The consumption of chemical substances that produce transient feelings of euphoria
or pleasure and the development of dependence on those substances by a subset of individuals
is as old as the human race itself. Currently, the cost of addiction to illicit drugs
in the United States is more than 600 billion dollars a year (National Institute on
Drug Abuse, 2015), with profound social and economic impacts. Despite the prevalence
and long history of addiction, it is still not clear what neurophysiological processes
are involved in the development and progression of addictive disorders. The challenge
of current and future studies is to understand how alcohol and drugs alter specific
brain systems to influence tolerance and/or lead to the addicted state with the overarching
goal of identifying vulnerable populations and improving on current treatment strategies.
Drug addiction is defined as a chronic relapsing disorder that is comprised of three
stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect.
These three stages are conceptualized as feeding into one other, becoming more intense
over time, and ultimately leading to the pathological state known as addiction. Different
drugs produce distinct patterns of addiction that engage different components of the
addiction cycle, depending on dose and length of use. As an individual moves from
being a “user” to “abuser” and then to “addicted” a shift occurs from positive reinforcement
driving the motivated behavior to negative reinforcement driving the motivated behavior.
Importantly, the progression of drug addiction involves alterations in normal brain
circuitry that result in long-lasting drug-induced neuroplastic changes (Koob and
Volkow, 2010). Critical neurotransmitters (i.e., gamma-aminobutyric acid, glutamate,
dopamine, opioid peptides, serotonin, acetylcholine, endocannabinoids, corticotropin
releasing factor) and neurocircuits (i.e., ventral tegmental area, nucleus accumbens,
amygdala, cerebellum, prefrontal cortex) underlie the pathological changes at each
of these stages (Figure 1). A better understanding of the main cellular mechanisms
and circuits affected by chronic drug use and the influence of environmental stressors,
developmental trajectories, and genetic factors on these mechanisms will lead to a
better understanding of the addictive process and to more effective therapeutic strategies
for the prevention and treatment of substance-use disorders. In the special topic
Frontiers journal “the neurobiology of addictive disorders,” we provide important
breakthroughs on the actions of commonly abused addictive substances (i.e., alcohol,
cocaine, nicotine, cannabinoids) on the function of neuronal circuits.
Figure 1
Diagram of the behavioral states and select brain areas discussed in this research
topic associated with the cycle of addiction.
Alcohol and drugs of abuse represent unique experimental challenges as they often
engage multiple molecular and intracellular systems in distinct brain regions. Current
work seeks to identify these molecular targets and how they are altered by acute and/or
chronic exposure. One important molecular target is phosphodiesterase 10A (Pde10a),
a regulator of cyclic nucleotide activity. Logrip and Zorrilla (2014) found that expression
of Pde10a, which is associated with relapse-like ethanol self-administration, was
differentially altered during different stages of alcohol withdrawal in the rat. During
acute withdrawal Pde10a expression was increased in the basolateral amygdala and medial
prefrontal cortex. During protracted withdrawal Pde10A expression remained elevated
in contrast to what has been observed in other brain regions.
Another emerging target is extracellular signal-regulated kinase (ERK). Zamora-Martinez
and Edwards (2014) reviewed emerging data in the important role of ERK activity in
the brain on the development and progression of drug and alcohol addiction. Varodayan
and Harrison (2013) investigated the molecular mechanisms underlying alcohol's effects
on neurotransmitter release at the presynaptic terminal. This study indicated that
alcohol induces heat shock factor 1 transcriptional activity to trigger a specific
coordinated adaptation in GABAergic presynaptic terminals in cultured cortical neurons.
This mechanism could explain some of the changes in synaptic function that occur soon
after alcohol exposure, and may underlie some of the more enduring effects of chronic
alcohol intake on local circuit function.
Addiction engages many brain regions at different stages of the development of the
disorder. Ongoing studies target distinct brain regions to pinpoint the specific intracellular
pathways employed by alcohol and drugs of abuse in the development of dependence.
