The neurobiology of methamphetamine induced psychosis

Abstract

Chronic methamphetamine abuse commonly leads to psychosis, with positive and cognitive symptoms that are similar to those of schizophrenia. Methamphetamine induced psychosis (MAP) can persist and diagnoses of MAP often change to a diagnosis of schizophrenia over time. Studies in schizophrenia have found much evidence of cortical GABAergic dysfunction. Methamphetamine psychosis is a well studied model for schizophrenia, however there is little research on the effects of methamphetamine on cortical GABAergic function in the model, and the neurobiology of MAP is unknown. This paper reviews the effects of methamphetamine on dopaminergic pathways, with focus on its ability to increase glutamate release in the cortex. Excess cortical glutamate would likely damage GABAergic interneurons, and evidence of this disturbance as a result of methamphetamine treatment will be discussed. We propose that cortical GABAergic interneurons are particularly vulnerable to glutamate overflow as a result of subcellular location of NMDA receptors on interneurons in the cortex. Damage to cortical GABAergic function would lead to dysregulation of cortical signals, resulting in psychosis, and further support MAP as a model for schizophrenia.

Keywords: GABA; cortex; neural circuitry; neurotoxicity; schizophrenia; sensitization.

Figure 1

Nigrostriatal, mesocortical, and mesolimbic pathways. When cortical neurons activate the NMDA receptors on neurons of the direct pathway (red) in the striatum, striatal neurons are primed to send GABA signals to the SNr/GPi, which would inhibit the tonic GABA to the thalamus, allow glutamate signals to fire in the cortex, and further activate cortical neurons. The indirect pathway (blue) is primed when cortical neurons activate the NMDA receptors on the striatal neurons that express D₂ receptors, which would send inhibitory signals to the globus pallidus externa (GPe), reduce GABA signaling to the STN, and stimulate the SNr/GPi to enhance GABA inhibiting of thalamocortical signaling. The mesolimbic pathway (green) consist of dopaminergic projections from the VTA to the NAcc, which sends inhibitory signals to the SNr/GPi. The mesocortical pathway (orange) consists of dopaminergic projections from the VTA to the cortex, innervating both pyramidal and non-pyramidal neurons which express D₁ receptors. Reciprocal pathways (purple) from the cortex to the VTA and NAcc provide cortical feedback to subcortical structures. CTX, cortex; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; GPe, globus pallidus externa; SNr, substantia nigra pars reticulata; GPi, globus pallidus interna; TH, thalamus; STN, sub thalamic nucleus; NAcc, nucleus accumbens core; VTA, ventral tegmental area. Round structures indicate dopamine cell bodies; star shaped structures indicate GABA cell bodies; triangular structures indicate glutamate cell bodies.

Figure 2

Healthy effects of dopamine on dopaminergic pathways. The substantia nigra pars compacta (SNc) releases dopamine into the striatum (large black arrows), and enhances thalamocortical glutamate release along the nigrostriatal pathway (blue and red). The direct pathway (red) becomes enhanced by D₁ activation, and the indirect pathway (blue) becomes inhibited by D₂ activation. Mesolimbic dopamine (green) to the NAc core increases GABA inhibition from the NAc core to the SNr/GPi, further increasing thalamocortical glutamate transmission. Mesocortical dopamine (orange) increases cortical pyramidal firing and simultaneously stimulates cortical interneurons, which sharpen the pyramidal signals to subcortical nuclei (blue, red, and purple). CTX, cortex; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; GPe, globus pallidus externa; SNr, substantia nigra pars reticulata; GPi, globus pallidus interna; TH, thalamus; STN, sub thalamic nucleus; NAcc, nucleus accumbens core; VTA, ventral tegmental area. Round structures indicate dopamine cell bodies; star shaped structures indicate GABA cell bodies; triangular structures indicate glutamate cell bodies.

Figure 3

Methamphetamine effects on dopaminergic pathways. Methamphetamine causes excessive amounts of dopamine to be released from the substantia nigra pars compacta (SNc) into the striatum (large black arrows), forcing pronounced inhibition of the SNr/GPi (red and blue). Dopamine from the VTA to the NAc increases NAc inhibition on the SNr/GPi (green). Enhanced cortical signals increases glutamate from the PFC to the NAc (purple) further increasing NAc inhibition on the SNr/GPi, and exacerbates glutamate excess in the cortex. CTX, cortex; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; GPe, globus pallidus externa; SNr, substantia nigra pars reticulata; GPi, globus pallidus interna; TH, thalamus; STN, sub thalamic nucleus; NAcc, nucleus accumbens core; VTA, ventral tegmental area. Round structures indicate dopamine cell bodies; star shaped structures indicate GABA cell bodies; triangular structures indicate glutamate cell bodies.

Figure 4

NMDA receptor localization in the cortex. (A) Glutamatergic pyramidal neurons express NMDAreceptors preferentially in the post synaptic density (PSD) region, around the soma, and apical dendrites. Glutamate stimulation causes more focused calcium ion influx, and the cell has lower vulnerability to neurotoxicity (B) GABAergic interneurons express NMDA receptors more diffusely over the neuron, often at extrasynaptic locations. Glutamate stimulation causes widespread calcium ion influx, and the cell has greater vulnerability to neurotoxicity.

Figure 5

Summary flow diagram.