The Dopamine Hypothesis of Drug Addiction and Its Potential Therapeutic Value

Abstract

Dopamine (DA) transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in the various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid, and other drug-dependent rats. Further, DA release in the Nucleus accumbens (Nacc) is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS) thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the medium spiny neuron of the Nacc, post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin, and alcohol-dependent subjects, thereby offering visual proof of the “dopamine-impoverished” addicted human brain. The lasting reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse, and drug-seeking/taking). In theory, it may be achieved pharmacologically and/or with novel interventions such as transcranial magnetic stimulation (TMS). Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts.

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats

“…In particular, it has been hypothesized that withdrawal after chronic administration of numerous drugs of abuse produces a hypodopaminergic state (2,12). Consistently, the observed reduction in TH immunoreactivity in the Nacc shell during ethanol withdrawal can be related to (and parallels) deficiencies in DA release (60) and decrements in neuronal activity observed in similar contexts (29,61).…”

“…Furthermore, DA modulates GLU inputs to Nacc neurons (6,7), both by directly influencing synaptic transmission and by modulating voltage-dependent conductances (8). Accordingly, interactions between DA and GLU are involved in druginduced locomotor stimulation and addiction (9,10) and may represent useful potential therapeutic targets (11,12). In the distal portion of the dendrites of MSNs a significant subpopulation of spines shows a particular synaptic architecture, called the "striatal microcircuit" or "synaptic triad" (13,14), which is characterized by a double, discrete, and reciprocal interaction between DA and GLU afferents: The former establishes synaptic contact on the spine neck, whereas the latter reaches the head (13).…”

Is Sugar a Gateway Drug?

“…In rats, artificially increasing the number of D2Rs reduces alcohol and cocaine intake [39][40][41]. These findings suggest the number of D2Rs correlates inversely with selfadministration of DOA's [26].…”

“…Reduced DA levels in addicts, along with increased sensitivity to the DA enhancing effects of DOA, have been proposed as mechanisms leading to drug-seeking behavior and subsequent addiction [26]. Dopaminergic hypofunction has been proposed as a common etiologic factor contributing to a number of impulsive, compulsive, and addictive disorders [47].…”

“…The behavioral consequence of this state is an increased use of substances that trigger DA release in an effort to regain homeostasis in the MLP [23]. Ingestion of DOA releases DA in the NAc [3, 21,[24][25][26][27][28]. Thus, the ingestion of food and drinks containing high concentrations of sugar would be expected to contribute to the repeated use of DOA in an attempt to restabilize MLP DA levels at a homeostatic level.…”