proteins located at synaptic connections between nerve cells (Figure 4). Several drugs of abuse mimic the brain’s endogenous neurotransmitters: opiates mimic endogenous opioids (e.g., endorphin, enkephalin); nicotine mimics the endogenous neurotransmitter acetylcholine; and cannabinoids mimic endogenous neurotransmitters called endogenous cannabinoids (e.g., anandamide). The stimulant drugs of abuse act on monoamine reuptake proteins. These reuptake proteins, or transmitters, normally function to pump monoamine neurotransmitters (dopamine, norepinephrine, serotonin) back into the nerve ending from which they were released. Cocaine blocks these transporters, while amphetamine and related drugs (methamphetamine, methylphenidate [Ritalin]) cause the transporter to work in the opposite direction and pump the monoamine out of the cell. The net functional effect is the same: an increase in monoamine neurotransmitter function. Still other neurotransmitters act directly on ion channels to increase or decrease the electrical excitability of nerve cells. Examples include alcohol (which reduces neuronal excitability) and phencyclidine (and related drugs such as ketamine). These acute protein targets of drugs of abuse are listed in Table 1.

However, despite the fact that drugs of abuse represent chemically divergent molecules each of which binds to a different acute target, all drugs of abuse can produce addiction, which shares key features. Thus, these drugs, despite many distinct actions in the brain, converge in producing some common actions.

Prominent among these common actions is activation of the mesolimbic dopamine system ( Figure 1, Figure 2, and Figure 3), which involves increased dopaminergic transmission from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc) (also called ventral striatum) and other regions of the limbic forebrain (e.g., prefrontal cortex). Several drugs of abuse also converge by activatingendogneous opioid and cannabinoid mechanisms. These several actions appear to produce some similar net effects (generally inhibition) of nerve cells in the NAc, in part because opioid, cannabinoid, and certain dopamine receptors, all of which are Gi-coupled, are expressed by some of the same NAc neurons. There is compelling evidence that these various mechanisms play a central role in mediating the acute rewarding properties shared by all drugs of abuse. The mesolimbic dopamine system and its forebrain targets are very old from an evolutionary point of view and are part of the brain’s motivational system that regulates responses to natural rewards such as food, drink, sex, and social interaction. It is thought that drugs of abuse affect this pathway with a power and persistence probably not seen in response to natural rewards and, consequently, induce chronic adaptations that underlie addiction.

Although the field has focused primarily on the VTA-NAc pathway as a key mediator of acute drug reward and addiction, several other brain regions are also important, and recent work has begun to examine these regions for chronic adaptations to repeated drug exposure ( Figure 1, Figure 2, and Figure 3). The amygdala is particularly important for conditioned aspects of drug exposure, for example, establishing associations between environmental cues and both the rewarding actions of acute drug exposure and the aversive symptoms of drug withdrawal. The hippocampus, a traditional memory circuit, is no doubt critical for memories of the context of drug exposure and withdrawal. The hypothalamus is important for mediating vast effects of drugs on the body’s physiologic state. Probably the most important, but least understood, are frontal regions of cerebral cortex, such as medial prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex, which provide executive control over drug use, which is severely impaired in many addicts. Of course, these various brain regions, and many more, do not function separately. Rather, they are parts of a complex and highly integrated circuit that is profoundly altered by drug exposure.

Examples of Chronic Adaptaions to Drugs of Abuse that Mediate Addiction

 

Upregulation of the cyclic AMP (cAMP Pathway)

One of the best established adaptations to chronic drug exposure is upregulation of the cAMP pathway after chronic opiate administration, illustrated in Figure 13. Acutely, opiates inhibit the functional activity of the cAMP pathway by inhibiting adenylyl cyclase, the enzyme that catalyzes the synthesis of cAMP. With continued opiate exposure, inhibition of the cAMP pathway gradually recovers, which can be viewed as a sign of tolerance. This recovery can also be viewed as a sign of dependence, because upon removal of the opiate (e.g., by administration of an opioid receptor antagonist such as naloxone) activity of the cAMP pathway increases far above control levels (which can be viewed as a sign of withdrawal).

