Differential Effects of Chronic Methamphetamine Treatment on High-Frequency Oscillations and Responses to Acute Methamphetamine and NMDA Receptor Blockade in Conscious Mice

Abstract

Dysregulation of high-frequency neuronal oscillations has been implicated in the pathophysiology of schizophrenia. Chronic methamphetamine (METH) use can induce psychosis similar to paranoid schizophrenia. The current study in mice aimed to determine the effect of chronic METH treatment on ongoing and evoked neuronal oscillations. C57BL/6 mice were treated with METH or vehicle control for three weeks and implanted with extradural recording electrodes. Two weeks after the last METH injection, mice underwent three EEG recording sessions to measure ongoing and auditory-evoked gamma and beta oscillatory power in response to an acute challenge with METH (2 mg/kg), the NMDA receptor antagonist MK-801 (0.3 mg/kg), or saline control. A separate group of mice pretreated with METH showed significantly greater locomotor hyperactivity to an acute METH challenge, confirming long-term sensitisation. Chronic METH did not affect ongoing or evoked gamma or beta power. Acute MK-801 challenge reduced ongoing beta power whereas acute METH challenge significantly increased ongoing gamma power. Both MK-801 and METH challenge suppressed evoked gamma power. Chronic METH treatment did not modulate these acute drug effects. There were minor effects of chronic METH and acute METH and MK-801 on selected components of event-related potential (ERP) waves. In conclusion, chronic METH treatment did not exert neuroplastic effects on the regulation of cortical gamma oscillations in a manner consistent with schizophrenia, despite causing behavioural sensitisation.

Keywords: gamma power; methamphetamine; mice; neural oscillations; sensitisation.

Figure 1

(A): Experimental timeline. Starting at 6 weeks of age, mice were treated with an escalating dosage regimen of METH or saline control each weekday for 3 weeks. The behavioural cohort (top) was subsequently tested at 12 weeks of age for the effect of an acute METH challenge on locomotor activity. The EEG cohort (bottom) underwent stereotactic surgery at 10 weeks of age to implant recording electrodes. (B): Location on the mouse skull where the electrodes are implanted (A = active; R = reference; G = ground), and a schematic of the experimental setup and daily procedure for recording. Over two weeks, three EEG sessions were conducted, during which the effect of METH or MK-801 was compared to saline control. (C): Example of a representative 2 s EEG recording at baseline. Top trace is unfiltered signal, middle trace is beta band (20–30 Hz) filtered and bottom trace is gamma band (30–80 Hz) filtered. Vertical scale depicts voltage (µV).

Figure 2

Representative ERP showing different wave components for analysis.

Figure 3

Acute METH-induced locomotor hyperactivity was significantly increased in METH-sensitised mice compared to vehicle-treated controls. * p < 0.05 for difference with pre-injection distance moved; ** p < 0.05 for difference with controls. METH5 = 5 mg/kg METH. n = 13 control mice; n = 13 sensitised mice.

Figure 4

Effects of METH sensitisation and acute drug challenge on ongoing cortical oscillations. The animals were chronically treated with either saline vehicle (Control) or METH (Sensitised) and acutely treated with a saline, MK-801 and METH challenge. (A) Ongoing beta power was significantly reduced by acute MK-801 and METH treatment. (B) Ongoing gamma power was significantly increased by acute METH. There were no effects of METH pretreatment. * p < 0.05 for difference with acute saline injection. n = 8 control mice; n = 10 sensitised mice.

Figure 5

Effects of METH sensitisation and acute drug challenge on auditory-evoked cortical oscillations. Mice were chronically treated with either saline vehicle (Control) or METH (Sensitised) and acutely treated with a saline, MK-801 and METH challenge. (A) There were no effects of acute MK-801 or METH treatment on changes in beta power. (B) Both acute MK-801 and METH reduced evoked gamma power. There were no significant effects of METH pretreatment. * p < 0.05 for difference with acute saline injection. n = 8 control mice; n = 10 sensitised mice.

Figure 6

Amplitude (A) and latency (B) of ERP wave form components (see Figure 2) shown from top to bottom. The mice were chronically treated with either saline vehicle (Control) or METH (Sensitised) and acutely treated with a saline, MK-801 and METH challenge. * p < 0.05 for difference with acute saline treatment; ** p < 0.05 for difference with acute METH treatment; # p < 0.05 for difference with both acute saline and acute MK-801 treatment. *** p < 0.05 for differences between control and sensitised animals. n = 8 control mice; n = 10 sensitised mice.