Convergent Neuronal Plasticity and Metaplasticity Mechanisms of Stress, Nicotine, and Alcohol

Abstract

Stress and tobacco smoking are risk factors for alcoholism, but the underlying neural mechanisms are not well understood. Although stress, nicotine, and alcohol have broad, individual effects in the brain, some of their actions converge onto the same mechanisms and circuits. Stress and nicotine augment alcohol-related behaviors, in part via modulation of alcohol-evoked neuronal plasticity and metaplasticity mechanisms. Stress modulates alcohol-evoked plasticity via the release of signaling molecules that influence synaptic transmission. Nicotine also activates some of the same signaling molecules, cells, and circuits, producing a convergence of both stress and nicotine onto common plasticity mechanisms that influence alcohol self-administration. We describe several forms of alcohol-induced plasticity, including classic Hebbian plasticity at glutamatergic synapses, and we highlight less appreciated forms, such as non-Hebbian and GABAergic synaptic plasticity. Risk factors such as stress and nicotine initiate lasting neural changes that modify subsequent alcohol-induced synaptic plasticity and increase the vulnerability to alcohol addiction.

Keywords: GABA; HPA axis; KCC2; alcohol use disorder; mesolimbic; nucleus accumbens.

Figure 1

Hebbian and non-Hebbian long-term potentiation (LTP) in the ventral tegmental area (VTA). (a) Presynaptic glutamate (Glu) release activates postsynaptic AMPA and N-methyl-D-aspartate (NMDA) receptors. AMPA receptor–mediated postsynaptic depolarization (plus sign) relieves the Mg²⁺ block of NMDA receptors, enabling them to become the main source of the increase in Ca²⁺ that triggers Hebbian LTP. (b) GluA1 AMPA receptor subunits provide another source of Glu postsynaptic Ca²⁺, which triggers plasticity independently of NMDA receptors. However, when Glu release is paired with significant postsynaptic depolarization, the decreased Ca²⁺ entry via GluA1 receptors then decreases the likelihood of LTP. (c) In contrast, pairing Glu release with postsynaptic hyperpolarization (minus sign) permits Ca²⁺ entry through GluA1 AMPA receptors, thereby increasing the likelihood of GluA1 non-Hebbian LTP (47). (d) In addition to Glu projections, VTA dopamine neurons receive inhibitory inputs from GABAergic neurons. Glu and GABA synapses (encircled on the left) on the dopamine neuron are expanded on the right. Postsynaptic GABA receptor activation prevents membrane depolarization, promoting non-Hebbian LTP.

Figure 2

Functional expression of the K⁺-Cl⁻ cotransporter (KCC2) regulates neural circuitry in the ventral tegmental area (VTA). (a) KCC2 mediates Cl⁻ extrusion from neurons, maintaining the concentration gradient that favors Cl⁻ entry through the GABA_A receptor. (b) Decreased KCC2 function leads to intracellular Cl⁻ accumulation, resulting in an impaired Cl⁻ gradient and decreased synaptic GABA_A receptor inhibition. (c) KCC2 mediates normal GABAergic inhibition of VTA GABA neurons projecting onto dopamine (DA) neurons (left minus sign). Exposure to stress downregulates KCC2 and shifts GABA_A receptor signaling toward excitation of VTA GABA neurons (plus sign). Excitation of VTA GABA neurons promotes inhibition of DA neurons (right minus sign) (11).

Figure 3

A schematic representation of the connectivity between the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Connections between the midbrain and the striatum form a spiral that emanates from medial parts of the VTA and NAc, moving toward lateral parts of the substantia nigra (SN) and the striatum. Dopamine (DA) neurons from the VTA project to GABAergic medium spiny projection neurons (MSNs) in the NAc. D1 MSNs from the NAc project back to VTA GABA and DA neurons. During early phases of addiction, exposure to drugs of abuse, including alcohol, potentiates synaptic connectivity in the most medial parts of the spiral. Repeated drug administration progressively activates more lateral parts of the spiral in the SN, eventually recruiting the dorsal striatum, a brain region implicated in habitual drug seeking. We hypothesize that stress promotes habitual drinking, in part via modulation of alcohol-evoked synaptic plasticity within the spiral (147).