The molecular mechanisms by which this upregulation occurs are now partly understood (Figure 13). With chronic opiate administration there is a gradual induction of adenylyl cyclase and of cAMP-dependent protein kinase (PKA), which mediates most of the effects of cAMP on neuronal function. Some of these effects occur at the level of gene expression (see below). Induction of these enzymes opposes acute opiate inhibition of adenylyl cyclase and explains the recovery in the functional activity of the cAMP pathway with repeated opiate administration (tolerance and dependence). Upon removal of the opiate, the upregulated cAMP pathway is no longer inhibited and becomes fully activated functionally (withdrawal).

Opiate-induced upregulation of the cAMP pathway occurs in many regions of the brain, where it is implicated in several features of addiction, depending on the role of that brain region. Much of the original description of cAMP pathway upregulation was based on work in the locus coeruleus, the major noradrenergic nucleus in brain normally involved in attention, vigilance and regulation of the autonomic nervous system. Opiate upregulation of the cAMP pathway in the locus coeruleus is an important mechanism of opiate physical dependence and withdrawal. In contrast, a similar upregulation of the cAMP pathway occurs in the nucleus acccumbens in response to opiates as well as several other drugs of abuse (e.g., cocaine and alcohol) cause a similar upregulation of the cAMP pathway. Thus, this molecular adaptation can be viewed as a common adaptation to drug exposure and perhaps a common mechanism of addiction. Upregulation of the the cAMP pathway in the NAc mediates tolerance and dependence to the rewarding effects of these drugs of abuse: it decreases an animals sensitivity to drug reward and creates a negative emotional state during early periods of drug withdrawal. One of the consequences of cAMP pathway upregulation is the sustained activation of the transcription factor CREB (cAMP response element-binding protein), which is an important mediator of drug-induced changes in the brain.

CREB

As mentioned, chronic exposure to opiates, cocaine, or alcohol upregulates the cAMP pathway in the NAc and, as expected, this is associated with sustained activation of CREB in this region. Activation of CREB is partly responsible for upregulation of the cAMP pathway itself (e.g., induction of adenylyl cyclases) and, like the cAMP pathway upregulation, mediates homeostatic responses to drug exposure. In the locus coeruleus, CREB is an important mechanism of opiate physical dependence and withdrawal, while in the NAc, CREB mediates tolerance and dependence to drug reward. These functions have been established by use of Viral Mediated Gene Transfer and Inducible, Cell-Targeted Mutations in Mice, where CREB itself or antagonists of CREB (called dominant negatives) are overexpressed in these brain regions and the functional consequences are defined in Behavioral Models of Drug Abuse and Addiction.

One target gene through which CREB produces its effects in the NAc is dynorphin, an opioid peptide expressed in a subset of nerve cells in the NAc, which is induced in this region after chronic drug exposure (Figure 6). Dynorphin release from the NAc is implicated in mediating dysphoria during withdrawal through a negative feedback loop to VTA dopamine neurons. Dynorphin binds to κ opioid receptors on VTA dopamine neuron cell bodies and terminals to inhibit their activity and decrease DA release in the NAc. This has raised the notion that Κ opioid antagonists may be useful in the treatment of drug withdrawal syndromes.

Δ FosB

Acute exposure to drugs of abuse rapidly (1-4 hr) induces all Fos family members in the NAc and related striatal regions. Even with continued drug exposure, levels of these proteins decline rapidly toward basal levels within 8-12 hr. Biochemically modified isoforms of ∆FosB (a truncated splice variant of the FosB gene) exhibit a different expression pattern (Figure 14). Acutely, ∆FosB expression is only modestly induced, but it persists long after the other Fos family members have returned to basal levels. This persistence is mediated by the high level of stability of the ∆FosB isoforms. As a result, ∆FosB levels gradually accumulate after repeated drug exposure and can persist for weeks after withdrawal, dynamics that allow it to play a longer-term role in drug regulation of gene expression. Such induction of ∆FosB occurs in response to chronic administration of virtually any drug of abuse, including cocaine, amphetamine, methamphetamine, opiates, nicotine, ethanol, cannabinoids, and phencyclidine.

