Origins Of Drug Liking

Many factors, both individual and environmental, influence whether a particular person who experiments with drugs will continue taking them long enough to become dependent or addicted. For individuals who do continue, the drug's ability to provide intense feelings of pleasure is a critical reason.

When abused drugs travel through the bloodstream to the brain, they attach to specialized proteins on the surface of neurons that may be receptors, transporters, or even structural elements of the neurons. For example, opiates such as heroin bind to mu opioid receptors, which are on the surfaces of opiatesensitive neurons, and have their effects by inhibiting the cyclic adenosine monophosphate (cyclic AMP) second messenger system. Inhibition occurs through a guanine nucleotide-binding (G)-protein-mediated coupling leading to a series of changes in phosphorylation for a wide range of intraneuronal proteins (Nestler, 2002). The linkage of heroin with the receptors imitates the linkage of endogenous opioids such as beta-endorphin with these same receptors and triggers the same biochemical brain processes that reward people with feelings of pleasure when they engage in activities that promote basic life functions, such as eating and sex. Opioids such as oxycodone or methadone are prescribed therapeutically to relieve pain, but when these exogenous opioids activate the reward processes in the absence of significant pain, they can motivate repeated use of the drug simply for pleasure.

One of the brain circuits activated by opioids and most, if not all, abused drugs is the mesolimbic (midbrain) reward system. This system generates signals in a part of the brain called the ventral tegmental area (VTA) that result in the release of the chemical dopamine (DA) in another part of the brain, the nucleus accumbens (N-Ac) (Figure 1.1). This release of DA into the N-Ac causes feelings of pleasure. Other areas of the brain create a lasting record or memory that associates these good feelings with the circumstances and environment in which they occur. These memories, called "conditioned associations," often lead to the craving for drugs when the abuser reencounters those persons, places, or things, and they drive abusers to seek out more drugs in spite of many obstacles.

Other abused drugs activate this same brain pathway, but via different mechanisms and by stimulating or inhibiting different neurons in this pathway.

FIGURE 1.1. Mesolimbic dopamine ("reward") pathways. PFC, prefrontal cortex; N-Ac, nucleus accumbens; VTA, ventral tegmental area.

FIGURE 1.1. Mesolimbic dopamine ("reward") pathways. PFC, prefrontal cortex; N-Ac, nucleus accumbens; VTA, ventral tegmental area.

For example, opioids and cannabinoids can inhibit activity in N-Ac directly, whereas stimulants such as cocaine and amphetamine act indirectly by binding to various DA transporters and either inhibiting the reuptake of DA into the VTA neurons (cocaine) or actively pumping DA out of the VTA (amphetamine) at its synapse with the N-Ac neurons (Kosten, 2002; Stahl, 1998). Since stimulation of the DA D2 receptor inhibits the cyclic AMP system, this increase in DA in the synapse leads to relative inhibition of the N-Ac neuron. The mechanism is more complex than this, however, since the D1 receptor has the opposite effect on the cyclic AMP system (e.g., it increases the amount of cyclic AMP) and both D1 and D2 receptors are present on the N-Ac neurons. The presumption is that the D2 receptor effects predominate perhaps simply due to more D2 receptors, or due to a higher affinity of the D2 than the Dt receptors for DA. Other substances may be even more indirect in their stimulation. For example, nicotine and benzodiazepines stimulate ion channels for calcium/ sodium and chloride, respectively (Stahl, 2002). The calcium/sodium channel is a nicotinic receptor that normally binds acetylcholine, while the chloride channel is associated with a gamma-aminobutyric acid (GABA) receptor. The stimulation of these ion channels can lead to depolarization of the VTA neuron and release of DA into the synapse between the VTA and N-Ac. The entry of calcium into the VTA neuron can also directly facilitate the merging of the synaptic vesicles in the VTA with the cell membrane, leading to release of DA from these vesicles (Kosten, 2002). For some substances, we do not yet have a clear idea of their biochemical mechanisms of reinforcement. For example, alcohol may act through the mu opioid receptor like heroin, or the GABA receptor like benzodiazepines. Inhalants have direct toxic effects on the structural proteins of neuronal membranes and may act directly to increase neurotransmission through the VTA to the N-Ac by damaging these structural proteins in neuronal membranes and allowing calcium entry into the VTA, thereby releasing DA vesicles into the synapse connecting the VTA with the N-Ac.

Particularly in the early stages of abuse, the drug's stimulation of the brain's reward system is a primary reason that some people take drugs repeatedly. However, the compulsion to use drugs builds over time to extend beyond a simple drive for pleasure. This increased compulsion is related to tolerance and dependence.

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