Nimitvilai et al. (2013) found that ethanol-induced excitation of dopamine neurons
in the rat ventral tegmental area (VTA) was significantly reduced in the presence
of a phorbol ester in a mechanism involving the theta isoform of protein kinase C.
These results shed new light on how ethanol alters the activity of the reward pathway,
specifically the activity of dopamine neurons that mediate the salience of “pleasurable”
stimuli. Soares-Simi et al. (2013) investigated changes in cyclic adenosine monophosphate
response element-binding protein (CREB) DNA-binding activity in the prefrontal cortex
and hippocampus of adolescent and adult mice in the context of alcohol-induced behavioral
sensitization. Significant and differential neuroadaptive changes in CREB DNA-binding
activity were reported in adolescent mice compared with adult mice. These differences
may contribute to the blunted ethanol-induced behavioral sensitization observed in
adolescent mice.
In addition to engaging molecular signaling pathways, alcohol and drugs of abuse also
produce changes in ion channels to alter neuronal activity. For example, Kreifeldt
et al. (2014) assessed the role of specific large conductance calcium-activated potassium
(BK) channel subunits in voluntary ethanol consumption and found that the selective
deletion of the β1 or β4 auxiliary subunit did not influence consumption in nondependent
mice but did produce opposite effects on drinking during withdrawal from chronic intermittent
ethanol. The results of this study suggest that auxiliary subunits of BK channels
may represent a novel therapeutic target for the treatment of alcoholism. In another
study, Botta et al. (2014) examined the effect of ethanol on the brief suppression
of firing of cerebellar Golgi cells induced by stimulation of granule cell axons in
the rat cerebellum. Acute ethanol diminished the pause in Golgi cell firing, an effect
that was mimicked by partial inhibition of the Na+/K+ pump (ATPase). This reduction
in feedback inhibition represents one way in which ethanol can dysregulate cerebellar
function that may contribute to alcohol intoxication. Alcohol has also been shown
to engage the immune pathway. Gruol et al. (2014) used a transgenic mouse model overexpressing
the immune cytokine CCL2 to determine if elevated levels of CCL2 interact with the
effects of ethanol in the hippocampus and found that elevated levels of CCL2 protected
against the effects of acute ethanol on synaptic plasticity (i.e., LTP).
Alcohol and drugs of abuse interact with many peptide and neurotransmitter systems
in distinct regions of the brain. Bajo et al. (2014), investigated the effects of
morphine on GABAergic transmission in rat central amygdala (CeA) neurons and found
that acute and chronic morphine exposure and withdrawal alters opioid and GABA signaling
in the central amygdala. These findings suggest that during the acute phase of withdrawal,
the CeA opioid and GABAergic systems undergo neuroadaptative changes conditioned by
a previous chronic morphine exposure and dependence. McCool et al. (2014) found that
the activation of 5-HT2A/C receptors in the rat basolateral amygdala (BLA) inhibits
behaviors related to reward-seeking by suppressing principal neuron activity, i.e.,
neurons that project out of the BLA. These data provide new insight into the role
of the BLA in modulating reward-related behaviors. Kallupi et al. (2014) investigated
a novel nonpeptidergic Nociception/Orphanin FQ (NOP) receptor agonist that interacted
with the GABAergic system in the rat central amygdala (CeA) in a similar manner to
the peptide nociceptin and prevented ethanol-induced augmentation of GABA signaling
in the CeA, suggesting that the NOP receptor may represent a useful therapeutic target
for the treatment of alcoholism. Pava and Woodward (2014) examined the effects of
repeated alcohol exposure on cannabinoid regulation of up-states in slice cultures
of the prefrontal cortex (PFC) and found that up-state duration was increased after
chronic ethanol and withdrawal. Chronic ethanol and withdrawal also blunted the effects
of cannabinoid 1 receptor agonism on up-state amplitude and inhibitory currents in
PFC neurons. These data suggest that chronic ethanol and withdrawal compromises the
control of PFC activity by the cannabinoid system. The cannabinoid system was also
the focus of Palomino et al. (2014), who examined the impact of acute and repeated
cocaine exposure on endocannabinoid (eCB) and glutamate signaling in the mouse cerebellum.