As with CREB, the functional consequences of ∆FosB induction in NAc has been investigated by use of of Viral Mediated Gene Transfer and Inducible, Cell-Targeted Mutations in Mice, where ∆FosB or a dominant negative antagonist is overexpressed in this brain region and the functional consequences are defined in Behavioral Models of Drug Abuse and Addiction. Substantial evidence now supports the view that ∆FosB induction is a mechanism of sensitization, in that it increases an animal’s sensitivity to the rewarding and other effects of drugs of abuse. It also increases motivation and incentive drive for drug exposure. In this way, ∆FosB would appear to function as a sustained molecular switch for addiction: a unique protein change that occurs during chronic drug exposure that first initiates and then maintains changes in drug reward long after cessation of drug administration due to the stability of the protein. A major goal of current research is to identify ∆FosB target genes. Examples are given below.

Consolidation of Drug-Induced Adaptations

Although induction of ∆FosB is the most long-lived molecular adaptation known to occur in response to a drug of abuse, it does degrade at a finite rate and therefore cannot underlie the near-permanent changes in behavior that are seen in many addicted individuals. This dilemma is analogous to challenges faced in the learning and memory field: although there are many elegant molecular and cellular models of memory, no long-lived molecular adaptations have yet been identified that could account for highly stable behavioral memory. By analogy with the learning and memory field, an evolving view in the addiction field is that some form of consolidation is needed, in the context of chronic drug exposure, to cause particularly long-lived adaptations in the brain.

One possibility is that such consolidation is mediated by structural changes in neurons. Indeed, drugs of abuse produce morphologic changes in particular neuronal cell types after long-term administration. Repeated opiate exposure decreases the size and caliber of dendrites and soma of midbrain VTA dopamine neurons that innervate the NAc. These changes appear to diminish drug reward and could be a mechanism of drug tolerance as well as the dysphoria that occurs during drug withdrawal. In contrast, repeated stimulant exposure increases the number of dendritic spines and dendritic branch points both of medium spiny neurons in the NAc and of pyramidal neurons in the medial prefrontal cortex (both of which receive dopaminergic inputs) (Figure 15). It has been proposed that such structural changes could represent the neural substrates for the near-permanent sensitization in drug responsiveness seen in some models of addiction, although this remains highly speculative. Early evidence suggests that ∆FosB may be one mechanism for these dendritic changes, which are mediated via several target genes for ∆FosB, such as cyclin-dependent kinase 5 (Cdk5).

Another possibility is that drugs of abuse, via regulation of specific transcription factors (e.g., CREB, ∆FosB, many others) produce alterations in the structure of chromatin, and that such changes in chromatin structure are even more long-lived that alterations in the transcription factors themselves. Examples of alterations in chromatin structure include acetylation or methylation of histone proteins or methylation of DNA itself. See Regulation of Gene Expression in Brain for a description of the methodologies that are now being used to study drug-induced changes in chromatin structure. While this work is in early stages of development, recent findings have been encouraging and have demonstrated that drugs of abuse such as cocaine induce profound alterations in chromatin remodeling mechanisms. For example, as shown in Figure 16 , cocaine, via the induction of ∆FosB, causes changes at specific target genes (e.g., Cdk5), which might drive stable changes in gene expression. Current research is now focused on evaluating the role played by these novel mechanisms in long-lasting features of addiction.

Future Considerations

This narrative provides some examples of changes that drugs of abuse induce in the brain, at the molecular and cellular level, which contribute to the highly stable behavioral abnormalities that define an addicted state. As knowledge of the neurobiologic basis of addiction becomes more complete, it can be exploited to develop more effective treatments and ultimately preventive measures for addictive disorders.

Answers to another key question in the study of addiction will be critical for the understanding of addiction and for the development of new strategies for clinical management: Why do some individuals transition from casual drug use to compulsive use (addiction) so readily, yet others are highly resistant? Epidemiologic studies show that addiction is highly heritable, with 40-60% of the risk for addiction to opiates, cocaine, nicotine, and alcohol being genetic. However, the individual genetic variations that comprise this risk have not been identified. Discovery of the genes involved will make it possible to better grasp the non-genetic factors that are also important. Such discoveries may allow individuals at risk for addiction to be targeted for prevention, and treatments for addiction to be targeted to certain individuals based on the underlying pathophysiology of their disorder.