The brain manages everything from basic survival functions to complex thought and personality. Psychoactive substances, such as drugs and alcohol, exert their effects by directly interfering with this highly organized communication network. These substances enter the bloodstream, travel rapidly to the central nervous system, and there mimic, block, or otherwise alter the chemical signals that neurons use to transmit information. This interference immediately disrupts the brain’s delicate internal balance, leading to the temporary behavioral changes associated with intoxication.
Hijacking the Brain’s Reward System
The initial appeal of drugs and alcohol stems from their ability to artificially stimulate the brain’s reward circuit, known as the mesolimbic pathway, which is primarily defined by the movement of dopamine. This circuit runs from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Its natural function is to reinforce life-sustaining behaviors like eating and social bonding. When a person consumes a rewarding substance, the VTA’s neurons are powerfully activated, causing a massive, unnatural surge of dopamine release into the NAc.
This flood of dopamine is significantly larger and more immediate than the bursts produced by natural rewards, effectively telling the brain that the substance is extremely valuable and must be sought again. Stimulants like cocaine and amphetamines directly block the reuptake of dopamine or force its release, leaving the neurotransmitter stranded in the synapse. Alcohol and opiates achieve a similar outcome by indirectly suppressing the activity of inhibitory neurons that normally put a “brake” on the VTA’s dopamine-releasing cells.
Alcohol enhances the inhibitory neurotransmitter, Gamma-aminobutyric acid (GABA), which slows down overall brain activity and contributes to initial feelings of relaxation and sedation. Conversely, alcohol also suppresses the excitatory neurotransmitter, glutamate, dampening the central nervous system’s responsiveness. This dual action of boosting inhibition and suppressing excitation creates the profound chemical imbalance that underlies the substance’s intoxicating effects. This chemical disruption powerfully reinforces the substance-seeking behavior.
Impairment of Key Cognitive and Motor Functions
Beyond the reward circuit, acute intoxication immediately compromises three major functional areas of the brain, leading to observable impairments in thought and movement. The prefrontal cortex (PFC), located at the front of the brain, is responsible for executive functions and is highly sensitive to these substances. When PFC activity is reduced, the ability to assess risk, control impulses, and make rational decisions is severely diminished.
The cerebellum is located at the back of the head and is the central coordinator for voluntary movement, balance, and posture. Alcohol severely disrupts communication within the cerebellum, specifically impairing Purkinje neurons critical for fine-tuning motor actions. This interference results in the signature signs of intoxication, such as the staggering gait known as ataxia and slurred speech.
Memory formation is also impaired, primarily within the hippocampus, a brain structure vital for transferring new information from short-term to long-term storage. Alcohol interferes with N-methyl-D-aspartate (NMDA) receptors, preventing the strengthening of synaptic connections known as long-term potentiation (LTP). This disruption explains the phenomenon of “blackouts,” where the brain is temporarily incapable of creating new, lasting memories even while the person remains conscious.
Neurobiological Mechanisms of Tolerance and Dependence
With repeated substance use, the brain initiates a powerful counter-response aimed at restoring its chemical equilibrium, a process called neuroadaptation. This defensive measure is the basis for both tolerance—the need for increasingly higher doses to achieve the original effect—and physical dependence. Tolerance occurs because the brain actively works to diminish the drug’s impact.
For substances that enhance a neurotransmitter’s effect, such as alcohol boosting GABA, the brain responds by reducing the number of GABA-A receptors available on the cell surface, a process called down-regulation. This reduction means that more of the substance is required to achieve a normal level of inhibition, as the existing receptors have become less sensitive. Similarly, chronic exposure to substances that block the reuptake of dopamine leads to a reduction in the number of dopamine receptors, dulling the brain’s sensitivity to pleasure.
The brain also attempts to compensate for the drug’s direct effects on excitatory pathways, particularly those involving glutamate and the NMDA receptor. Since alcohol suppresses NMDA receptor activity, chronic use causes the brain to increase the number of these receptors, or up-regulate them. This adjustment pushes the system back toward a normal excitatory state. This homeostatic adjustment creates a state of dependence, where the brain requires the substance just to function normally.
When the substance is suddenly removed, the counter-adapted system is exposed, leading to a severe neurochemical imbalance that manifests as withdrawal. The up-regulated NMDA receptors, no longer suppressed, become hyperactive, leading to excitotoxicity, anxiety, and in severe cases, seizures. The brain’s stress response system is also recruited, driving the negative emotional state and intense cravings that characterize dependence.
Structural Reorganization and Cellular Damage
Prolonged exposure to drugs and alcohol can lead to physical and structural changes that persist long after acute intoxication. Neuroimaging studies often reveal a measurable reduction in gray matter volume. This shrinkage is particularly notable in the prefrontal cortex and the hippocampus, areas associated with decision-making and memory storage.
This structural alteration is often linked to neurotoxicity, a form of cellular stress where the substance or its byproducts damage neurons. Stimulants like methamphetamine can cause significant reductions in dopamine-producing neurons through oxidative stress. Other damage occurs indirectly, such as neuron death caused by oxygen deprivation (hypoxia) following an opioid-induced respiratory overdose.
Chronic use alters neural plasticity, the brain’s fundamental ability to reorganize pathways and form new connections. Substances can reduce the formation of new neurons in the hippocampus, a process called neurogenesis, which impairs the brain’s ability to adapt and recover. These long-term physical changes, including atrophy and altered connectivity, contribute to enduring cognitive deficits and a persistent vulnerability to relapse.