Their findings indicate that acute cocaine modulates the expression of the eCB and
glutamate systems. Repeated cocaine results in normalization of glutamate receptor
expression, although sustained changes in eCB are observed. These findings in the
cerebellum have particular relevance in the context of behavioral sensitization, a
critical component in the addiction process. Furthermore, Blanco-Calvo et al. (2014)
evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations
in cell proliferation in the adult rat and found that while acute cocaine exposure
decreased hippocampal cell proliferation, blockade of the cannabinoid receptors restored
proliferative actions and prevented the conditioned locomotion induced by cocaine
exposure.
As the neurophysiology of alcohol and drugs of abuse in the brain are explored in
more detail, an important area of study has emerged concerning sex differences in
how drugs and ethanol interact with various brain systems to produce behavioral effects.
Melis et al. (2013) examined sex differences in dopamine neuronal properties and activity
of the cannabinoid system in the ventral tegmental area (VTA) in the rat and found
that females displayed larger depolarization-induced suppression of inhibition (DSI)
than male rats via tonic 2-arachidonoylglycerol signaling. These findings highlight
sex-specific differences in VTA endocannabinoid activity that may regulate responses
to aversive intrinsic properties to cannabinoids and contribute to differences in
cannabinoid consumption. McCall et al. (2013) utilized a mouse model of selective
deletion of the neuropeptide Y 2 (Y2) receptor in GABA neurons to examine sex differences
in the role of Y2 receptor on anxiety and drinking. Females displayed greater basal
anxiety, higher levels of ethanol consumption, and faster fear conditioning than males,
and Y2 knockout mice exhibited enhanced depressive-like behavior in the forced swim
test. This study extends work on sex differences in ethanol consumption and highlights
the importance of Y2R function in GABAergic systems in the expression of depressive-like
behavior.
The process of addiction is characterized by patterns of addictive behavior, many
of which can be modeled in experimental paradigms using rodents. For example, McClure
et al. (2014) presented a new method of isolating individual components of impulsive
choice, specifically delay discounting and reward quantity in adolescent rats, and
find that differences in timing and delay discounting are not causally related, but
instead are more likely influenced by a common factor. As impulsive behavior is closely
associated with addiction, this important new method allows for an improved understanding
of a complex aspect of addictive behavior. Sommer et al. (2014) used a mouse model
of rotarod training to demonstrate phase-and region-specific alterations in dopamine
receptor binding and transcription levels (decreased D1 binding in the dorsomedial
striatum after early training and a reduction in D2-like binding in the dorsolateral
striatum after prolonged training) in the dorsal striatum. These findings have profound
implications for the role of striatal dopamine in the “automated” behaviors associated
with dependence. In another study, Butler et al. (2014) looked at the relationship
between early life stress and ethanol self-administration. Adolescent rats exposed
to social isolation exhibited a dysregulated hypothalamic-pituitary-adrenal axis seen
in the significant correlation between baseline corticosterone levels and increased
anxiety as well as increased ethanol intake. These results illustrate the profound
effects of early life stress on anxiety and an increased vulnerability for developing
addictive disorders.
The breadth and depth of the studies in this topic illustrate the complex actions
of alcohol and drugs of abuse on various neurobiological systems. Together this work
represents the most current understanding of how acute and/or chronic exposure to
abused substances engages and/or pathologically alters distinct brain circuits. Although
much progress has been made in understanding addiction as a disease with biological
underpinnings, much work is still required to understand the mosaic of actions that
drugs of abuse promote in various brain systems and to facilitate the development
of therapeutics that can better serve a significant clinical population that struggles
with addiction.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.