Methamphetamine (MA) is worldwide known drug with high potential for addiction that causes dopamine, noradrenaline and serotonin release. MA is also able to increase acetylcholine levels in adult rodents. The aim of this study was to map changes in D1-like dopamine receptors (DR), M1 and M2 muscarinic receptors (MR), and the total number of MR (M1-M5 MR) in the CNS of rats exposed to MA prenatally and in adulthood. Rat mothers were exposed to MA (5mg/kg s.c.) or saline during the entire gestation period and their male offspring were administered in adulthood with single MA (1mg/kg) or saline injection. Thus, the animals were divided into 4 groups: prenatally MA-exposed rats treated with saline (MA/S) or MA (MA/MA) in adulthood and prenatally saline-exposed rats treated with saline (S/S) or MA (S/MA) in adulthood. One hour after the acute treatment animals were sacrificed and their brains were removed. The numbers of M1, M2, total MR, and D1-DR were measured by autoradiography. The main effect was detected in the hippocampus with the most affected M1 MR. D1-DR were decreased in motor cortex and substantia nigra. M1MR were decreased in caudate-putamen, dorsal hippocampus, CA1, CA3 and dentate gyrus (DG). M2MR were decreased in DG only. Total number of MR was moreover decreased in dorsal hippocampus, CA1, CA3 and DG. Our results have shown different patterns of changes in DR and MR, suggesting a pilot role of M1 MR in the CNS changes induced by prenatal and adult MA exposure.

Since it enters breast milk, methamphetamine (MA) abuse during lactation can not only affect the quality of maternal behavior but also postnatal development of pups. The aim of the present study was to examine the effect of injected MA (5mg/kg) on maternal behavior of rats and the differences in postnatal development, during postnatal days (PD) 1-11, of pups when the pups were directly exposed (i.e., injected) to MA or received MA indirectly via breast milk. Maternal behavior was examined using observation test (PD 1-22) and pup retrieval test (PD 1-12). The following developmental tests were also used: surface righting reflex (PD 1-12), negative geotaxis (PD 9), mid-air righting reflex (PD 17), and the rotarod and beam-balance test (PD 23). The weight of the pups was recorded during the entire testing period and the day of eye opening was also recorded. MA-treated mothers groomed their pups less and returned the pups to the nest slower than control dams. The weight gain of pups indirectly exposed to MA was significantly slower. In addition, pups indirectly exposed to MA were slower on the surface righting reflex (on PD 1 and PD 2) and the negative geotaxis test. In females, indirect exposure to MA led to earlier eye opening compared to controls. At the end of lactation, males who received MA indirectly via breast milk performed worse on the balance beam test compared to males who received MA directly. However, direct exposure to MA improved performance on rotarod relative to controls. Our results suggest that indirect MA exposure, via breast milk, has a greater impact than direct MA exposure.

Už několik let dominuje metamfetamin (MA) drogovému trhu jak v České republice, tak na Slovensku, avšak alarmující je i jeho spotřeba celosvětově. Stále rostoucí počet studií poukazuje na fakt, že vystavení MA in utero nezpůsobuje jenom vývojové vady a poruchy ve vývoji centrálního nervového systému, ale může vést k takovým změnám ve vyvíjejícím se systému odměny mozku, které zvýší pravděpodobnost k rozvoji drogové závislosti později v životě. Dostupné studie na animálních modelech poukazují na fakt, že potomci matek, kteří byli vystaveni prenatálně účinkům MA, jsou citlivější k aplikaci MA v dospělosti. Pro zvýšenou citlivost na účinky drogy byl zaveden termín senzitizace, a je definována jako zvýšená psychomotorická aktivita po jednorázové aplikaci drogy, když dříve došlo k návyku na tuto drogu. Senzitizace byla pozorována nejen po opakovaném podávání drogy v dospělosti, ale také po chronické prenatální expozici účinkům drogy. Výsledky našich studií ukazují, že prenatální expozice MA zvyšuje citlivost k účinku aplikace drog v dospělosti, konkrétně k těm s podobným mechanizmem účinku.

The global use of methamphetamine (MA) is increasing, including in pregnant women. Women seem to be more vulnerable to some aspects of MA abuse than men. MA is thought to exert its effects among others via direct interactions with dopamine transporters (DATs) in the brain tissue. Sexual dimorphism of the DAT system could be a base of sex-dependent actions of MA observed in behavioural and neurochemical studies. We examined the striatal synaptosomal DATs (the activity and density of surface expressed DATs and total DAT expression) in preadolescent male and female Wistar rats exposed prenatally and/or postnatally to MA (daily 5 mg/kg, s.c. to mothers during pregnancy and lactation). To distinguish between specific and nonspecific effects of MA on DATs, we evaluated the in vitro effects of lipophilic MA on the fluidity of striatal membranes isolated from preadolescent and young adult rats of both sexes. We observed similar changes in the DATs of preadolescent rats exposed prenatally or postnatally (MA-mediated drop in the reserve pool but no alterations in surface-expressed DATs). However, prenatal exposure evoked significant changes in males and postnatal exposure in females. A significant decrease in the aktivity of surface-expressed DATs was found only in postnatally exposed females sensitized to MA via prenatal exposure. MA applied in vitro increased the fluidity of striatal membranes of preadolescent female but not male rats. In summary, DATs of preadolescent males are more sensitive to prenatal MA exposure via changes in the reserve pool and those of preadolescent females to postnatal MA exposure via the same mechanism. The combination of prenatal and postnatal MA exposure increases the risk of dopaminergic deficits via alterations in the activity of surface-expressed DATs especially in preadolescent females. MA-mediated changes in DATs of preadolescent females could be still enhanced via nonspecific disordering actions of MA on striatal membranes.

The aim of the present study was an evaluation of prenatal exposure to acute methamphetamine (MA)
treatment on manifestations of anxiety. Anxiety was evaluated in adult animals in three different experimental
models: the Elevated plus-maze (EPM), Social interaction test (SIT) and Ultrasound vocalization
(USV). Female rats were administered saline (S) or MA (5 mg/kg) daily throughout their entire gestation
period. The male progeny, in adulthood, were administered with challenge dose of S or MA (1 mg/kg)
prior to evaluation of anxiety. The study demonstrated that prenatal MA exposure increased the anxiogenic
effect on evaluated behaviour patterns in the USV model and to a lesser degree in the EPM model.
In addition, the acute MA challenge in adulthood decreased the time spent during social interaction suggesting
an anxiogenic effect in the SIT model as well. On the other hand, some of the evaluated parameters
(e.g. the number of head-dipping in the EPM and number of dropped boluses in the SIT) also suggest MAinduced
anxiolytic effects. Sensitization to aMA challenge was apparent in several parameters of the EPM
(e.g. increased number of entries to the closed arms, increased stretched attend postures and increased
approach-avoid conflicts) and SIT (total social interaction and following). The present data demonstrate
that prenatalMAexposure and adult challenge of the same drug have diverse effects on animal behaviour
that depends on the type of anxiety model used.