Methamphetamine-induced locomotor sensitization in mice is not associated with deficits in a range of cognitive, affective and social behaviours: interaction with brain-derived neurotrophic factor Val66Met genotype

Abstract

Chronic methamphetamine (Meth) abuse may induce psychosis similar to that observed in schizophrenia. Brain-derived neurotrophic factor (BDNF) has been implicated in the development of psychosis. We have previously shown long-term protein expression changes in mice treated chronically with Meth depending on BDNF Val66Met genotype. The aim of this study was to investigate if these protein expression changes were associated with differential changes in a range of behavioural paradigms for cognition, anxiety, social and other behaviours. Male and female Val/Val, Val/Met and Met/Met mice were treated with an escalating Meth dose protocol from 6 to 9 weeks of age, with controls receiving saline injections. Several overlapping cohorts were tested in the Y-maze for short-term spatial memory, novel-object recognition test, context and cued fear conditioning, sociability and social preference, elevated plus maze for anxiety-like behaviour and prepulse inhibition (PPI) of acoustic startle. Finally, the animals were assessed for spontaneous exploratory locomotor activity and acute Meth-induced locomotor hyperactivity. Acute Meth caused significantly greater locomotor hyperactivity in mice previously treated with the drug than in saline-pretreated controls. Meth-pretreated female mice showed a mild increase in spontaneous locomotor activity. There were no Meth-induced deficits in any of the other behavioural tests. Val/Met mice showed higher overall social investigation time and lower PPI compared with the Val/Val genotype independent of pretreatment. These results show limited long-term effects of chronic Meth on a range of cognitive, affective and social behaviours despite marked drug-induced locomotor sensitization in mice. There was no interaction with BDNF Val66Met genotype.

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

“…Similar to gamma oscillations, changes in beta oscillations have been found in psychosis and schizophrenia [ 23 , 56 , 57 ] with increases in beta power correlating with positive symptoms [ 56 , 57 ]. While in the lack of changes in gamma power in the present study may be unsurprising given the absence of cognitive deficits in our METH model [ 55 ], the correlation of beta power and psychotic symptoms in patients with schizophrenia would predict similar effects of chronic METH. Nonetheless, in our mice, ongoing beta power was not altered following chronic METH pretreatment.…”

“…Cognitive deficits have been described as well in individuals who use METH [ 1 , 51 , 52 ] and in animal models of METH abuse [ 53 , 54 ]. However, we recently performed a detailed analysis of a range of cognitive, affective and social behaviours in mice treated with the same METH protocol as in the present study [ 55 ]. Of particular relevance to the present results, METH-pretreated mice did not show changes in the Y-maze for short-term spatial memory, novel-object recognition test (NORT), context and cued fear conditioning, and prepulse inhibition (PPI) of acoustic startle.…”

“…Gender differences have been described in the prevalence, symptom profile, and treatment response in schizophrenia [ 62 ]. Moreover, we recently found sex differences in the metabolism of METH [ 63 ], and female mice show greater locomotor hyperactivity to a given acute dose of METH than male mice [ 55 ]. Therefore, further studies on the long-term effects of chronic METH on neural oscillations should include female mice.…”

Interaction of Brain-derived Neurotrophic Factor, Exercise, and Fear Extinction: Implications for Post-traumatic Stress Disorder

“…2A - C ). Interestingly, these mice were the vehicle-treated controls in a study in which the effects of a chronic methamphetamine treatment paradigm were investigated, including daily intraperitoneal injections [ 91 ]. It is possible that even in the vehicle-treated control mice in this study, the added chronic stress of repeated injections diminished underlying genotype differences, similar to the more controlled stress simulation by corticosterone treatment in other studies [ 90 ].…”

“…Of note, these animals were part of a study which used a chronic treatment protocol including daily intraperitoneal injections, which may have constituted additional stress and influenced underlying genotype differences. For methodological details and further results, see [ 91 ] from which this figure was adapted.…”